341 results on '"Schwinger R"'
Search Results
152. Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently.
- Author
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Schwinger RH, Pietsch M, Frank K, and Brixius K
- Subjects
- Adenylyl Cyclases metabolism, Calcium metabolism, Dose-Response Relationship, Drug, Humans, Middle Aged, Ouabain metabolism, Plant Extracts pharmacology, Sodium-Potassium-Exchanging ATPase metabolism, Tritium, Biflavonoids, Cardiotonic Agents pharmacology, Catechin pharmacology, Cyclic AMP metabolism, Flavonoids pharmacology, Myocardial Contraction drug effects, Myocardium metabolism, Proanthocyanidins, Rosales chemistry
- Abstract
The mode of action of Crataegus extracts in the treatment of heart failure is still under examination. WS 1442, a standardized special extract from Crataegus leaves with flowers, exerts direct positive inotropic effects. This study was designed to investigate the mode of inotropic action of WS 1442 in human myocardium from patients with congestive heart failure (left ventricular myocardium from explanted hearts; NYHA IV, n = 8) as well as in nonfailing controls (right auricular trabeculae from patients with coronary heart disease, n = 8). WS 1442 effectively displaced specifically bound 3H-ouabain but did not influence the activity of adenylate cyclase [control, + Gpp(NH)p (10(-4) microM) 3,500 pmol cyclic adenosine monophosphate (cAMP)/20 min). In isolated left ventricular papillary muscle strips, WS 1442 significantly increased the force of contraction [basal, 1.8+/-0.2 mN; WS 1442 (50 microg/ml), 2.4+/-0.1 mN (130%)] and improved the frequency-dependent force generation (0.5 vs. 2.5 Hz: control, +0.1+/-0.01 mN; WS 1442, +0.9+/-0.3 mN) even in failing human myocardium. In fura-2-loaded muscle strips (right atrial trabeculae), WS 1442 increased both the Ca2+-transient and force generation. These effects also were observed in the lipophilic ethyl acetate-soluble fraction A, enriched in flavone derivatives. In conclusion, these findings suggest a pharmacologic mechanism of WS 1442 similar to the cAMP-independent positive inotropic action of cardiac glycosides. In addition, WS 1442 improves the force-frequency relation in failing human myocardium.
- Published
- 2000
- Full Text
- View/download PDF
153. [Role of nitrates in the treatment of ischemia].
- Author
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Schwinger RH
- Subjects
- Angina Pectoris drug therapy, Emergencies, Humans, Hypotension, Orthostatic chemically induced, Isosorbide Dinitrate administration & dosage, Nitrates administration & dosage, Nitrates adverse effects, Nitroglycerin administration & dosage, Time Factors, Vasodilator Agents administration & dosage, Coronary Disease drug therapy, Isosorbide Dinitrate therapeutic use, Nitrates therapeutic use, Nitroglycerin therapeutic use, Vasodilator Agents therapeutic use
- Published
- 2000
154. Myofilament calcium regulation in human myocardium.
- Author
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Hajjar RJ, Schwinger RH, Schmidt U, Kim CS, Lebeche D, Doye AA, and Gwathmey JK
- Subjects
- Cadaver, Cardiac Output, Low metabolism, Cardiac Output, Low physiopathology, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclic GMP metabolism, Heart Ventricles, Humans, Hydrogen-Ion Concentration, Myocardial Contraction, Osmolar Concentration, Phosphates metabolism, Actin Cytoskeleton metabolism, Calcium metabolism, Myocardium metabolism
- Abstract
Background: We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure., Methods and Results: Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F(max)) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus 0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0. 56 micromol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts., Conclusions: We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.
- Published
- 2000
- Full Text
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155. The enhanced contractility in phospholamban deficient mouse hearts is not associated with alterations in (Ca2+)-sensitivity or myosin ATPase-activity of the contractile proteins.
- Author
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Schwinger RH, Brixius K, Savvidou-Zaroti P, Bölck B, Zobel C, Frank K, Kranias EG, Hoischen S, and Erdmann E
- Subjects
- Animals, Female, Male, Mice, Mice, Mutant Strains, Calcium metabolism, Calcium-Binding Proteins deficiency, Calcium-Transporting ATPases deficiency, Muscle Proteins physiology, Myocardial Contraction physiology, Myosins metabolism
- Abstract
Work performing heart preparations from hypercontractile, phospholamban deficient mouse hearts showed no change in parameters of contraction or relaxation in response to isoproterenol stimulation. Thus, the aim of the present study was to investigate whether or not changes at the level of the contractile apparatus occur in addition to the altered expression of Ca2+-regulating proteins observed in these mouse models, e.g., phospholamban, ryanodine receptors. Triton-X skinned fiber preparations from phospholamban deficient (n = 9) and wild-type (n = 10) mice were used and the Ca2+-activated force as well as the myosin ATPase-activity were simultaneously measured. The tension dependent ATPase-activity was unchanged in phospholamban deficient animals when compared to controls. The SERCA 2a-inhibitor cyclopiazonic acid did not affect myosin ATPase-activity in this system. The Ca2+-sensitivity of Ca2+-activated force and myosin ATPase were unchanged as well. Comparison of the concentrations needed to achieve half maximal activation of the myosin ATPase-activity and force demonstrated that the Ca2+-sensitivity of the myosin ATPase was higher compared to the Ca2+-sensitivity of tension development. This holds true for phospholamban deficient mice (EC50 ATPase: 0.9 +/- 0.2 micromol/l; tension: 1.7 +/- 0.3 micromol/l; p < 0.001) and wild-type controls (1.1 +/- 0.01 micromol/l; 2.2 +/- 0.4 micromol/l; p < 0.01). The myosin ATPase-activity and force were correlated to each other in both, phospholamban deficient mice and controls and did not change at submaximal Ca2+ concentrations. The ATPase/ force-ratio, as a parameter of tension cost, was similar in either phospholamban deficient mice or controls. Thus, the present study provides evidence that at the level of the contractile proteins regulation of Ca2+-activated force and energy demand of force development are not altered in phospholamban deficient mice with enhanced myocardial performance. At the level of the regulation of crossbridge interaction, no adaptive or compensatory mechanisms have been initiated by ablation of phospholamban.
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- 2000
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156. [Peripartal cardiomyopathy--its pathophysiology, diagnosis and current therapy].
- Author
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Zobel C, Deutsch HJ, Schwinger RH, and Erdmann E
- Subjects
- Cardiomyopathy, Dilated diagnosis, Cardiomyopathy, Dilated etiology, Cardiomyopathy, Dilated therapy, Cardiovascular Agents therapeutic use, Female, Heart Transplantation, Humans, Pregnancy, Pregnancy Complications, Cardiovascular diagnosis, Pregnancy Complications, Cardiovascular etiology, Pregnancy Complications, Cardiovascular therapy, Prognosis, Puerperal Disorders diagnosis, Puerperal Disorders etiology, Puerperal Disorders therapy, Risk Factors, Cardiomyopathy, Dilated physiopathology, Pregnancy Complications, Cardiovascular physiopathology, Puerperal Disorders physiopathology
- Published
- 2000
- Full Text
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157. Isoform expression of the sarcoplasmic reticulum Ca2+ release channel (ryanodine channel) in human myocardium.
- Author
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Münch G, Bölck B, Sugaru A, and Schwinger RH
- Subjects
- Adult, Antibody Specificity, Blotting, Western, Female, Heart Atria metabolism, Heart Septum metabolism, Heart Ventricles metabolism, Humans, Male, Middle Aged, Protein Isoforms genetics, Protein Isoforms metabolism, RNA, Messenger metabolism, Ryanodine Receptor Calcium Release Channel genetics, Ryanodine Receptor Calcium Release Channel immunology, Myocardium metabolism, Ryanodine Receptor Calcium Release Channel metabolism, Sarcoplasmic Reticulum metabolism
- Abstract
The Ca2+ release channel of the sarcoplasmic reticulum (SR) is essential for the release of Ca2+ from intracellular stores and is expressed widely in various excitable cells. It plays a key role particularly in excitation contraction coupling in myocytes in skeletal and cardiac muscle. Three isoforms of the SR Ca2+ release channel have been cloned. Recently coexpression of different isoforms was reported in different animal species and various tissues. In human cardiac tissue, however, isoform expression is not yet established. Therefore the aim of this study was to characterize isoform expression of the SR Ca2+ release channel in the human heart. We examined specific isoform expression of mRNA and proteins of the SR Ca2+ release channel in the four different chambers of the heart and the interventricular septum from explanted human hearts from nonfailing organ donors (n=8). Reverse transcriptase PCR from total cardiac RNA with isoform specific primers and western blots from myocardial homogenates with isoform specific antibodies were performed. Quantification of protein expression was achieved by densitometric scanning and computer analysis and is expressed as densitometric units per microgram of protein. A single band DNA signal was detected by reverse transcriptase PCR for the skeletal isoform 1 and the cardiac isoform 2 and isoform 3 in all regions of the human heart investigated. Specific protein expression was detected in all five myocardial regions of the human heart in western blots for the skeletal isoform I and cardiac isoform 2, and a weaker specific band was also detectable for isoform 3 of the SR Ca2+ release channel. Quantification of protein expression showed significant (P=0.008) lower expression of isoform 1 in the right ventricle (42+/-4 densitometric units/g tissue) and similar expression in all other regions (right atrium 58+/-3; septum 51+/-5, left atrium 54+/-5; left ventricle 51+/-6). Isoform 2 of the SR Ca2+ release channel was also significantly lower (P=0.001) in the right ventricle (33+/-4 densitometric/g tissue) and similar in the other heart chambers (right atrium 42+/-5: septum 41+/-3, left atrium 52+/-6, left ventricle 42+/-3). Differences in isoform 3 of the SR Ca2+ release channel for the various myocardial regions did not reach significant levels (right atrium 45+/-6, right ventricle 38+/-5, septum 49+/-8, left atrium 46+/-7, and in left ventricle 45+/-3 densitometric units/g tissue). In conclusion, all three isoforms of the SR Ca2+ release channel were determined in the human heart at both mRNA and protein levels with different quantitative expression in the different heart chambers. Coexpression of the three different isoforms with different functional properties might increase the complexity of regulation of excitation contraction coupling in the human heart in a chamber specific mode.
- Published
- 2000
- Full Text
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158. [Unclear pulmonary infiltrates with eosinophilia, a problem of differential diagnosis]
- Author
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Münch G, Wassermann K, Schwinger RH, and Erdmann E
- Abstract
Unclear pulmonary infiltrates with eosinophilia, a problem of differential diagnosis. HISTORY AND ADMISSION FINDINGS: A 60-year-old woman was admitted for the diagnosis of pulmonary infiltrates. A year before she had been exposed to tuberculosis when working as a doctor in Manila, the Philippines. Ten days before admission she had spent 10 days in Sao Paulo, Brazil. On admission she complained of fatigue, dry cough and nocturnal sweating. Her body temperature was 37.8; C. At auscultation of the chest fine rales were heard with diminished percussion sounds over both lungs. INVESTIGATIONS: The chest radiogram showed bilateral apical infiltrates. Blood count indicated normal white and red cells, but platelets were raised to 606 x 10 9/l. The differential blood count revealed an eosinophilia of 30%, ESR was raised at 91 mm/h and C-reactive protein increased to 103 mg/l. Angiotensin-converting enzyme, IgG, IgA, IgM, IgE, C3 and C4, paraproteins, antinuclear antibodies and double-strand DNA antibodies were all within normal limits. There was no direct or indirect evidence of tuberculosis and no parasites were found in sputum, stool, urine and blood. DIAGNOSIS, TREATMENT AND COURSE: After bronchoscopy with bronchial biopsy had failed to establish a diagnosis, an open lung biopsy with partial lung resection was performed. This revealed histologically an eosinophilic pneumonia with intra-alveolar protein precipitation and multinucleated giant cells, as well as interstitial fibroblast proliferation without demonstrable mincroorganisms. Under cortisone administration there was striking improvement of symptoms within a few days, and C-reactive proteins fell to 3 mg/l, ESR to 25 mm/h and the eosino-philia to 2%. CONCLUSION: Eosinophilic pneumonia should be included in the differential diagnosis of unclear pulmonary infiltrations with eosinophilia, once parasitological and malignant diseases, tuberculosis and allergic pulmonary aspergillosis have been excluded.
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- 2000
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159. [Value of diuretics and aldosterone antagonists in the treatment of heart failure].
- Author
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Schwinger RH
- Subjects
- Benzothiadiazines, Diuretics administration & dosage, Diuretics adverse effects, Drug Interactions, Drug Resistance, Heart Failure mortality, Humans, Hyponatremia chemically induced, Mineralocorticoid Receptor Antagonists administration & dosage, Mineralocorticoid Receptor Antagonists adverse effects, Nephrons drug effects, Randomized Controlled Trials as Topic, Sodium Chloride Symporter Inhibitors administration & dosage, Sodium Chloride Symporter Inhibitors adverse effects, Sodium Chloride Symporter Inhibitors therapeutic use, Spironolactone administration & dosage, Spironolactone therapeutic use, Time Factors, Diuretics therapeutic use, Heart Failure drug therapy, Mineralocorticoid Receptor Antagonists therapeutic use
- Published
- 1999
160. [The aldosterone antagonist spironolactone prolongs the survival of chronic heart failure patients. The results of the RALES study. The Randomized Aldactone Evaluation Study].
- Author
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Schwinger RH
- Subjects
- Chronic Disease, Heart Failure mortality, Humans, Randomized Controlled Trials as Topic, Heart Failure drug therapy, Mineralocorticoid Receptor Antagonists therapeutic use, Spironolactone therapeutic use
- Published
- 1999
161. The force-frequency relationship is dependent on Ca(2+)-influx via L-type- and SR-Ca(2+)-channels in human heart.
- Author
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Reuter H, Zobel C, Brixius K, Bölck B, and Schwinger RH
- Subjects
- 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester pharmacology, Adult, Aged, Calcium Channel Agonists pharmacology, Calcium Channel Blockers pharmacology, Heart Ventricles pathology, Humans, Ion Transport physiology, Middle Aged, Myocardial Contraction drug effects, Nifedipine pharmacology, Calcium physiology, Calcium Channels physiology, Myocardial Contraction physiology, Sarcoplasmic Reticulum physiology, Ventricular Function
- Abstract
Unlabelled: The present study investigated the influence of Bay K 8644 and nifedipine (Nif) on the force-frequency relationship and on tetanic tension and force of contraction of failing human myocardium (PAP, n = 12). In addition, ryanodine (Rya) was studied on the force-frequency relationship. Bay K 8644 (0.1 microM) increased, but Nif (0.01 microM) reduced isometric force of contraction significantly. However, both, Bay K 8644 (2 Hz vs. 0.5 Hz:, Control: -31.6 +/- 7.8%; +Bay K 8644: +103 +/- 30% (% basal); p < 0.005) as well as Nif (2 Hz vs. 0.5 Hz:, Control: -8.8 +/- 9.7%; +Nif: +90.9 +/- 31.5% (% basal); p < 0.05), were able to restore a positive FFR in PAP. By measurement of tetanic tension and posttetanic potentiation in the presence of the 1,4-dihydropyridines, we support the hypothesis of the existence and functional relevance of a dihydropyridin-ryanodine receptor junctional complex. In skinned fiber preparations, Bay K 8644 showed no effect on Ca(2+)-sensitivity or caffeine induced Ca(2+)-release. Rya (10 microM) decreased force of contraction in PAP and was effective in restoring a positive FFR (2 Hz vs. 0.5 Hz:, Control: -7.3 +/- 5.1%; +Rya: +98.0 +/- 31.9% (% basal); p < 0.05). Thus, the altered FFR and Ca(2+)-homeostasis in failing human myocardium may result from changes in sarcolemmal Ca(2+)-influx and/or from altered SR-Ca(2+)-load.
- Published
- 1999
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162. The intracellular Ca(2+)-homeostasis influences the frequency-dependent force-generation in man.
- Author
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Brixius K, Pietsch M, and Schwinger RH
- Subjects
- Aged, Atrial Function, Electric Stimulation, Electrophysiology, Female, Fluorescent Dyes, Fura-2, Humans, Male, Middle Aged, Calcium physiology, Heart physiology, Myocardial Contraction physiology
- Abstract
The present study investigates the effect of stimulation frequency and external Ca(2+)-concentration on intracellular systolic and diastolic Ca2+ as well as on the force-frequency relationship (FFR, 0.5 to 3.0 Hz, 1.0 mmol/l extracellular Ca2+) in human myocardium using fura-2 AM loaded electrically stimulated right atrial muscle strips (coronary bypass surgery, n = 15, age: 60.0 +/- 1.9 years). The FFR was positive (3.0 vs. 0.5 Hz: 184 +/- 43% of basal value) and linked to an increase in peak systolic (R340/380sys, 119 +/- 7%) as well as diastolic Ca2+ (R340/380ED, delta fura-2 ratio +0.20 +/- 0.02). After elevating the extracellular Ca2+ concentration from 1.0 to 2.4 mmol/l, force of contraction (FOC) increased from 0.5 up to 1.0 Hz (128 +/- 8%) and declined after further augmentation of stimulation frequency (3.0 Hz: 87 +/- 15%). However, this decrease in FOC was accompanied by an increase in diastolic Ca2+ (delta fura-2 ratio +0.45 +/- 0.08), while systolic Ca2+ declined at high stimulation frequencies. In conclusion, the frequency-dependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels. Thus, especially at high stimulation frequencies the Ca(2+)-lowering mechanisms may become crucial and may be responsible for the blunted force-frequency relationship in failing human myocardium.
- Published
- 1999
- Full Text
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163. Reduced sodium pump alpha1, alpha3, and beta1-isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure.
- Author
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Schwinger RH, Wang J, Frank K, Müller-Ehmsen J, Brixius K, McDonough AA, and Erdmann E
- Subjects
- Adolescent, Adult, Binding Sites, Calsequestrin metabolism, Cardiomyopathy, Dilated metabolism, Female, Heart Failure surgery, Heart Transplantation, Heart Ventricles, Humans, Isoenzymes metabolism, Male, Middle Aged, Ouabain metabolism, Papillary Muscles physiology, Papillary Muscles physiopathology, Reference Values, Heart Failure metabolism, Myocardium metabolism, Sodium-Calcium Exchanger metabolism, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
Background: Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na+, K+-ATPase), thereby decreasing Ca2+ extrusion by the Na+-Ca2+ exchanger, which increases the cellular content of Ca2+. In patients with heart failure the sensitivity toward cardiac glycosides is enhanced., Methods and Results: Because the inotropic effect of cardiac glycosides may be a function of the sodium pump and Na+-Ca2+ exchanger (NCE) expression levels, the present study aimed to investigate protein expression of both transporters (immunoblot with specific antibodies against the sodium pump catalytic alpha1-, alpha2-, alpha3-, and glycoprotein beta1-isoforms and against NCE) in left ventricle from failing (heart transplantations, New York Heart Association class IV, n=21) compared with nonfailing (donor hearts, NF, n=22) human myocardium. The density of 3H-ouabain-binding sites (Bmax) and the Na+,K+-ATPase activity were also measured. In NYHA class IV, protein levels of Na+,K+-ATPase alpha1- (0.62+/-0.06 of control), alpha3- (0.70+/-0.09), and beta1- (0.61+/-0.04) but not alpha2-isoforms were significantly reduced (P<0.01), whereas levels of NCE (0.92+/-0.13 of control) and calsequestrin (0.98+/-0.06) remained unchanged. Both Na+,K+-ATPase activity (NF: 1.9+/-0.29; NYHA class IV: 1.1+/-0.17 micromol ATP/min per milligram of protein) and the 3H-ouabain binding sites (Bmax NF: 15.9+/-1.9 pmol/mg protein; NYHA class IV: 9.7+/-1.5) were reduced in NYHA class IV and correlated significantly to each other (r2=0. 73; P<0.0001), as did beta1-subunit expression. In left ventricular papillary muscle strips from NYHA class IV compared with nonfailing tissue the Na+-channel modulator BDF 9198 exerted an increase in force of contraction with unchanged effectiveness but enhanced potency., Conclusions: The enhanced sensitivity of failing human myocardium toward cardiac glycosides may be, at least in part, attributed to a reduced protein expression and activity of the sarcolemmal Na+,K+-ATPase without a change in Na+-Ca2+ exchanger protein expression.
- Published
- 1999
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164. Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation.
- Author
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Schwinger RH, Münch G, Bölck B, Karczewski P, Krause EG, and Erdmann E
- Subjects
- Adult, Blotting, Western, Cyclic AMP-Dependent Protein Kinases metabolism, Densitometry, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Female, Humans, Kinetics, Male, Middle Aged, Phosphorus Radioisotopes metabolism, Phosphorylation, Calcium metabolism, Calcium-Binding Proteins metabolism, Calcium-Transporting ATPases metabolism, Heart Failure metabolism, Myocardium metabolism
- Abstract
It is still a matter of debate, whether decreased protein expression of SERCA 2a and phospholamban (PLB), or alterations in the phosphorylation state of PLB are responsible for the reduced SERCA 2a function in failing human myocardium. Thus, in membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (NYHA IV. heart transplants) and control hearts (NF), SERCA 2a activity was measured with an NADH coupled assay with as well as without stimulation with protein kinase A (PKA). The protein expression of SERCA 2a, PLB and calsequestrin as well as the phosphorylation status of PLB (Back-phosphorylation technique: Serine-16-PLB specific antibody) were analysed using Western blotting technique and specific antibodies. In NF, the maximal activity (Vmax) and the Ca(2+)-sensitivity of SERCA 2a activity were significantly higher compared to NYHA IV. Protein expression of SERCA 2a, PLB and calsequestrin were unchanged, whereas both, the phosphorylation status of PLB as well as serine-16-PLB-phosphorylation, were significantly reduced in NYHA IV. After stimulation with PKA only the Ca(2+)-sensitivity, but not Vmax increased concentration-dependently. Therefore, in human myocardium, the Ca(2+)-sensitivity but not the Vmax of SERCA 2a is regulated by cAMP-dependent phosphorylation of phospholamban at position serine-16. Threonine-17-PLB-phosphorylation or direct phosphorylation of SERCA 2a may be candidates for regulation of maximal SERCA 2a activity in human myocardium.
- Published
- 1999
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165. Regional expression and functional characterization of the L-type Ca2+-channel in myocardium from patients with end-stage heart failure and in non-failing human hearts.
- Author
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Schwinger RH, Hoischen S, Reuter H, and Hullin R
- Subjects
- Adolescent, Adult, Aged, Binding Sites physiology, Blotting, Northern, Blotting, Western, Calcium metabolism, Calcium Channel Blockers metabolism, Calcium Channels, L-Type, Calsequestrin pharmacology, Cardiomyopathy, Dilated, Dihydropyridines analysis, Dihydropyridines metabolism, Dose-Response Relationship, Drug, Female, Heart physiology, Heart Failure, Humans, Male, Middle Aged, Nifedipine pharmacology, Tissue Distribution, Calcium Channels physiology, Myocardium metabolism
- Abstract
The purpose of the present study was to investigate the expression and functional relevance of sarcolemmal L-type Ca2+-channels in failing and non-failing human myocardium. The protein expression of sarcolemmal L-type Ca2+-channels was determined with 3H-(+)-PN 200-110-binding experiments and Western blot analysis using a specific antibody against the alpha1-subunit in membrane preparations of ventricular and atrial myocardium from both failing (n = 15) and non-failing hearts (n = 8). The gene expression of the ion conducting pore of the L-type Ca2+-channel was examined with Northern blot technique in human failing and non-failing RNA. For normalization the RNA expression of calsequestrin was used. In electrically driven ventricular papillary muscle strips and auricular trabeculae, the responses to nifedipine and Ca2+ as parameters of myocardial function were studied. The protein expression as measured by 3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis with calsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both were reduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KD remained unchanged. Calsequestrin levels were unaltered in failing and non-failing hearts. The gene expression of the alpha1-subunit was similar in human failing and non-failing hearts. The L-type Ca2+-channel antagonist nifedipine reduced force of contraction with the same potency and efficiency in ventricular failing and non-failing myocardium. In contrast, the potency of nifedipine was higher in atrial than in ventricular tissue. Consistently, atrial myocardium from patients with dilated cardiomyopathy was more sensitive towards Ca2+ than those of the control group. In conclusion, the altered Ca2+-homeostasis in failing human myocardium may be less due to changes in sarcolemmal L-type Ca2+-channel expression or function than due to an altered intracellular Ca2+-handling.
- Published
- 1999
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166. Frequency dependent force generation correlates with sarcoplasmic calcium ATPase activity in human myocardium.
- Author
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Frank K, Bölck B, Bavendiek U, and Schwinger RH
- Subjects
- Adult, Blotting, Western, Calcium-Binding Proteins analysis, Calcium-Binding Proteins metabolism, Calcium-Transporting ATPases analysis, Calsequestrin analysis, Calsequestrin metabolism, Cells, Cultured, Enzyme Activation physiology, Female, Humans, Male, Middle Aged, Muscle Contraction physiology, Muscle Fibers, Skeletal chemistry, Muscle Fibers, Skeletal cytology, Muscle Fibers, Skeletal enzymology, Myocardium chemistry, Myocardium cytology, Ventricular Function, Left, Calcium-Transporting ATPases metabolism, Heart Failure metabolism, Myocardium enzymology, Sarcoplasmic Reticulum enzymology
- Abstract
Objective: In congestive heart failure both a decreased function of the sarcoplasmic Ca(2+)-ATPase and a negative force-frequency relationship have been shown. This study aimed to investigate a possible relationship between frequency potentiation, sarcoplasmic Ca(2+)-ATPase activity, and SERCA2 protein expression in human myocardium., Methods: Frequency potentiation was studied in electrically stimulated, isometric, left ventricular papillary muscle strip preparations (37 degrees C, 0.5-3.0 Hz) from terminally failing (NYHA i.v.; n = 5, dilated cardiomyopathy) and nonfailing (donor hearts, n = 5) human myocardium. In the identical samples the Ca(2+)-ATPase activity (NADH coupled assay) and the protein expression of sarcoplasmic Ca(2+)-ATPase (SERCA2), phospholamban, and calsequestrin (western blot) were determined. The frequency dependent change in the force of contraction and Vmax of the Ca(2+)-ATPase activity and the protein expression of SERCA2 were correlated with each other., Results: In terminally failing myocardium the force-frequency relationship was negative (2.0 Hz vs. 0.5 Hz: -0.2 +/- 0.1 delta mN) contrasting a positive rate dependent potentiation of force in nonfailing tissue (2.0 Hz vs. 0.5 Hz: +0.8 +/- 0.2 delta mN; p < 0.01). In failing myocardium the corresponding maximal sarcoplasmic Ca(2+)-ATPase activity (Vmax) was reduced significantly compared to nonfailing myocardium (174 +/- 24 vs. 296 +/- 31 nmol ATP/mg.min, p < 0.01). The protein expression of SERCA2, phospholamban, and calsequestrin remained unchanged in failing myocardium. The maximal Ca(2+)-ATPase activity significantly correlated with the frequency dependent change in force of contraction (2 Hz vs. 0.5 Hz: r = 0.88, p = 0.001; 3 Hz vs. 0.5 Hz: r = 0.84, p = 0.004). No correlation between protein expression of SERCA2 and Ca(2+)-ATPase activity or change in force of contraction was observed., Conclusion: Due to a significant correlation between sarcoplasmic Ca(2+)-ATPase activity and frequency potentiation, the negative rate dependent force potentiation in human heart failure could be at least in part be attributed to decreased function of the sarcoplasmic Ca(2+)-ATPase.
- Published
- 1998
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167. cAMP-dependent protein kinase A-stimulated sarcoplasmic reticulum function in heart failure.
- Author
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Schwinger RH, Bölck B, Münch G, Brixius K, Müller-Ehmsen J, and Erdmann E
- Subjects
- Calcium-Binding Proteins metabolism, Calcium-Transporting ATPases metabolism, Heart physiology, Humans, Myocardium metabolism, Phosphorylation, Cardiomyopathy, Dilated physiopathology, Cyclic AMP-Dependent Protein Kinases metabolism, Heart physiopathology, Heart Failure physiopathology, Sarcoplasmic Reticulum physiology
- Abstract
It is unclear whether decreased protein expression of SERCA2 (SR-Ca(2+)-ATPase) and phospholamban (PLB), or alterations in the phosphorylation state of PLB leading to increased inhibition of SERCA2 are responsible for the reduced SERCA2 function in failing human myocardium. In crude membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (DCM) and control hearts (NF), SERCA2 activity was measured with a NADH coupled assay. Protein expression of SERCA2 and PLB and the phosphorylation state at the two phosphorylation sites, serine-16-PLB and threonine-17-PLB, were investigated with specific (phosphorylation) antibodies and Western blot technique. In NF, the Vmax and the Ca2+ sensitivity of SERCA2 activity were significantly higher compared to DCM. Protein expression of SERCA2 and PLB were unchanged, whereas the phosphorylation status at both serine-16-PLB and threonine-17-PLB were significantly reduced in DCM. The native phosphorylation status of PLB measured by the back-phosphorylation technique was reduced in DCM as well. After stimulation with protein kinase A only the Ca2+ sensitivity, but not Vmax, increased. The reduced phosphorylation state of PLB may lead to decreased Ca2+ sensitivity of SERCA2 in failing human myocardium. The altered regulation of the SR-CA(2+)-ATPase in human heart failure may offer an opportunity for an improvement in the therapy of heart failure.
- Published
- 1998
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168. Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle.
- Author
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Schröder F, Handrock R, Beuckelmann DJ, Hirt S, Hullin R, Priebe L, Schwinger RH, Weil J, and Herzig S
- Subjects
- 8-Bromo Cyclic Adenosine Monophosphate pharmacology, Calcium Channels, L-Type, Cells, Cultured, Cyclic AMP physiology, Heart physiopathology, Heart Ventricles, Humans, Ion Channel Gating, Kinetics, Membrane Potentials, Probability, Reference Values, Time Factors, Calcium Channels physiology, Cardiomyopathies physiopathology, Cardiomyopathy, Dilated physiopathology, Heart physiology, Myocardial Ischemia physiopathology
- Abstract
Background: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings., Methods and Results: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure., Conclusions: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.
- Published
- 1998
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169. Potent vasodilatory with minor cardiodepressant actions of mibefradil in human cardiac tissue.
- Author
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Brixius K, Mohr V, Müller-Ehmsen J, Hoischen S, Münch G, and Schwinger RH
- Subjects
- Adult, Aged, Arteries drug effects, Arteries physiology, Calcium metabolism, Diltiazem pharmacology, Fluorescent Dyes, Fura-2, Humans, Mibefradil, Middle Aged, Myocardium metabolism, Nifedipine pharmacology, Benzimidazoles pharmacology, Calcium Channel Blockers pharmacology, Heart drug effects, Tetrahydronaphthalenes pharmacology, Vasodilator Agents pharmacology
- Abstract
1. The present study compared the cardiovascular effects of mibefradil (MIB), a novel Ca2+-channel antagonist with high selectivity for T-type Ca2+-channels to the effect of the L-type Ca2+-channel-antagonists nifedipine (NIF) and diltiazem (DIL) in left ventricular myocardium and coronary arteries of hearts obtained from patients suffering from dilated cardiomyopathy (NYHA IV). Right atrial myocardium from patients undergoing aortocoronary bypass surgery without signs of cardiac failure was studied as well. 2. NIF and DIL (100 micromol l(-1)) completely depressed force of contraction (FOC) in electrically driven left ventricular myocardium (NIF 6.5+/-1.4% and DIL 7.1+/-1.2% of control), whereas a similar concentration of MIB only reduced force of contraction to 55.1+/-4.0% of the basal FOC. The negative inotropic potency as measured by the concentration needed to reduce basal FOC for 25% was NIF (0.0095 micromol l(-1))>DIL (0.041 micromol l(-1))>MIB (9.47 micromol l(-1)). 3. All three Ca2+-channel antagonists were more potent in human atrial compared to human left ventricular myocardium to reduce FOC. 4. The rank order of Ca+-antagonistic moiety as measured by the decrease of the intracellular Ca2+-transient (fura-2 ratio method) was NIF>DIL>MIB. 5. All Ca2+-channel antagonists completely relaxed human coronary arteries (% of papaverine effect: MIB 81.7+/-5.5%, DIL 91.3+/-0.9%, NIF 96.4+/-3.7%) precontracted with PGF2alpha (0.3 micromol l(-1)). The rank order of vasodilatory potency was NIF (EC50; 0.02 micromol l(-1))>DIL (0.13 micromol l(-1))>MIB (2.05 micromol l(-1)). 6. The vasoselectivity measured by the ratio of the concentration needed to achieve a 25% decrease in force and the concentration needed for 25% vasodilatation was 316 for MIB, 1.5 for NIF and 1.0 for DIL. 7. The present study provides evidence that blockade of T-type Ca2+-channels (e.g. mibefradil) results in potent vasodilatory properties with only minor cardiodepressant effects.
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- 1998
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170. T- and L-type Ca2+-channel antagonists reduce contractility in guinea pig cardiac myocytes.
- Author
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Hoischen S, Brixius K, and Schwinger RH
- Subjects
- Animals, Calcium metabolism, Calcium Channels metabolism, Calcium Channels, L-Type, Diltiazem pharmacology, Guinea Pigs, Male, Mibefradil, Myocardium metabolism, Benzimidazoles pharmacology, Calcium Channel Blockers pharmacology, Calcium Channels drug effects, Myocardial Contraction drug effects, Tetrahydronaphthalenes pharmacology
- Abstract
The aim of this study was to investigate the influence of L- and T-type Ca2+-channel blockade on myocardial contractility in guinea pig cardiomyocytes. Left ventricular myocardium from guinea pig contains both L- and T-type Ca2+ channels. The T-type Ca2+ influx was inhibited with mibefradil (1-100 microM), a novel compound with a threefold higher affinity for T- compared with L-type Ca2+ channels. In comparison, L-type Ca2+ influx was reduced by the benzodiazepine diltiazem (1-100 microM). The effect of mibefradil and diltiazem on electrically driven (0.5 Hz) isolated cardiomyocytes (n = 12) was studied in a concentration-dependent manner. The change of the contraction amplitude (percentage of cell shortening) was continuously recorded with an one-dimensional high-speed camera. Both mibefradil and diltiazem concentration-dependently reduced (p < 0.05 vs. control) the contraction amplitude in isolated myocytes from guinea pig. The concentration at which the contraction amplitude of guinea pig cardiomyocytes was reduced by 50% (EC50) was 31.6 microM for diltiazem and 6.3 microM for mibefradil, indicating that the T-type Ca2+-channel blocker mibefradil is more potent in reducing contractility in guinea pig cardiac myocytes in comparison with the L-type Ca2+-channel antagonist diltiazem. Mean values for cell shortening in percentage +/- SEM for mibefradil (0, 1, 10, 100 microM) were 100%, 78 +/- 9.2%, 36 +/- 5.4%, and 24 +/- 3.6%. The corresponding values for diltiazem were 100%, 92 +/- 12.5%, 79 +/- 8.9%, and 35 +/- 2.6%. In contrast, the increase of the extracellular Ca2+ concentration (2-7.5 mM) resulted in a significant increase of the contraction amplitude (+213 +/- 14%). Therefore, blockade of the Ca2+ influx through voltage-dependent T- or L-type Ca2+ channels decreases contraction in isolated cardiac myocytes from guinea pigs containing L- and T-type Ca2+ channels.
- Published
- 1998
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171. Positive inotropic effects of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium.
- Author
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Müller-Ehmsen J, Brixius K, and Schwinger RH
- Subjects
- Azetidines pharmacology, Cell Membrane drug effects, Cell Membrane metabolism, Electric Stimulation, Heart physiology, Humans, Isoproterenol pharmacology, Myocardium metabolism, Papillary Muscles drug effects, Papillary Muscles physiology, Receptors, Adrenergic, beta metabolism, Ventricular Function, Left drug effects, Cardiotonic Agents pharmacology, Heart drug effects, Heart Failure physiopathology, Myocardial Contraction drug effects
- Abstract
The aim of this study was to investigate the inotropic properties of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium. For comparison the Na+-channel modulator BDF 9148, the beta-adrenoceptor-agonist isoprenaline, and calcium were studied. Concentration-response curves for BDF 9198 (0.01-30 microM), BDF 9148 (0.01-30 microM), isoprenaline (0.001-1 microM), and calcium (1.8-15 mM) were obtained in electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilated cardiomyopathy, NYHA IV, heart transplantation; nonfailing, donor hearts). Whereas isoprenaline was significantly less effective and less potent in increasing the force of contraction in failing human myocardium than in nonfailing myocardium (p < 0.01), BDF 9198 and BDF 9148 were (in NYHA IV) as effective as in nonfailing human tissue. In both tissues, BDF 9198 and BDF 9148 exerted similar positive inotropic effects as calcium, with the novel Na+-channel modulator BDF 9198 being more potent in increasing force of contraction than was the preceding agent BDF 9148. The potencies of both Na+-channel modulators, BDF 9198 and BDF 9148, were enhanced in human failing myocardium when compared with nonfailing myocardium. In summary, the novel Na+-channel modulator BDF 9198 increases force of contraction to the same extent as calcium and with a higher potency than BDF 9148. The sensitivity of failing human myocardium to Na+-channel modulators is increased when compared with nonfailing myocardium, which might be the result of an altered Na+ homeostasis in human heart failure.
- Published
- 1998
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172. Calcium sequestration by the sarcoplasmic reticulum in heart failure.
- Author
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Movsesian MA and Schwinger RH
- Subjects
- Adenosine Triphosphate metabolism, Animals, Calcium-Binding Proteins metabolism, Humans, Mice, Ca(2+) Mg(2+)-ATPase metabolism, Calcium metabolism, Heart Failure metabolism, Models, Cardiovascular, Sarcoplasmic Reticulum metabolism
- Published
- 1998
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173. Effect of inotropic interventions on the force-frequency relation in the human heart.
- Author
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Bavendiek U, Brixius K, Münch G, Zobel C, Müller-Ehmsen J, and Schwinger RH
- Subjects
- Adrenergic beta-Agonists pharmacology, Azetidines pharmacology, Biomechanical Phenomena, Drug Evaluation, Preclinical, Humans, In Vitro Techniques, Isoproterenol pharmacology, Ouabain pharmacology, Papillary Muscles drug effects, Cardiac Output, Low drug therapy, Cardiotonic Agents pharmacology, Cyclic AMP metabolism, Heart Rate drug effects, Myocardial Contraction drug effects
- Abstract
In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.
- Published
- 1998
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174. Effect of cyclopiazonic acid on the force-frequency relationship in human nonfailing myocardium.
- Author
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Schwinger RH, Brixius K, Bavendiek U, Hoischen S, Müller-Ehmsen J, Bölck B, and Erdmann E
- Subjects
- Adult, Calcium metabolism, Calcium-Transporting ATPases antagonists & inhibitors, Dose-Response Relationship, Drug, Humans, In Vitro Techniques, Middle Aged, Sarcoplasmic Reticulum enzymology, Sodium-Calcium Exchanger analysis, Calcium-Transporting ATPases physiology, Enzyme Inhibitors pharmacology, Indoles pharmacology, Myocardial Contraction drug effects
- Abstract
The present study investigated the functional role of the sarcoplasmic reticulum Ca++-ATPase in contraction and relaxation, intracellular Ca++-transients, as well as on the force-frequency relationship in human myocardium. The Ca++-ATPase activity of membrane vesicles isolated from sarcoplasmic reticulum (SR) obtained from nonfailing donor hearts (n = 7) was measured in the presence of cyclopiazonic acid (CPA, 0-30 microM), a highly specific inhibitor of the Ca++-ATPase of the SR (SERCA). The effects of CPA on parameters of contraction and relaxation, force-frequency relationship and [Ca++]i transients (with fura-2) were studied on isolated left ventricular muscle strips from human nonfailing myocardium. CPA concentration-dependently inhibited SERCA activity of isolated SR vesicles. In the presence of CPA (30 microM) the former positive force-frequency relationship in human left ventricular nonfailing myocardium became negative. Especially at high frequencies of stimulation, CPA decreased developed tension, peak rate of tension rise and systolic fura-2-light emission, whereas time to peak tension, time to peak [Ca++]i, time to 95% relaxation, diastolic tension and diastolic Ca++ levels were increased. Peak rate of tension decay and time to half-relaxation and half-decay of [Ca++]i were not altered significantly after treatment with CPA. These findings provide evidence that the SERCA plays a functional role in the frequency-dependent increase in force of contraction in human myocardium. Because an impaired function of the SERCA is predominantly followed by alterations of inotropic and to a lesser degree of lusitropic function, other important factors to lower [Ca++]i and influence relaxation may be present in human myocardium to compensate for the reduced SERCA activity, e.g., Na+-Ca++ exchanger.
- Published
- 1997
175. Effect of inotropic interventions on contraction and Ca2+ transients in the human heart.
- Author
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Brixius K, Pietsch M, Hoischen S, Müller-Ehmsen J, and Schwinger RH
- Subjects
- Adult, Aged, Calcium pharmacology, Female, Humans, Isometric Contraction, Isoproterenol pharmacology, Male, Middle Aged, Ouabain pharmacology, Quinolines pharmacology, Thiadiazines pharmacology, Calcium metabolism, Cardiotonic Agents pharmacology, Myocardial Contraction drug effects, Myocardium metabolism
- Abstract
The present study investigated the influences of inotropic intervention on the intracellular Ca2+ transient (intracellular Ca2+ concentration ([Ca2+]i)) and contractile twitch. Isometric twitch and [Ca2+]i (fura 2 ratio method) were measured simultaneously (1 Hz, 37 degrees C) after stimulation with Ca2+ (0.9-3.2 mM), the cardiac glycoside ouabain (Oua; 0.1 microM), the beta1- and beta2-adrenoceptor-agonist isoprenaline (Iso; 1-10 nM), and the Ca2+ sensitizer EMD-57033 (30 microM) by using isolated human nonfailing right auricular trabeculae (n = 19). Inotropic interventions increased force of contraction and peak rate of tension rise (+T) significantly. Only Iso stimulated peak rate of tension decay (-T) higher than +T (P < 0.05), thereby reducing time of contraction (Ttwitch). EMD-57033 increased +T more effectively than -T and prolonged Ttwitch (P < 0.05). Ca2+, Oua, and Iso, but not EMD-57033, increased systolic Ca2+. Diastolic Ca2+ increased after stimulation with Oua or Ca2+, but not in the presence of EMD-57033. Iso shortened the Ca2+ transient and did not influence diastolic Ca2+. In conclusion, positive inotropic agents differently affect force and [Ca2+]i depending on their mode of action. Inotropic interventions influence diastolic Ca2+ and thus may be less advantageous in a situation with altered intracellular Ca2+ homeostasis (e.g., heart failure due to dilated cardiomyopathy).
- Published
- 1997
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176. [Therapy of heart failure. II. Therapy of chronic heart failure].
- Author
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Schwinger RH and Erdmann E
- Subjects
- Angiotensin-Converting Enzyme Inhibitors adverse effects, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Cardiotonic Agents adverse effects, Diuretics adverse effects, Diuretics therapeutic use, Drug Therapy, Combination, Heart Failure etiology, Heart Failure physiopathology, Hemodynamics drug effects, Hemodynamics physiology, Humans, Cardiotonic Agents therapeutic use, Heart Failure drug therapy
- Abstract
Current medical treatment of chronic heart failure makes use of a combination of diuretics, cardiac glycosides and ACE inhibitors. The latter have improved the chances of survival of patients with chronic cardiac insufficiency. The combination of hydralazine hydrochloride and isosorbide dinitrate also improves survival, but direct comparison of both regimens provided evidence for a less favourable effect than that of the ACE inhibitors. Inhibition of neuroendocrine activation has been demonstrated only for ACE inhibitors and cardiac glycosides. The use of beta blockers represents a new therapeutic strategy that over the long term improves cardiomyocyte function, cardiac output at rest, and physical performance. For this indication, however, beta blockers should be used with extreme caution and at very low initial doses. New approaches in the area of clinical research are, for example, calcium sensitizers, modulators of intracellular calcium and/or sodium homeostasis, imidazolin receptor antagonists with an action on the central nervous system and AT1 receptor antagonists.
- Published
- 1997
177. [Therapy of heart failure. I. Definition, pathophysiology, therapy of acute heart failure].
- Author
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Schwinger RH and Erdmann E
- Subjects
- Cardiotonic Agents adverse effects, Cardiotonic Agents therapeutic use, Diagnosis, Differential, Heart Failure drug therapy, Heart Failure physiopathology, Hemodynamics drug effects, Hemodynamics physiology, Humans, Myocardial Contraction drug effects, Myocardial Contraction physiology, Heart Failure etiology
- Abstract
Acute cardiac insufficiency is often the result of acute or chronic overloading of the heart due to arterial hypertension, coronary heart disease and/or a reduction in ventricular muscle mass following myocardial infarction. Whenever possible, treatment should be causal (e.g. treatment of hypertension, operative correction of valvular disease). While the incidence of heart failure continues to increase, morbidity and mortality associated with the disease process have remained essentially unchanged. About 30% of the patients die within the first 12 months. The prognosis and outcome of heart failure patients strongly correlate with markers of neuroendocrine activation. While numerous drugs are capable of improving hemodynamics at rest or physical performance, they fall to prolong survival. It is hoped, that new pathophysiological information might lead to the development of new, effective therapeutic approaches.
- Published
- 1997
178. Increase in force of contraction by activation of the Na+/Ca(2+)-exchanger in human myocardium.
- Author
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Müller-Ehmsen J, Frank K, Brixius K, and Schwinger RH
- Subjects
- Adrenergic beta-Agonists pharmacology, Antiporters drug effects, Calcium metabolism, Calcium pharmacology, Dose-Response Relationship, Drug, Electric Stimulation, Heart Failure surgery, Heart Transplantation, Humans, Isoproterenol pharmacology, Muscle Contraction drug effects, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal metabolism, Muscle, Smooth, Vascular drug effects, Papillary Muscles drug effects, Sodium metabolism, Sodium-Calcium Exchanger, Antiporters metabolism, Azetidines pharmacology, Cardiotonic Agents pharmacology, Enzyme Inhibitors pharmacology, Myocardial Contraction drug effects, Ouabain pharmacology, Sodium-Potassium-Exchanging ATPase antagonists & inhibitors
- Abstract
Aims: The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP-independently, remain effective in failing human myocardium., Methods: Cumulative concentration-response curves with (+/-)BDF 9148 (0.01-10 mumol l-1), a Na(+)-channel activator, and ouabain (0.01-0.1 mumol l-1), a Na+/K(+)-ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilative cardiomyopathy, NYHA IV, heart transplantation, n = 16; nonfailing, donor hearts, n = 5). The beta-adrenoceptor agonist isoprenaline (0.001-1 mumol l-1) and Ca2+ (1.8-15 mmol l-1) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n = 7) in the presence of BDF 9148 (1 mumol l-1) or a high Na+ concentration (50 mmol l-1) to investigate a possible direct or indirect interaction of (+/-)BDF 9148 with the myofilaments., Results: While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P < 0.01), in NYHA IV, (+/-)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (+/-)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca2+. However, the potency for (+/-)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P < 0.05). Neither (+/-)BDF 9148 (1 mumol l-1) nor an increased concentration of Na+ (50 mmol l-1) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres., Conclusions: The enhanced sensitivity of the failing human myocardium towards Na(+)-channel modulation is not due to a direct or indirect interaction of (+/-)BDF 9148 with cardiac myofilaments but may be due to an altered Na(+)-homeostasis in human heart failure.
- Published
- 1997
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179. Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium.
- Author
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Flesch M, Schwinger RH, Schiffer F, Frank K, Südkamp M, Kuhn-Regnier F, Arnold G, and Böhm M
- Subjects
- Adult, Atrial Natriuretic Factor genetics, Azetidines pharmacology, Carrier Proteins genetics, Female, Humans, Immunohistochemistry, Isoproterenol pharmacology, Male, Middle Aged, RNA, Messenger analysis, Sodium-Calcium Exchanger, Calcium metabolism, Carrier Proteins analysis, Heart Failure metabolism, Sodium metabolism
- Abstract
Background: The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium., Methods and Results: Na(+)-Ca2+ exchanger mRNA and protein levels were examined in nonfailing (NF, n = 8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n = 8) or ischemic heart disease (ICM, n = 6). The inotropic effect of the Na+ channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37 degrees C) from nonfailing (n = 8) and failing (n = 8) human hearts. Na(+)-Ca2+ exchanger mRNA levels were significantly increased, by 79% (P < .001) in DCM and by 58% (P < .01) in ICM compared with NF; protein levels increased by 36% (P < .001) and by 20% (P < .05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (P < .01) EC50 value (NYHA class IV, 0.18 [0.16 to 0.22] mumol/L; NF, 1.65 [1.3 to 3.0] mumol/L). In NYHA class IV, BDF 9148 (0.1 mumol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction., Conclusions: The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.
- Published
- 1996
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180. Effect of epinine on tension of human renal arteries.
- Author
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Schwinger RH, Schulz C, Brixius K, Böhm M, Müller-Ehmsen J, and Erdmann E
- Subjects
- Adrenergic alpha-Antagonists pharmacology, Adrenergic beta-Antagonists pharmacology, Benzazepines pharmacology, Deoxyepinephrine antagonists & inhibitors, Dopamine pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Humans, Phentolamine pharmacology, Propranolol pharmacology, Vasodilation drug effects, Deoxyepinephrine pharmacology, Muscle Contraction drug effects, Renal Artery drug effects
- Abstract
Background: The present study aimed to characterize the effects of epinine, the active metabolite of ibopamine on tension development in human renal arteries., Methods and Results: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors (n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF2 alpha) human renal artery rings (P < 0.05) in the presence of phentolamine, as effectively (epinine -30 +/- 4 mN, dopamine -31 +/- 5 mN) and with the same potency as dopamine (epinine EC50 0.7 mumol/l (0.4-1.2 mumol/l), dopamine 0.5 mumol/l (0.2-1.7 mumol/l). This effect was antagonized by the specific D1-receptor-antagonist SCH 23390. Effective beta-adrenoceptor antagonistic concentrations of propranolol did not affect epinine-induced vasorelaxation. In the absence of alpha- and beta-adrenoceptor-antagonists the potency of epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of epinine to alpha-adrenoceptors., Conclusion: The present study provides evidence for direct vasodilatory effects of epinine via activation of D1-receptors on human renal arteries.
- Published
- 1996
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181. [Visual evoked potentials in low blood alcohol concentrations].
- Author
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Behrendt S, Kaatsch HJ, and Schwinger R
- Subjects
- Adult, Dose-Response Relationship, Drug, Ethanol pharmacology, Evoked Potentials, Visual physiology, Female, Humans, Male, Middle Aged, Reaction Time drug effects, Reaction Time physiology, Reference Values, Visual Cortex drug effects, Visual Cortex physiopathology, Alcohol Drinking physiopathology, Alcoholic Intoxication physiopathology, Ethanol pharmacokinetics, Evoked Potentials, Visual drug effects
- Abstract
Background: Both the acute toxic effects of ethanol on the central nervous system and the effects of chronic alcohol consumption on the optic nerve (tobacco-alcohol amblyopia) are well known. We investigated the acute effect of low blood alcohol concentrations on visual evoked potentials., Materials and Methods: A pattern VEP (stimulation by TV monitor, alternating chequerboard patterns, 45', 2 Hz, contrast 90%) was performed in ten healthy volunteers in sober condition and 0, 30, 60, 90 and 120 min following ingestion of 1 g/kg body weight ethanol (resulting in a blood alcohol concentration of 0.8-1.1%). Blood samples were drawn from the cubital vein simultaneously with each recording to determine blood alcohol concentration., Results: Neither peak latencies nor amplitudes showed significant changes related to blood alcohol concentration., Conclusion: No acute impairment of the optic nerve caused by ingestion of low doses of alcohol could be found using pattern VEP.
- Published
- 1996
182. Enhanced sensitivity of the failing human myocardium to cardiac glycosides and Na(+)-channel activators.
- Author
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Schwinger RH, Müller-Ehmsen J, Frank K, Koch A, and Erdmann E
- Subjects
- Adolescent, Adult, Calcium Channels drug effects, Cardiomyopathy, Dilated physiopathology, Female, Humans, In Vitro Techniques, Male, Middle Aged, Myocardium pathology, Ouabain pharmacology, Papillary Muscles pathology, Papillary Muscles physiopathology, Cardiac Glycosides pharmacology, Cardiomyopathy, Dilated pathology, Heart drug effects, Sodium Channels drug effects
- Abstract
Cardiac glycosides and Na+ -channel activators increase intracellular Na+ and thereby enhance the transport rate of the sarcolemmal Na+/Ca2+ exchanger. We tested the hypothesis of whether increased expression of the Na+/Ca2+ exchanger in failing human myocardium is accompanied by enhanced sensitivity of the failing human myocardium toward cardiac glycosides and Na+ -channel activators. We studied the positive inotropic effects of the new Na+ -channel activator BDF and the cardiac glycoside ouabain in human failing (New York Heart Association [NYHA] functional class IV, heart transplants for dilated cardiomyopathy, n = 11) and nonfailing (donor hearts, n = 5) myocardium on electrically driven left ventricular papillary muscle strips (1 Hz, 37 degrees C). The effectiveness of ouabain and BDF to increase force of contraction was similar in human nonfailing and failing myocardium. BDF was more potent to increase force of contraction in failing than in nonfailing tissue (p < 0.05). The time until maximal inotropic effect developed after ouabain was significantly shorter in NYHA IV (mean 150 +/- 16 min) than in nonfailing myocardium (mean 240 +/- 20 min). These results suggest that human failing myocardium exerts and enhanced sensitivity to cardiac glycosides and Na+ -channel activators, possibly because of enhanced expression of the Na+/Ca2+ exchanger or because of an altered intracellular Na+ -homeostasis.
- Published
- 1996
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183. [Altered calcium homeostasis in chronic heart failure].
- Author
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Erdmann E, Schwinger RH, Beuckelmann D, and Böhm M
- Subjects
- Calcium-Transporting ATPases physiology, Culture Techniques, Humans, Myocardial Contraction physiology, Myocardium enzymology, Papillary Muscles physiopathology, Sarcoplasmic Reticulum physiology, Calcium metabolism, Calcium Channels physiology, Heart Failure physiopathology, Homeostasis physiology
- Abstract
Intracellular calcium homoeostasis is greatly altered in heart failure. This does not seem to be due to altered calcium influx through L-type calcium channels but rather due to altered calcium uptake mechanisms of the sarcoplasmic reticulum. Recently, a negative force-frequency behaviour of the human myocardium has been detected in hearts from patients with severe heart failure. In the myocardium from these patients, SR-Ca(2+)-ATPase activity was decreased. The same defect has been reported in human isolated cardiac myocytes. A disturbed calcium release from the SR may also contribute to this finding of the inverse force-frequency-relationship in the failing myocardium. The altered intracellular calcium handling is connected with the diastolic and systolic failure of the myocardium. Mg++ and Na(+)-channel modulators are able to restore the positive force-frequency-relationship even in severely failing myocardium.
- Published
- 1996
184. Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.
- Author
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Schwinger RH, Böhm M, Schmidt U, Karczewski P, Bavendiek U, Flesch M, Krause EG, and Erdmann E
- Subjects
- Adult, Blotting, Northern, Blotting, Western, Cardiomyopathy, Dilated physiopathology, Female, Gene Expression, Humans, Male, Myocardial Contraction physiology, RNA, Messenger analysis, Adenosine Triphosphatases metabolism, Calcium metabolism, Calcium-Binding Proteins metabolism, Calcium-Transporting ATPases metabolism, Cardiomyopathy, Dilated metabolism, Myocardium metabolism, Sarcoplasmic Reticulum metabolism
- Abstract
Background: The aim of the present study was to investigate whether Ca2+ uptake into the sarcoplasmic reticulum (SR) is altered in failing human myocardium resulting from dilated cardiomyopathy., Methods and Results: Ca(2+)-ATPase (SERCA II) activity and Ca(2+)-dependent 45Ca2+ uptake (oxalate supported, steady state) in isolated vesicles from the SR (VSR) and in crude membrane preparations (CSR) (free Ca2+, 0.01 to 100 mumol/L) from nonfailing (donor hearts, n = 13) and terminally failing (heart transplants, dilated cardiomyopathy, n = 17) human myocardium were studied. In the same hearts, protein levels (Western blot analysis) and mRNA levels (Northern blot analysis) of SERCA II and phospholamban were measured. Increasing concentrations of Ca2+ were followed by an increased Ca(2+)-ATPase activity and Ca2+ uptake. Ca2+ uptake activity and Ca(2+)-ATPase activity in CSR preparations from failing myocardium were significantly reduced compared with nonfailing hearts (Ca(2+)-ATPase, 163 +/- 8 and 125 +/- 7 nmol ATP/mg protein per minute for nonfailing tissue and failing tissue in New York Heart Association [NYHA] class IV, respectively; Ca2+ uptake, 7.1 +/- 0.8 and 3.5 +/- 0.3 nmol/mg protein per minute in CSR from nonfailing and NYHA class IV hearts, respectively P < .05). In contrast, no significant difference was measured in VSR. In the same preparations (CSR and VSR), both SERCA II and phospholamban levels (Western blot technique with monoclonal antibodies) were unchanged in failing compared with nonfailing tissue. mRNA expression relative to GAPDH mRNA for SERCA IIa and for phospholamban was significantly reduced in failing human myocardium (P < .05)., Conclusions: These findings provide evidence that in failing human myocardium caused by dilated cardiomyopathy, protein levels of SERCA II and phospholamban are unchanged even though mRNA levels for SERCA II and phospholamban and the SERCA II function are reduced compared with nonfailing myocardium.
- Published
- 1995
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- View/download PDF
185. Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium.
- Author
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Kilter H, Lenz O, La Rosée K, Flesch M, Schwinger RH, Mädge M, Kuhn-Regnier F, and Böhm M
- Subjects
- Arginine pharmacology, Cyclic GMP metabolism, Humans, Isoproterenol pharmacology, Papillary Muscles drug effects, omega-N-Methylarginine, Arginine analogs & derivatives, Carbachol pharmacology, Myocardial Contraction drug effects, Nitric Oxide physiology, Nitric Oxide Synthase antagonists & inhibitors, Receptors, Cholinergic physiology
- Abstract
Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-L-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37 degrees C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mumol/l) was studied in the presence of the beta-adrenoceptor agonist isoprenaline (0.03 mumol/l). After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to beta-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mumol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mumol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
- Full Text
- View/download PDF
186. Halothane restores the altered force-frequency relationship in failing human myocardium.
- Author
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Schmidt U, Schwinger RH, and Böhm M
- Subjects
- Calcium metabolism, Dose-Response Relationship, Drug, Female, Homeostasis drug effects, Humans, In Vitro Techniques, Male, Middle Aged, Myocardium metabolism, Halothane pharmacology, Myocardial Contraction drug effects
- Abstract
Background: The terminally failing human myocardium exerts a negative force-frequency relationship (FFR), whereas a positive FFR occurs in nonfailing myocardium. To study the possibility of pharmacologically influencing this defect of the failing human heart, the effect of halothane on the basal FFR and the FFR in the presence of isoproterenol and ouabain was investigated., Methods: Experiments were performed on isolated, electrically driven (0.5-2 Hz, 37 degrees C, Ca2+ 1.8 mmol/l) ventricular preparations. Myocardium from human failing and nonfailing hearts was obtained at cardiac surgery. To further characterize the studied myocardium, the positive inotropic effect of isoproterenol and the density of beta-adrenoceptors were measured using the radioligand 125I-CYP., Results: Halothane produced a negative inotropic effect. The anesthetic (0.38 mmol/l) reversed the negative FFR in failing myocardium, antagonized the effect of isoproterenol (0.1 mumol/l) on FFR, and restored the FFR in the presence of ouabain., Conclusions: Halothane restores the FFR in human failing myocardium possibly by influencing the intracellular Ca2+ homeostasis. These findings provide evidence that pharmacologic interventions, e.g., during anesthesia, may influence contractility also as a result of a depressed or enhanced FFR.
- Published
- 1995
- Full Text
- View/download PDF
187. Alterations of cardiac alpha- and beta-adrenoceptors and inotropic responsiveness in hypertensive transgenic rats harbouring the mouse renin gene (TGR(mREN2)27).
- Author
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Tawfik-Schlieper H, Moll M, Schmid B, Schwinger RH, Paul M, Ganten D, and Böhm M
- Subjects
- Animals, Animals, Genetically Modified, Hypertension genetics, Isoproterenol pharmacology, Male, Mice, Myocardial Contraction drug effects, Myocardium pathology, Organ Size, Phenylephrine pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Hypertension physiopathology, Myocardium metabolism, Receptors, Adrenergic, alpha metabolism, Receptors, Adrenergic, beta metabolism, Renin genetics
- Abstract
In the present study, we investigated the alpha- and beta-adrenoceptor-mediated effects on myocardial force of contraction (using phenylephrine in the presence of propranolol and isoprenaline) and receptor densities (binding studies using [3H]-prazosin and [125I]-iodocyanopindolol) in hypertensive transgenic rats (TGR(mREN2)27) and age-matched Sprague-Dawley rats (SP) as controls. In TGR(mREN2)27 the positive inotropic effects of isoprenaline and phenylephrine were reduced, while the effect of Ca2+ was unchanged. The EC50-values did not differ in both groups. A down-regulation of the beta-adrenoceptors was observed in the hypertrophied left ventricles of transgenic rats, which is postulated to be involved in the reduced beta-adrenoceptor-mediated positive inotropic effect. The alpha-adrenoceptor density was increased, which could represent a compensatory mechanism for the impaired effectiveness of the beta-adrenergic pathway. However, since the effect of alpha-adrenoceptor agonist is not enhanced but even reduced, an uncoupling of alpha-adrenoceptors from post receptor events could play a role in the observed effects.
- Published
- 1995
- Full Text
- View/download PDF
188. Cardiac cannulation, sodium and water balance, and ANF plasma levels.
- Author
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Böhm S, Arendt RM, Reichart B, Schwinger RH, and Böhm M
- Subjects
- Heart Atria, Homeostasis, Humans, Atrial Natriuretic Factor blood, Cardiac Catheterization, Water-Electrolyte Balance
- Published
- 1995
- Full Text
- View/download PDF
189. [Clinico-pharmacologic aspects of cardioactive drugs].
- Author
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Erdmann E, Schwinger RH, and Böhm M
- Subjects
- Animals, Calcium Channel Agonists adverse effects, Calcium Channel Agonists therapeutic use, Cardiac Glycosides adverse effects, Cardiac Glycosides therapeutic use, Cardiovascular Agents adverse effects, Catecholamines adverse effects, Catecholamines therapeutic use, Cyclic AMP metabolism, Heart Diseases physiopathology, Heart Failure drug therapy, Heart Failure physiopathology, Hemodynamics physiology, Humans, Phosphodiesterase Inhibitors adverse effects, Phosphodiesterase Inhibitors therapeutic use, Quinolines adverse effects, Quinolines therapeutic use, Sodium Channels drug effects, Sodium Channels physiology, Vasodilator Agents adverse effects, Vasodilator Agents therapeutic use, Cardiovascular Agents therapeutic use, Heart Diseases drug therapy, Hemodynamics drug effects
- Published
- 1995
190. Evidence for reduction of norepinephrine uptake sites in the failing human heart.
- Author
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Böhm M, La Rosée K, Schwinger RH, and Erdmann E
- Subjects
- Adult, Aged, Dose-Response Relationship, Drug, Drug Interactions, Female, Heart Transplantation, Heart Valve Prosthesis, Humans, In Vitro Techniques, Male, Middle Aged, Mitral Valve, Myocardial Contraction drug effects, Myocardium chemistry, Myocardium cytology, Neurons chemistry, Neurons drug effects, Neurons metabolism, Norepinephrine analysis, Norepinephrine pharmacology, Radioligand Assay, Receptors, Adrenergic analysis, Receptors, Adrenergic drug effects, Heart Failure metabolism, Myocardium metabolism, Norepinephrine metabolism, Receptors, Adrenergic metabolism
- Abstract
Objectives: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes., Background: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved., Methods: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes., Results: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05)., Conclusions: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.
- Published
- 1995
- Full Text
- View/download PDF
191. cAMP concentrations, cAMP dependent protein kinase activity, and phospholamban in non-failing and failing myocardium.
- Author
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Böhm M, Reiger B, Schwinger RH, and Erdmann E
- Subjects
- Adenosine Triphosphatases analysis, Adult, Autoradiography, Calcium-Binding Proteins analysis, Cyclic AMP analysis, Cyclic AMP pharmacology, Female, Humans, Male, Middle Aged, Myocardium chemistry, Myocardium enzymology, Adenosine Triphosphatases metabolism, Calcium-Binding Proteins metabolism, Cardiomyopathy, Dilated metabolism, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Myocardial Ischemia metabolism, Myocardium metabolism
- Abstract
Objective: Several signal transduction defects such as a reduction of myocardial cAMP formation and an altered intracellular Ca2+ handling have been observed in the failing human myocardium. The aim of the study was to obtain data on changes beyond cAMP formation involving cAMP dependent protein kinase and its substrates., Methods: cAMP dependent protein kinase activity and cAMP concentrations were measured in the particulate and soluble fraction of failing human hearts (ischaemic, and dilated cardiomyopathy) and non-failing donor hearts. Phospholamban was quantified by cAMP dependent phosphorylation using 32P-ATP as substrate and on western blots using a monoclonal antibody., Results: cAMP concentrations were reduced in the particulate fraction in both ischaemic and dilated cardiomyopathy and in the soluble fraction in dilated cardiomyopathy, but there was no difference in cAMP dependent protein kinase activity. Both phospholamban levels and cAMP dependent phosphorylation of phospholamban were similar in non-failing myocardium and in both ischaemic and dilated cardiomyopathy., Conclusions: These findings show that the reduction of cAMP formation is the predominant alteration in heart failure, but cAMP dependent protein kinase and phospholamban are evidently unchanged.
- Published
- 1994
- Full Text
- View/download PDF
192. Influence of halothane on the effect of cAMP-dependent and cAMP-independent positive inotropic agents in human myocardium.
- Author
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Schmidt U, Schwinger RH, Müller-Ehmsen J, Böhm S, von Meyer L, Uberfuhr P, Reichart B, Erdmann E, and Böhm M
- Subjects
- 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester pharmacology, Adult, Aged, Calcium pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Female, Humans, In Vitro Techniques, Male, Middle Aged, Milrinone, Norepinephrine pharmacology, Pyridones pharmacology, Cardiotonic Agents pharmacology, Cyclic AMP physiology, Halothane pharmacology, Myocardial Contraction drug effects
- Abstract
Volatile anaesthetics have a variety of effects on the myocardium, namely a negative inotropic effect and a catecholamine sensitizing effect. The present study was designed to see if the hydrocarbon anaesthetics interact specifically with subcellular targets of the myocardial cell, by examining the effects of halothane in the presence of positive inotropic agents with different mechanisms of action. Experiments were performed in isolated electrically driven left ventricular preparations (1 Hz, 37 degrees C, Ca2+ 1.8 mmol litre-1) from human hearts obtained at cardiac surgery. The concentration-response curves of noradrenaline, milrinone, BayK 8644 and Ca2+ were investigated in the absence and in the presence of halothane. Halothane enhanced the efficacy of noradrenaline and milrinone but not of Ca2+ or BayK 8644. The potency of milrinone was also increased by halothane, whereas the potency of BayK 8644 was decreased and those of noradrenaline and Ca2+ were unchanged. Halothane differentially influences the effects of agents with different positive inotropic mechanisms. This experimental approach can be taken as a functional method to localize the mechanisms of action of the inhalation anaesthetics in human myocardium, namely sensitization of cAMP formation and interaction with L-type Ca2+ channels.
- Published
- 1994
- Full Text
- View/download PDF
193. The failing human heart is unable to use the Frank-Starling mechanism.
- Author
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Schwinger RH, Böhm M, Koch A, Schmidt U, Morano I, Eissner HJ, Uberfuhr P, Reichart B, and Erdmann E
- Subjects
- Cardiomyopathy, Dilated metabolism, Electric Stimulation, Humans, Myocardial Contraction drug effects, Myocardium metabolism, Ouabain pharmacology, Papillary Muscles physiopathology, Ventricular Function, Left physiology, Calcium metabolism, Cardiomyopathy, Dilated physiopathology, Myocardial Contraction physiology
- Abstract
There is evidence that the failing human left ventricle in vivo subjected to additional preload is unable to use the Frank-Starling mechanism. The present study compared the force-tension relation in human nonfailing and terminally failing (heart transplants required because of dilated cardiomyopathy) myocardium. Isometric force of contraction of electrically driven left ventricular papillary muscle strips was studied under various preload conditions (2 to 20 mN). To investigate the influence of inotropic stimulation, the force-tension relation was studied in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured after stretching the preparations to 150% of the resting length. To evaluate the length-dependent activation of cardiac myofibrils by Ca2+ in failing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction gradually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle length, or cross-sectional area of the muscles between both groups. Pretreatment with ouabain (0.02 mumol/L) restored the force-tension relation in failing myocardium and preserved the force-tension relation in nonfailing tissue. In skinned-fiber preparations of the same hearts, developed tension increased significantly after stretching only in preparations from nonfailing but not from failing myocardium. The Ca2+ sensitivity of skinned fibers was significantly higher in failing myocardium (EC50, 1.0; 95% confidence limit, 0.88 to 1.21 mumol/L) compared with nonfailing myocardium (EC50, 1.7; 95% confidence limit, 1.55 to 1.86 mumol/L). After increasing the fiber length by stretching, a significant increase in the sensitivity of the myofibrils to Ca2+ was observed in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing human myocardium. On the subcellular level, this phenomenon might be explained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.
- Published
- 1994
- Full Text
- View/download PDF
194. Coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium.
- Author
-
Böhm M, Gierschik P, Schwinger RH, Uhlmann R, and Erdmann E
- Subjects
- Atropine pharmacology, Binding, Competitive, GTP-Binding Proteins metabolism, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guanosine Diphosphate pharmacology, Heart drug effects, Heart Atria, Heart Ventricles, Humans, In Vitro Techniques, Isoproterenol pharmacology, Kinetics, Myocardial Contraction drug effects, Papillary Muscles drug effects, Quinuclidinyl Benzilate metabolism, Receptors, Muscarinic drug effects, Receptors, Muscarinic metabolism, Receptors, Purinergic P1 drug effects, Receptors, Purinergic P1 metabolism, Theophylline pharmacology, Carbachol pharmacology, Heart physiology, Myocardial Contraction physiology, Myocardium metabolism, Papillary Muscles physiology, Phenylisopropyladenosine pharmacology, Receptors, Muscarinic physiology, Receptors, Purinergic P1 physiology
- Abstract
This study investigated the coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium. Carbachol reduced force of contraction in atria and ventricles by 60 and 35% (in the presence of 0.03 microM isoprenaline), respectively. Addition of (-)-N6-(2-phenylisopropyl)adenosine (R-PIA) in the presence of carbachol did not further reduce force of contraction. R-PIA reduced force of contraction less than carbachol in atria (ventricles) by 35% (25%), but addition of carbachol after R-PIA reduced force of contraction further by 35% (15%). Carbachol increased 35S-labeled guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding maximally 14-fold only when GDP was present by an excess of > 100 times [35S]GTP gamma S, while R-PIA increased binding only 2-fold. Activation of [35S]GTP gamma S binding by A1 adenosine receptor and M-cholinoceptor stimulation was antagonized by theophylline and atropine, respectively. Addition of R-PIA to carbachol did not further increase [35S]GTP gamma S binding. Activation of high-affinity [35S]GTP gamma S binding by agonists showed that carbachol activated [35S]GTP gamma S binding to 20 pmol/mg protein [35S]GTP gamma S binding sites, i.e., 25% of the total number of binding sites (80 pmol/mg protein). With R-PIA, activation of high-affinity [35S]GTP gamma S binding could not reliably be detected with this technique. From the number of M-cholinoceptors (atria, 360 fmol/mg protein; ventricle, 270 fmol/mg protein), it is estimated that 1 M-cholinoceptor activates approximately 50-80 G protein alpha-subunits in atria and ventricles, respectively. It is concluded that stimulation of M-cholinoceptors but not A1 adenosine receptors is able to maximally activate a pool of G protein alpha-subunits.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
- Full Text
- View/download PDF
195. Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium.
- Author
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Böhm M, Weinhold C, Schwinger RH, Müller-Ehmsen J, Böhm D, Reichenspurner H, Reichart B, and Erdmann E
- Subjects
- Adult, Affinity Labels, Aged, Carbachol pharmacology, Cardiac Pacing, Artificial, Carrier Proteins metabolism, Dipyridamole pharmacology, Erythrocyte Membrane drug effects, Erythrocyte Membrane metabolism, Female, Humans, In Vitro Techniques, Male, Membrane Proteins metabolism, Middle Aged, Myocardial Contraction drug effects, Nucleoside Transport Proteins, Phenylisopropyladenosine pharmacology, Radioligand Assay, Thioinosine analogs & derivatives, Thioinosine pharmacology, Carrier Proteins antagonists & inhibitors, Heart drug effects, Membrane Proteins antagonists & inhibitors, Myocardium metabolism, Piperazines pharmacology
- Abstract
1. The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation. 2. Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5. The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.
- Published
- 1994
- Full Text
- View/download PDF
196. Titin, myosin light chains and C-protein in the developing and failing human heart.
- Author
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Morano I, Hädicke K, Grom S, Koch A, Schwinger RH, Böhm M, Bartel S, Erdmann E, and Krause EG
- Subjects
- Carrier Proteins, Connectin, Electrophoresis, Gel, Two-Dimensional, Female, Heart embryology, Humans, Male, Middle Aged, Myocardial Contraction, Heart growth & development, Heart Failure metabolism, Muscle Proteins metabolism, Myocardium metabolism, Myosins metabolism, Protein Kinases
- Abstract
We investigated relative amounts of titin, myosin light chains (MLC), C-protein, and myosin heavy chains (MHC) in the functionally intact contractile apparatus of embryonic, adult normal, and adult failing human left ventricle by SDS polyacrylamide gel electrophoresis and Western blot analysis. The amount of titin and the titin-MHC ratio was significantly (P < 0.05) lower in the embryonic and adult failing human compared to the adult normal fibres. Additionally, we found a protein band having a lower molecular weight but the same immunoreactivity as native titin (fast-migrating titin; FM-titin) in the failing heart only. The MLC-1/MLC-2 ratio was about 1.0 in normal and failing hearts but about 2.0 in the embryonic heart. Relative amount of C-protein was the same in normal and failing fibres but lower in the embryonic ventricles. Length-tension ratio of chemically skinned fibres prepared from terminally failing hearts was impaired compared to normal heart fibres. We conclude that both the reduced titin/MHC ratio and the expression of a structurally different titin form may be involved in the impaired contractile function of the terminally failing human heart.
- Published
- 1994
- Full Text
- View/download PDF
197. Magnesium restores the altered force-frequency relationship in failing human myocardium.
- Author
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Schwinger RH, Böhm M, Uhlmann R, Schmid U, Uberfuhr P, Kreuzer E, Reichart B, and Erdmann E
- Subjects
- Adult, Aged, Cardiomyopathy, Dilated complications, Cardiomyopathy, Dilated physiopathology, Female, Heart Failure etiology, Humans, In Vitro Techniques, Male, Middle Aged, Myocardial Contraction physiology, Papillary Muscles drug effects, Papillary Muscles physiopathology, Heart Failure physiopathology, Magnesium pharmacology, Myocardial Contraction drug effects
- Published
- 1993
- Full Text
- View/download PDF
198. [Current pathophysiologic aspects of heart failure].
- Author
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Böhm M, Beuckelmann DJ, Schwinger RH, and Erdmann E
- Subjects
- Animals, Heart innervation, Humans, Myocardial Contraction physiology, Renin-Angiotensin System physiology, Sympathetic Nervous System physiopathology, Heart Failure physiopathology
- Published
- 1993
199. Evidence for an interaction of halothane with the L-type Ca2+ channel in human myocardium.
- Author
-
Schmidt U, Schwinger RH, Böhm S, Uberfuhr P, Kreuzer E, Reichart B, Meyer L, Erdmann E, and Böhm M
- Subjects
- 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester pharmacology, Binding Sites, Calcium Channels drug effects, Calcium Channels metabolism, Drug Interactions, Female, Humans, Isradipine metabolism, Male, Middle Aged, Halothane pharmacology, Heart drug effects, Myocardial Contraction drug effects, Myocardium metabolism
- Abstract
Background: The present study was aimed at investigating the underlying mechanisms for the cardiac depressant effect of halothane. To test the hypothesis, whether there is an interaction of halothane with the L-type Ca2+ channels in human myocardium and whether this interaction has functional consequences for force generation in the human myocardium, effects of halothane were studied in human myocardial membranes and isolated cardiac preparations., Methods: The experiments were performed on isolated, electrically driven ventricular preparations (1 Hz, 37 degrees C) and cardiac membranes with radioligand binding experiments using 3H-PN 200-110. Myocardium from human failing and non-failing hearts was obtained at cardiac surgery., Results: Halothane produced a negative inotropic effect, which was similar in nonfailing and failing myocardium. Halothane shifted the concentration-response curve for the positive inotropic effect of the L-type Ca2+ channel agonist BayK 8644 to the right. The density of dihydropyridine receptors as judged from 3H-PN 200-110 radioligand binding experiments was similar in nonfailing and failing myocardium, whereas the density of beta-adrenoceptors was reduced. Halothane concentration dependently reduced the binding of 3H-PN 200-110, an antagonist at the 1,4 dihydropyridine receptor site of the Ca2+ channel, to myocardial membranes. Furthermore, halothane produced a rightward shift of the competition curve of BayK 8644 for binding of 3H-PN 200-110 to cardiac membranes., Conclusions: In human ventricular myocardium, halothane exhibits an interaction with the L-type Ca2+ channel by interfering with its dihydropyridine binding sites. This may explain, at least in part, the observed negative inotropic effect of this agent and could hypothetically play a general role in its anesthetic effects.
- Published
- 1993
- Full Text
- View/download PDF
200. Force-frequency-relation in human atrial and ventricular myocardium.
- Author
-
Schwinger RH, Böhm M, Koch A, Uhlmann R, Uberfuhr P, Kreuzer E, Reichart B, and Erdmann E
- Subjects
- Adult, Diacetyl analogs & derivatives, Diacetyl pharmacology, Heart Atria drug effects, Heart Ventricles drug effects, Humans, In Vitro Techniques, Male, Middle Aged, Myocardial Contraction drug effects, Heart Atria physiopathology, Heart Failure physiopathology, Heart Ventricles physiopathology, Myocardial Contraction physiology
- Abstract
In human heart failure, an increase in frequency of stimulation is followed by a reduced force of contraction in vivo and in vitro. The present study aimed to investigate whether a different origin of the myocardial sample or pretreatment with the cardioprotective agent 2,3-butanedione-monoxime (BDM) influences the force-frequency-relationship in electrically driven muscle strips taken from failing and nonfailing human myocardium. With as well as without pretreatment with BDM, the altered force-frequency-relationship in failing compared to nonfailing human ventricular myocardium can be observed. The effectiveness and the potency to increase force of contraction following an increase in frequency of stimulation was significantly higher in atrial than in ventricular myocardium in nonfailing and failing tissue. The different observations in atrial and ventricular myocardium provide evidence for functionally relevant differences in the electromechanical coupling between the human atrial and ventricular myocardium.
- Published
- 1993
- Full Text
- View/download PDF
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