21 results on '"Schwinger R"'
Search Results
2. Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium.
- Author
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Brixius K, Reicke S, Reuter H, and Schwinger RH
- Subjects
- Calcium metabolism, Cardiomyopathy, Dilated physiopathology, Culture Techniques, Cyclic AMP metabolism, Dose-Response Relationship, Drug, Heart Atria physiopathology, Heart Ventricles physiopathology, Humans, Myocardial Contraction physiology, Azocines pharmacology, Calcium Channels drug effects, Cardiotonic Agents pharmacology, Heart Atria drug effects, Heart Ventricles drug effects, Myocardial Contraction drug effects, Quinolines pharmacology, Thiadiazines pharmacology
- Abstract
Ca2+ sensitizers like EMD 57033 (EMD) and CGP 48506 (CGP) may be advantageous for the treatment of human heart failure, as they increase force of contraction without increasing the intracellular Ca2+ transients or energy consumption. However, whether or not Ca2+ sensitizers differ in their mode of action in human myocardium is not fully understood. The present study investigates the influence of EMD and CGP on force of contraction (FOC) and the intracellular Ca2+ transient (fura-2 ratio method) in left ventricular papillary muscle strips from left ventricular failing human myocardium (DCM, n = 28) as well as in right atrial trabeculae (RA, n = 21) obtained from patients undergoing cardiac bypass surgery. In isolated trabeculae of DCM, FOC was more efficacious and potently increased after application of EMD (EC50 EMD: 4.7 +/- 1.0 mumol/l, max. PIE EMD: + 12.0 +/- 2.0 mN/mm2) than CGP (EC50: 16.9 +/- 7.6 mumol/l, max. PIE: +6.4 +/- 2.8 mN/mm2). Similar results were obtained in RA. Application of carbachol (100 mumol/l) had no effect on the positive inotropic effect of EMD or CGP. Both Ca2+ sensitizers significantly increased time to half peak relaxation as well as diastolic tension in DCM. EMD (10 mumol/l) and CGP (30 mumol/l) did not affect the Ca2+ transients in RA. The Ca2+ sensitizers EMD and CGP increase cAMP and Ca2+ independently from the force of contraction in the human myocardium. However, their therapeutic use in human heart failure may be limited as they impair relaxation.
- Published
- 2002
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3. [The Ca(2+) sensitizers CGP 48506 and EMD 57033, but not the Na(+) channel modulator BDF 9148, prolong relaxation in isolated cardiomyocytes of the guinea pig].
- Author
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Brixius K, Hoischen S, Zobel C, Lasek K, and Schwinger RH
- Subjects
- Animals, Cells, Cultured, Diastole drug effects, Dose-Response Relationship, Drug, Guinea Pigs, Male, Azetidines pharmacology, Azocines pharmacology, Calcium Channels drug effects, Cardiotonic Agents pharmacology, Myocardial Contraction drug effects, Quinolines pharmacology, Sodium Channels drug effects, Thiadiazines pharmacology
- Abstract
The sodium channel modulator DPI 201-106 has been described to posses Ca(2+)-sensitizing properties. Therefore, the present study investigated the inotropic effect of the Na(+)-channel modulator BDF 9148 (1 microM), a congener of DPI 201-106, in comparison with the Ca(2+)-sensitizers CGP 48506 (1-50 mumol/l) and EMD 57033 (1-30 mumol/l) in electrically driven left ventricular cardiomyocytes isolated from guinea pigs. The changes of the contraction amplitude in comparison to the basal cell shortening (cell shortening in micron and %) were continuously recorded with a one-dimensional high speed camera. BDF 9148, CGP 48506, and EMD 57033 exerted a significant increase in the contraction amplitude (p < 0.05 vs. control). The maximal positive inotropic effects of CGP 48506 (50 mumol/l) and EMD 57033 (30 mumol/l) were +249 +/- 30% and +226 +/- 28%, respectively. The corresponding value for BDF 9148 (1 mumol/l) was +176 +/- 16%. However, only the Ca(2+)-sensitizers CGP 48506 and EMD 57033, but not BDF 9148, prolonged the contractile twitch. Especially in patients with an already enhanced intracellular myocardial Ca(2+)-concentration, Ca(2+)-sensitizers, which impair relaxation, may be disadvantageous for therapeutical use despite their positive inotropic effect.
- Published
- 2001
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4. Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium.
- Author
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Brixius K, Mehlhorn U, Bloch W, and Schwinger RH
- Subjects
- Adult, Diacetyl analogs & derivatives, Diacetyl pharmacology, Female, Humans, Male, Middle Aged, Troponin I physiology, Azocines pharmacology, Calcium pharmacology, Cardiotonic Agents pharmacology, Myocardial Contraction drug effects, Quinolines pharmacology, Thiadiazines pharmacology
- Abstract
Ca(2+) sensitizers may be advantageous for treatment in human heart failure by increasing cardiac force without increasing the Ca(2+) transient or energy consumption. To study the mode of action of the Ca(2+) sensitizers EMD 57033 (EMD) and CGP 48506 (CGP), their influence on butanedione monoxime (BDM)-mediated depression of cross-bridge cycling was analyzed in human myocardium (explanted hearts, dilated cardiomyopathy, n = 19). In Triton X (1%)-skinned fiber preparations of left ventricular myocardium from patients suffering from dilated cardiomyopathy, troponin I was extracted by vanadate (10 mM) treatment, resulting in a Ca(2+)-independent contraction. In troponin I-depleted fibers BDM (5-50 mM) was applied in the absence and presence of EMD (10 microM) or CGP (10 microM). To analyze the influence on cross-bridge kinetics, tension cost (ratio of ATPase activity and tension development) was studied. BDM exerted a dose-dependent force inhibition in troponin I-depleted fibers (IC(50) = 7.22 mM), which was antagonized by EMD (IC(50) of BDM + EMD = 19.97 mM) and CGP (IC(50) of BDM + CGP = 15.30 mM). EMD increased Ca(2+) sensitivity of force and maximal force in Triton X-skinned fibers. The Ca(2+)-sensitizing effect of CGP was accompanied by an increased Ca(2+) sensitivity of myosin-ATPase activity, an increased slope of the Ca(2+) force and Ca(2+) ATPase curve, as well as a reduced maximal myosin ATPase activity. CGP and EMD reduced tension cost. In conclusion, EMD and CGP antagonize the BDM-mediated relaxation in troponin I-depleted cardiac muscle fibers. The Ca(2+)-sensitizing effect of CGP seems to be dependent on an improvement of the myofilament cooperativity, whereas EMD seems to operate by increasing the force per cross-bridge.
- Published
- 2000
5. 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
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6. Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium.
- Author
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Müller-Ehmsen J, Näbauer M, and Schwinger RH
- Subjects
- Cyclic AMP metabolism, Enzyme Inhibitors pharmacology, Heart drug effects, Humans, In Vitro Techniques, Myocardial Contraction drug effects, Myocardium cytology, Ouabain metabolism, Papillary Muscles drug effects, Sodium-Potassium-Exchanging ATPase antagonists & inhibitors, Stereoisomerism, Ventricular Function, Left drug effects, Azetidines pharmacology, Cardiotonic Agents pharmacology, Myocardium metabolism, Sodium Channels drug effects
- Abstract
S(-)BDF 9196, the active enantiomer of racemic (+/-)BDF 9148, has been shown to increase force of contraction in myocardium from different species including humans. The present study aimed to investigate the mechanism of the positive inotropic action of the active enantiomer S(-)BDF 9196 in human myocardium. In electrically driven human left ventricular papillary muscle strips (dilated cardiomyopathy, NYHA IV, cardiac transplantation, n=9), S(-)BDF 9196 increased force of contraction concentration-dependently. The maximal positive inotropic effect remained unchanged after the addition of carbachol (1 mmol/l, indicating a cAMP-independent mode of action of S(-)BDF 9196. While [3H]ouabain binding in human myocardial membranes was not influenced by S(-)BDF 9196 up to 10 micromol/l, the inward Na(+)-current in isolated human left ventricular myocytes was increased significantly by S(-)BDF 9196 (1 micromol/l, n=5). These results provide evidence that S(-)BDF 9196 increases force of contraction in human myocardium primarily by enhancing Na(+)-influx, while cAMP-dependent or Na(+),K(+)-ATPase blocking effects do not seem to play a role.
- Published
- 1999
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7. Effect of the Na+-channel modulator BDF 9148 on Ca2+-sensitivity and force of contraction of hypertrophic myocardium from transgene rats harboring the mouse Renin gene (TG(mREN2)27).
- Author
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Zobel C, Brixius K, Frank K, and Schwinger RH
- Subjects
- Animals, Animals, Genetically Modified, Cardiomegaly enzymology, Cardiomegaly genetics, Histological Techniques, In Vitro Techniques, Male, Mice, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal enzymology, Rats, Rats, Sprague-Dawley, Sodium-Potassium-Exchanging ATPase metabolism, Azetidines pharmacology, Cardiomegaly drug therapy, Cardiotonic Agents pharmacology, Myocardial Contraction drug effects, Renin genetics, Sodium Channels drug effects
- Abstract
Unlabelled: The present study aimed to investigate the inotropic effect of the Na+-channel modulator BDF 9148 in hypertrophic myocardium compared to control tissue. Thus, TG(mREN2)27 rats (TGR), a model with hypertension induced cardiac hypertrophy, was compared with age matched Sprague-Dawley rats (SPDR). The effect of BDF 9148 (0.01-10 microM) on force of contraction (1 Hz, 37 degrees C), the force-frequency relationship (0.5-7 Hz) and the frequency-dependent diastolic tension (0.5-7 Hz) was studied on left ventricular papillary muscles from SPDR and TGR. Chemically skinned muscle fibers of the same hearts were used to examine the influence of BDF 9148 on the Ca2+-sensitivity of the contractile proteins. For control the Ca2+-sensitizer EMD 57033 was examined. In addition the Na+/K+-ATPase activity was measured in both, SPDR and TGR. BDF 9148 showed a concentration dependent positive inotropic effect in SPDR and TGR cardiac preparations. Comparing SPDR and TGR, a higher effectiveness of BDF 9148 on TGR was found, while the potency was unchanged. With increasing stimulation rates a significant higher decrease in force of contraction in TGR compared to SPDR was observed. In addition, a significant higher increase in diastolic tension was found in TGR. After exposure to 1 microM BDF 9148 the decrease in force of contraction was significantly reduced in both SPDR and TGR, while only in TGR the increase in diastolic tension was reduced. BDF 9148 had no effect on the Ca2+-sensitivity or maximal developed tension of skinned fiber preparations from SPDR or TGR. In contrast, the Ca2+-sensitizer EMD 57033 increased the Ca2+-sensitivity. The activity of the Na+/K+-ATPase was significantly reduced in TGR compared to controls., Conclusions: The Na+-channel modulator BDF 9148 was more effective in hypertrophic compared to control myocardium in increasing force of contraction, enhancing frequency-dependent force generation and reducing diastolic tension. These effects were not mediated via interaction with the contractile apparatus. The enhanced effectiveness of Na+-channel modulation in hypertrophic myocardium could result from alterations of the Na+ homeostasis, i. e. a reduced Na+/K+-ATPase activity.
- Published
- 1998
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8. 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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9. 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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10. 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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11. [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
12. 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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13. Enantioselective inotropic actions of the Na+-channel activators BDF 9148, BDF 9196 and BDF 9167 in human failing and nonfailing myocardium.
- Author
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Schwinger RH, Müller-Ehmsen J, Böhm M, and Erdmann E
- Subjects
- Carbachol pharmacology, Dose-Response Relationship, Drug, Humans, Azetidines pharmacology, Cardiotonic Agents pharmacology, Heart drug effects, Sodium Channels drug effects
- Abstract
Our study investigated the inotropic effect of the novel Na+-channel activator BDF 9148 and its enantiomeres [S(-)BDF 9169, R(+)BDF 9167] in human failing [New York Heart Association Class (NYHA IV) heart transplants, n = 15] and nonfailing myocardium (NF, donor hearts, n = 5). We studied the effect of BDF 9148 (BDF, 0.03-10 micromol/liter) and of its enantiomeres [S(-) BDF 9196; R(+)BDF 9167] on isometric force of contraction (1 Hz) as well as on the force-frequency-relationship (0.5-3 Hz) in electrically driven (37 degrees C) left ventricular papillary muscle strips, BDF and S-BDF, but not R-BDF, increased force of contraction in a dose-dependent manner in NYHA IV and NF. The effectiveness of BDF, S-BDF and Ca2+ (15 mmol/liter) to increase force of contraction was similar in human nonfailing and failing myocardium. The potency of BDF and S-BDF to increase force of contraction was significantly higher in NYHA IV compared to NF. Carbachol (1 mmol/liter) did not affect the positive inotropic response of the studied compounds. In the presence of 3 micromol/liter BDF or S-BDF force of contraction increased after an increase in stimulation frequency only from 0.5 to 1 Hz in NYHA IV and human nonfailing myocardium. At frequencies above 1 Hz the force-frequency-relationship was negative in human nonfailing myocardium and NYHA IV in the presence of high concentrations of BDF or S-BDF. These results suggest that the racemic Na+-channel activator BDF 9148 and the S(-) BDF-enantiomere, but not the R(+) BDF-enantiomere, are effective to increase force development maximally in NYHA IV and in nonfailing myocardium. Human failing myocardium exerts an enhanced sensitivity toward the Na+-channel activator BDF 9148 and its S(-) enantiomere to increase force of contraction when compared to nonfailing tissue. As Na+-channel activators increase force in a frequency-dependent mode of action the force-frequency-relationship may depend on the intracellular Ca2+- and Na+- homeostasis.
- Published
- 1996
14. EMD 53998 acts as Ca(2+)-sensitizer and phosphodiesterase III-inhibitor in human myocardium.
- Author
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Uhlmann R, Schwinger RH, Lues I, and Erdmann E
- Subjects
- Adolescent, Adrenergic beta-Agonists pharmacology, Adult, Aged, Cyclic Nucleotide Phosphodiesterases, Type 3, Female, Heart Failure physiopathology, Humans, Isoproterenol pharmacology, Male, Middle Aged, Papillary Muscles metabolism, Papillary Muscles physiopathology, Pyridazines pharmacology, 3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors, Calcium metabolism, Cardiotonic Agents pharmacology, Heart Failure drug therapy, Myocardial Contraction drug effects, Papillary Muscles drug effects, Phosphodiesterase Inhibitors pharmacology, Quinolines pharmacology, Thiadiazines pharmacology
- Abstract
Unlabelled: The effect of EMD 53998 (EMD) (0.1-100 mumol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca(2+)-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0.1-300 mumol/l), isoprenaline (Iso) (0.001-3 mumol/l) as well as CaCl2 (1.8-15 mmol/l Ca2+) were investigated. The positive inotropic responses were examined in electrically driven (1 Hz, 37 degrees C) human left ventricular papillary muscle strips from terminally failing hearts (NYHAIV, n = 24) and nonfailing donor hearts (NF, n = 9). The effect of EMD on the Ca(2+)-sensitivity of skinned fiber preparations from the very same human failing hearts were studied as well. EMD and pimobendan increased force of contraction (FOC) in a concentration-dependent manner. As judged from the EC50-values, EMD increased FOC more potently than pimobendan. EMD was significantly more effective than pimobendan to increase FOC in papillary muscle strips from NYHA IV (EMD: +2.5 +/- 0.1 mN; pimobendan: +0.8 +/- 0.2 mN) as well as from nonfailing hearts (EMD: +3.1 +/- 0.5 mN; pimobendan: +1.2 +/- 0.2 mN). Only in terminally failing myocardium, EMD increased FOC as effectively as Iso. After inotropic stimulation with EMD, pimobendan, or Iso, carbachol (1000 mumol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP-dependent mode of action. In skinned fiber experiments, EMD increased Ca(2+)-sensitivity significantly more (p < 0.01) than pimobendan., In Conclusion: EMD increases FOC in human myocardium via sensitizing of the contractile proteins towards Ca2+ and by inhibition of phosphodiesterase III-isoenzymes. EMD is a potent calcium sensitizing agent in human myocardium. Thiadiazinone derivatives could be one step in the evolution to more potent and selective calcium-sensitizers.
- Published
- 1995
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15. 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.
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- 1994
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16. Cardiac inotropic as well as coronary and pulmonary artery actions of epinine in human isolated tissues.
- Author
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Schwinger RH, Böhm M, Schulz C, Schmidt U, Schmidt U, Schmid B, Dienemann H, Reichart B, and Erdmann E
- Subjects
- Adenylyl Cyclases metabolism, Adult, Aged, Coronary Vessels physiology, Female, Heart Diseases metabolism, Humans, In Vitro Techniques, Isometric Contraction drug effects, Male, Middle Aged, Myocardial Contraction drug effects, Myocardium enzymology, Myocardium metabolism, Pulmonary Artery physiology, Receptors, Adrenergic, beta metabolism, Cardiotonic Agents pharmacology, Coronary Vessels drug effects, Deoxyepinephrine pharmacology, Heart drug effects, Pulmonary Artery drug effects
- Abstract
The present study was aimed to characterize the effects of epinine, the metabolite of the p.o. active dopamine derivate ibopamine in human cardiovascular tissues such as myocardium, coronary artery and pulmonary artery. Isometric force of contraction was studied in electrically driven papillary muscle strips from nonfailing (brain death), moderately failing (New York Heart Association class II-III, mitral valve replacement) and terminally failing human myocardium (New York Heart Association class IV, heart transplants) as well as in auricular trabeculae (aortocoronary bypass operation). Epinine increased force development in a concentration-dependent manner. In comparison to isoprenaline, epinine had a significantly lower potency but a similar efficacy to enhance force of contraction. Depending on the degree of myocardial failure, the effectiveness of epinine was reduced, whereas the potency was similar. Only in nonfailing myocardium, epinine increased force of contraction as effectively as Ca++. Prestimulation with forskolin or milrinone enhanced the potency of the epinine-mediated inotropic effect. In contrast, the beta-1-selective antagonist CGP 207.12A [2-hydroxy-5-(2-(hydroxy-3-(4-((1-methyl-4-trifluoromethyl)-1-H-imidazol -2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide] and the beta-2-selective antagonist ICI 118.551 [erythro-(+-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride] shifted the concentration-response curve of epinine significantly to the right, indicating action at both beta-2 and beta-1 adrenoceptors. Epinine exerted higher affinity at beta-2 compared to beta-1 adrenoceptors in radioligand binding experiments ([125I]iodocyanopinodolol). In human coronary artery rings and pulmonary artery rings epinine alone as well as epinine in the presence of propranolol initiated a concentration-dependent increase in tension development in precontracted (prostaglandin F2 alpha, 0.3 mumol/l) as well as in non-precontracted rings. These results suggest that epinine exerts no direct vasodilatory activity in human coronary and pulmonary arteries at concentrations which are capable to produce positive inotropic activity. The supposed beneficial effects of ibopamine in the treatment of heart failure may not be due to positive inotropic actions as the concentrations producing positive inotropy are much higher than the clinically observed plasma concentrations.
- Published
- 1993
17. Na(+)-channel activators increase cardiac glycoside sensitivity in failing human myocardium.
- Author
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Schwinger RH, Böhm M, La Rosée K, Schmidt U, Schulz C, and Erdmann E
- Subjects
- Adult, Drug Interactions, Female, Heart Transplantation, Humans, In Vitro Techniques, Male, Middle Aged, Myocardium metabolism, Ouabain metabolism, Papillary Muscles drug effects, Sodium Channels drug effects, Azetidines pharmacology, Cardiomyopathy, Dilated physiopathology, Cardiotonic Agents pharmacology, Myocardial Contraction drug effects, Ouabain pharmacology
- Abstract
Na(+)-channel activators increase intracellular Na+ and thereby enhance the transport rate of sarcolemmal Na+,K(+)-ATPase. We investigated the interaction of the new Na(+)-channel activator BDF 9148 (BDF) with the cardiac glycoside ouabain (OUA) in human myocardium. The influence of OUA (0.01-0.1 microM) and of OUA after prestimulation with BDF (0.1 microM, 1 microM; BDF+OUA) on isometric force of contraction (FOC, force of contraction; +T/-T, peak rate of tension increase/decay) of electrically driven (1 Hz, 37 degrees C) papillary muscle strips from terminally failing [New York Heart Association classification IV (NYHA IV) heart transplants, n = 19] human myocardium was studied. We also examined the effects of BDF and OUA on nonfailing human myocardium (brain death resulting from traumatic injury, n = 5). 0.01 microM OUA enhanced FOC only after prestimulation with BDF (NYHA IV+2.9 +/- 0.4 mN; p less than 0.01). The time until maximal (Tmax: BDF+OUA 117 min, OUA 166 min), half-maximal (T1/2max: BDF+OUA 47 min, OUA 85 min) inotropic effects and time until toxic signs (contracture, extrasystoles) occurred were significantly shorter with BDF+OUA as compared with OUA alone. BDF influenced Tmax, T1/2max, and time until toxic side effects occurred (Ttox) of the OUA-mediated inotropism in a concentration-dependent manner. Both OUA and BDF enhanced +T and -T. The effectiveness of OUA and BDF in increasing FOC was similar to that of Ca2+ (1.8-15 mM) but significantly (p less than 0.01) higher as compared with the beta-adrenoceptor-agonist isoprenaline in NYHA IV. In myocardial membranes, [3H]ouabain binding (Bmax, Kd) was not affected by BDF.(ABSTRACT TRUNCATED AT 250 WORDS)
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- 1992
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18. Evidence for a sustained effectiveness of sodium-channel activators in failing human myocardium.
- Author
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Schwinger RH, Böhm M, Mittmann C, La Rosée K, and Erdmann E
- Subjects
- Adult, Azetidines chemistry, Azetidines therapeutic use, Cell Membrane metabolism, Dose-Response Relationship, Drug, Female, Humans, In Vitro Techniques, Isoproterenol pharmacology, Kinetics, Male, Middle Aged, Molecular Structure, Myocardial Contraction drug effects, Myocardium metabolism, Ouabain metabolism, Piperazines pharmacology, Azetidines pharmacology, Cardiomyopathy, Dilated drug therapy, Cardiotonic Agents chemistry, Cardiotonic Agents therapeutic use, Heart drug effects, Sodium Channels drug effects
- Abstract
Elevation of cytosolic sodium is thought to be correlated with an increase in force of contraction due to an activation of sodium-calcium exchange. We investigated the inotropic response mediated by the new sodium-channel activator BDF 9148 (0.01-100 mumol/l) on failing human myocardium. Force of contraction was studied using electrically driven human papillary muscle strips from moderately (NYHA II-III, mitral valve replacement) and terminally (NYHA IV, heart transplantation) failing hearts. We also investigated the effects in auricular trabeculae from non-failing hearts (aortocoronary bypass operation). Results were compared with inotropic responses to DPI 201-106 (DPI, 0.1-3 mumol/l), Ca2+ (1.8-15 mmol/l) and isoprenaline (0.001-1 mumol/l). Carbachol (100 mumol/l) and adenosine (1000 mumol/l) were examined in the presence of BDF 9148 and isoprenaline. Both sodium-channel activators, BDF 9148 and DPI 201-106, increased force of contraction in a dose-dependent manner in papillary muscle strips as well as in auricular trabeculae. BDF 9148 and DPI 201-106 were more effective (max. PIE NYHA II-III 1.6 +/- 0.2 mN, NYHA IV 5.9 +/- 0.7 mN, P less than 0.05) and more potent (EC50 (in mumol/l): NYHA IV 0.35, 0.19-0.66; NYHA II-III 1.85, 1.37-2.41) in terminally failing as compared to moderately failing left ventricular myocardium. Moreover, the positive inotropic effects of BDF 9148 were greater than those of DPI 201-106 in NYHA IV (max. PIE 2.7 +/- 0.3 mN, P less than 0.05). In NYHA IV, BDF 9148 was as effective as CA2+ (max. PIE 5.1 +/- 0.4 mN). In the same hearts, the positive inotropic effects of isoprenaline were reduced in NYHA IV (max. PIE 2.1 +/- 0.3 mN) compared to NYHA II-III (max. PIE 3.4 +/- 0.4 mN, P less than 0.05). Adenosine as well as carbachol did not affect the positive inotropic response of BDF 9148 or DPI 201-106 but reduced the effectiveness of isoprenaline (P less than 0.05). In myocardial membranes, BDF 9148 was 1000-fold less effective in competition experiments with 3H-ouabain than ouabain. We conclude that (1) sodium-channel activators may produce a significant cAMP-independent positive inotropic effect in left ventricular myocardium from failing human hearts; (2) the inotropic effect of sodium-channel activators were more potent and more effective in NYHA IV as compared to NYHA II-III. The degree of myocardial failure does not reduce the effectiveness of the sodium-channel activator BDF 9148.
- Published
- 1991
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19. Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium.
- Author
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Ungerer M, Böhm M, Schwinger RH, and Erdmann E
- Subjects
- Adult, Binding, Competitive drug effects, Electric Stimulation, Guanylyl Imidodiphosphate pharmacology, Heart Failure metabolism, Humans, Imidazoles pharmacology, In Vitro Techniques, Membranes drug effects, Membranes metabolism, Milrinone, Piperazines pharmacology, Pyridazines pharmacology, Pyridones pharmacology, Quinuclidinyl Benzilate, Xanthines, Cardiotonic Agents antagonists & inhibitors, Heart drug effects, Myocardium metabolism, Receptors, Cholinergic drug effects, Receptors, Purinergic drug effects
- Abstract
The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.Cl and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K1-values, the rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. The new inotropic agents also displaced the binding of 3H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean Ki-values were considerably higher at m-cholinoceptors than at A1 adenosine receptors. The rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. Competition of the A1 adenosine receptor agonist R-PIA to 3H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient nH = 0.63) and revealed two affinity states of the A1 adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient nH = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the super-high affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
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20. Beta-blocking agents and positive inotropic agents in the therapy of chronic heart failure.
- Author
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Erdmann E, Schwinger R, and Böhm M
- Subjects
- Adrenergic beta-Antagonists pharmacology, Animals, Cardiotonic Agents pharmacology, Digitalis Glycosides pharmacology, Digitalis Glycosides therapeutic use, Humans, Ouabain pharmacology, Ouabain therapeutic use, Receptors, Adrenergic, alpha metabolism, Sodium-Potassium-Exchanging ATPase metabolism, Adrenergic beta-Antagonists therapeutic use, Cardiotonic Agents therapeutic use, Heart Failure drug therapy, Receptors, Adrenergic, beta metabolism
- Abstract
Positive inotropic stimulation of the failing cardiac muscle seems to be useful, if certain requirements are met: (a) there is some cardiac contractile reserve left, (b) the positive inotropic agent of choice is able to mobilize this contractile reserve, and (c) peripheral vascular resistance is not increased permanently by this agent. On the other hand, the physiological response (i.e., positive inotropic effect) to circulating catecholamines in heart failure is decreased or even absent due to receptor desensitization and an alteration of guanine nucleotide-binding proteins (increased Gi). It has been proved that functionally active beta-adrenoceptors may be restored by treatment with beta-adrenoceptor antagonists. However, these agents necessarily will have negative inotropic effects in the failing cardiac muscle, if the force of contraction is largely dependent on a permanent stimulation by catecholamines and if there are no spare beta-adrenoceptors. To clarify these as-yet unresolved problems, we have determined the contractile reserve as well as its utilization by positive inotropic agents in human cardiac muscles of failing and nonfailing hearts. The number and functional activity of cardiac glycoside receptors, beta-adrenoceptors, and alpha-adrenoceptors were measured as well as the positive inotropic and negative inotropic effects of partial agonists. Furthermore, we have accumulated evidence that, in fact, there are no spare beta-adrenoceptors in the human cardiac muscle. The lack of spare beta-adrenoceptors has consequences for the therapeutic approach in patients with heart failure. At least initially, the administration of beta-adrenoceptor-blocking agents to patients with heart failure depending on agonist-induced stimulation will lead to a worsening of cardiac function. If this situation can be tolerated, however, the subsequent restoration of functionally active beta-adrenoceptors after beta-blockade may lead to restored physiological regulation of force of contraction by norepinephrine.
- Published
- 1990
21. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial
- Author
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Maggioni, Aldo P., Greene, Stephen J., Fonarow, Gregg C., Böhm, Michael, Zannad, Faiez, Solomon, Scott D., Lewis, Eldrin F., Baschiera, Fabio, Hua, Tsushung A., Gimpelewicz, Claudio R., Lesogor, Anastasia, Gheorghiade, Mihai, Ramos, Silvina, Luna, Alejandra, Miriuka, Santiago, Diez, Mirta, Perna, Eduardo, Luquez, Hugo, Pinna, Jorge Garcia, Castagnino, Jorge, Alvarenga, Pablo, Ibañez, Julio, Blumberg, Eduardo Salmon, Dizeo, Claudio, Guerrero, Rodolfo Ahuad, Schygiel, Pablo, Milesi, Rodolfo, Sosa, Carlos, Hominal, Miguel, Marquez, Lilia Lobo, Poy, Carlos, Hasbani, Eduardo, Vico, Marisa, Fernandez, Alberto, Vita, Nestor, Vanhaecke, Johan, De Keulenaer, Gilles, Striekwold, Harry, Vervoort, Geert, Vrolix, Mathias, Henry, Philippe, Dendale, Paul, Smolders, Walter, Marechal, Patrick, Vandekerckhove, Hans, Oliveira, Mucio, Neuenschwande, Fernando, Reis, Gilmar, Saraiva, Jose, Bodanese, Luiz, Canesin, Manoel, Greco, Oswaldo, Bassan, Roberto, Marino, Roberto Luis, Giannetti, Nadia, Moe, Gordon, Sussex, Bruce, Sheppard, Richard, Huynh, Thao, Stewart, Robert, Haddad, Haissam, Echeverria, Luis, Quintero, Adalberto, Torres, Adriana, Jaramillo, Mónica, Lopez, Mónica, Mendoza, Fernan, Florez, Noel, Cotes, Carlos, Garcia, Magali, Belohlavek, Jan, Hradec, Jaromir, Peterka, Martin, Gregor, Pavel, Monhart, Zdenek, Jansky, Petr, Kettner, Jiri, Reichert, Petr, Spinar, Jindrich, Brabec, Tomas, Hutyra, Martin, Solar, Miroslav, Pietilä, Mikko, Nyman, Kai, Pajari, Risto, Cohen, Ariel, Galinier, Michel, Gosse, Philippe, Livarek, Bernard, Neuder, Yannick, Jourdain, Patrick, Picard, François, Isnard, Richard, Hoppe, Uta, Kaeaeb, Stefan, Rosocha, Stefan, Prondzinsky, Roland, Felix, Stephan, Duengen, Hans-Dirk, Figulla, Hans-Reiner, Fischer, Sven, Behrens, Steffen, Stawowy, Philipp, Kruells-Muench, Juergen, Knebel, Fabian, Nienaber, Christoph, Werner, Dierk, Aron, Wilma, Remppis, Bjoern, Hambrecht, Rainer, Kisters, Klaus, Werner, Nikos, Hoffmann, Stefan, Rossol, Siegbert, Geiss, Ernst, Graf, Kristof, Hamann, Frank, von Scheidt, Wolfgang, Schwinger, Robert, Tebbe, Ulrich, Costard-Jaeckle, Angelika, Lueders, Stephan, Heitzer, Thomas, Leutermann-Oei, Marie-Louise, Braun-Dullaeus, Ruediger, Roehnisch, Jens-Uwe, Muth, Gerhard, Goette, Andreas, Rotter, Achim, Ebelt, Henning, Olbrich, Hans-Georg, Mitrovic, Veselin, Hengstenberg, Christian, Schellong, Sebastian, Zamolyi, Karoly, Vertes, Andras, Matoltsy, Andras, Palinkas, Attila, Herczeg, Bela, Apro, Dezso, Lupkovics, Geza, Tomcsanyi, Janos, Toth, Kalman, Mathur, Atul, Banker, Darshan, Bharani, Anil, Arneja, Jaspal, Khan, Aziz, Gadkari, Milind, Hiremath, Jagdish, Patki, Nitin, Kumbla, Makund, Santosh, M.J., Ravikishore, A.G., Abhaichand, Rajpal, Maniyal, Vijayakukmar, Nanjappa, Manjunath, Reddy, P. Naveen, Chockalingam, Kulasekaran, Premchand, Rajendra, Mahajan, Vijay, Lewis, Basil, Wexler, Dov, Shochat, Michael, Keren, Andre, Omary, Muhamad, Katz, Amos, Marmor, Alon, Lembo, Giuseppe, Di Somma, Salvatore, Boccanelli, Alessandro, Barbiero, Mario, Pajes, Giuseppe, De Servi, Stefano, Greco, Dott Cosimo, De Santis, Fernando, Floresta, Agata, Visconti, Luigi Oltrona, Piovaccari, Giancarlo, Cavallini, Claudio, Di Biase, Matteo, Masini, Dott Franco, Vassanelli, Corrado, Viecca, Maurizio, Cangemi, Dott Francesco, Pirelli, Salvatore, Borghi, Claudio, Volpe, Massimo, Branzi, Angelo, Percoco, Dott Giovanni, Severi, Silvia, Santini, Alberto, De Lorenzi, Ettore, Metra, Marco, Zacà, Valerio, Mortara, Andrea, Tranquilino, Francisco P., Babilonia, Noe A., Ferrolino, Arthur M., Manlutac, Benjamin, Dluzniewski, Miroslaw, Dzielinska, Zofia, Nowalany-Kozie, Ewa, Mazurek, Walentyna, Wierzchowiecki, Jerzy, Wysokinski, Andrzej, Szachniewicz, Joanna, Romanowski, Witold, Krauze-Wielicka, Magdalena, Jankowski, Piotr, Berkowski, Piotr, Szelemej, Roman, Kleinrok, Andrzej, Kornacewicz-Jac, Zdzislawa, Vintila, Marius, Vladoianu, Mircea, Militaru, Constantin, Dan, Gheorghe, Dorobantu, Maria, Dragulescu, Stefan, Kostenko, Victor, Vishnevsky, Alexandr, Goloschekin, Boris, Tyrenko, Vadim, Gordienko, Alexander, Kislyak, Oxana, Martsevich, Sergey, Kuchmin, Alexey, Karpov, Yurii, Fomin, Igor, Shvarts, Yury, Orlikova, Olga, Ershova, Olga, Berkovich, Olga, Sitnikova, Maria, Pakhomova, Inna, Boldueva, Svetlana, Tyurina, Tatiana, Simanenkov, Vladimir, Boyarkin, Mikhail, Novikova, Nina, Tereschenko, Sergey, Zadionchenko, Vladimir, Shogenov, Zaur, Gordeev, Ivan, Moiseev, Valentin, Wong, Raymond, Ong, Hean Yee, Le Tan, Ju, Goncalvesova, Eva, Kovar, Frantisek, Skalina, Ivan, Kasperova, Viera, Hojerova, Silvia, Szentivanyi, Miroslav, Stancak, Branislav, Babcak, Marian, Kycina, Peter, Poliacik, Pavol, Toth, Peter, Sirotiakova, Jana, de Sa, Esteban Lopez, Bueno, Manuel Gomez, Selles, Manuel Martinez, Cabrera, Jose Angel, Freire, Ramon Bover, Gonzalez Juanatey, Jose Ramon, Comin, Josep, Soriano, FranciscoRidocci, Lopez, Alejandro, Vicho, Raul, Lama, Manuel Geraldia, Schaufelberger, Maria, Brunotte, Richard, Ullman, Bengt, Hagerman, Inger, Cizinsky, Stella, Cherng, Wen-Jin, Yu, Wen-Chung, Kuo, Chi-Tai, Chang, Kuan-Cheng, Lai, Wen-Ter, Kuo, Jen-Yuan, Ural, Dilek, Badak, Ozer, Akin, Mustafa, Yigit, Zerrin, Yokusoglu, Mehmet, Yilmaz, Mehmet, Abaci, Adnan, Ebinc, Haksun, Perlman, Richard, Parish, David, Bergin, James, Burnham, Kenneth, Brown, Christopher, Lundbye, Justin, Williams, Celeste, Eisen, Howard, Juneman, Elizabeth, Joseph, Susan, Peberdy, Mary Ann, Peura, Jennifer, Gupta, Vishal, Habet, Kalim, French, William, Mody, Freny, Graham, Susan, Hazelrigg, Monica, Chung, Eugene, Dunlap, Stephanie, Nikolaidis, Lazaros, Najjar, Samer, Katz, Richard, Murali, Srinivas, Izzo, Joseph L., Callister, Tracy, Phillips, Roland, Lippolis, Nicholas, Winterton, John, Meymandi, Sheba, Heilman, Karl, Oren, Ron, Zolty, Ronald, Brottman, Michael, Gunawardena, D.R., Adams, Kirkwood, Barnard, Denise, Klapholz, Marc, Fulmer, James, Maggioni AP, Greene SJ, Fonarow GC, Böhm M, Zannad F, Solomon SD, Lewis EF, Baschiera F, Hua TA, Gimpelewicz CR, Lesogor A, Gheorghiade M, Ramos S, Luna A, Miriuka S, Diez M, Perna E, Luquez H, Pinna JG, Castagnino J, Alvarenga P, Ibañez J, Blumberg ES, Dizeo C, Guerrero RA, Schygiel P, Milesi R, Sosa C, Hominal M, Marquez LL, Poy C, Hasbani E, Vico M, Fernandez A, Vita N, Vanhaecke J, De Keulenaer G, Striekwold H, Vervoort G, Vrolix M, Henry P, Dendale P, Smolders W, Marechal P, Vandekerckhove H, Oliveira M, Neuenschwande F, Reis G, Saraiva J, Bodanese L, Canesin M, Greco O, Bassan R, Marino RL, Giannetti N, Moe G, Sussex B, Sheppard R, Huynh T, Stewart R, Haddad H, Echeverria L, Quintero A, Torres A, Jaramillo M, Lopez M, Mendoza F, Florez N, Cotes C, Garcia M, Belohlavek J, Hradec J, Peterka M, Gregor P, Monhart Z, Jansky P, Kettner J, Reichert P, Spinar J, Brabec T, Hutyra M, Solar M, Pietilä M, Nyman K, Pajari R, Cohen A, Galinier M, Gosse P, Livarek B, Neuder Y, Jourdain P, Picard F, Isnard R, Hoppe U, Kaeaeb S, Rosocha S, Prondzinsky R, Felix S, Duengen HD, Figulla HR, Fischer S, Behrens S, Stawowy P, Kruells-Muench J, Knebel F, Nienaber C, Werner D, Aron W, Remppis B, Hambrecht R, Kisters K, Werner N, Hoffmann S, Rossol S, Geiss E, Graf K, Hamann F, von Scheidt W, Schwinger R, Tebbe U, Costard-Jaeckle A, Lueders S, Heitzer T, Leutermann-Oei ML, Braun-Dullaeus R, Roehnisch JU, Muth G, Goette A, Rotter A, Ebelt H, Olbrich HG, Mitrovic V, Hengstenberg C, Schellong S, Zamolyi K, Vertes A, Matoltsy A, Palinkas A, Herczeg B, Apro D, Lupkovics G, Tomcsanyi J, Toth K, Mathur A, Banker D, Bharani A, Arneja J, Khan A, Gadkari M, Hiremath J, Patki N, Kumbla M, Santosh MJ, Ravikishore AG, Abhaichand R, Maniyal V, Nanjappa M, Reddy PN, Chockalingam K, Premchand R, Mahajan V, Lewis B, Wexler D, Shochat M, Keren A, Omary M, Katz A, Marmor A, Lembo G, Di Somma S, Boccanelli A, Barbiero M, Pajes G, De Servi S, Greco DC, De Santis F, Floresta A, Visconti LO, Piovaccari G, Cavallini C, Di Biase M, Masini DF, Vassanelli C, Viecca M, Cangemi DF, Pirelli S, Borghi C, Volpe M, Branzi A, Percoco DG, Severi S, Santini A, De Lorenzi E, Metra M, Zacà V, Mortara A, Tranquilino FP, Babilonia NA, Ferrolino AM, Manlutac B, Dluzniewski M, Dzielinska Z, Nowalany-Kozie E, Mazurek W, Wierzchowiecki J, Wysokinski A, Szachniewicz J, Romanowski W, Krauze-Wielicka M, Jankowski P, Berkowski P, Szelemej R, Kleinrok A, Kornacewicz-Jac Z, Vintila M, Vladoianu M, Militaru C, Dan G, Dorobantu M, Dragulescu S, Kostenko V, Vishnevsky A, Goloschekin B, Tyrenko V, Gordienko A, Kislyak O, Martsevich S, Kuchmin A, Karpov Y, Fomin I, Shvarts Y, Orlikova O, Ershova O, Berkovich O, Sitnikova M, Pakhomova I, Boldueva S, Tyurina T, Simanenkov V, Boyarkin M, Novikova N, Tereschenko S, Zadionchenko V, Shogenov Z, Gordeev I, Moiseev V, Wong R, Ong HY, Le Tan J, Goncalvesova E, Kovar F, Skalina I, Kasperova V, Hojerova S, Szentivanyi M, Stancak B, Babcak M, Kycina P, Poliacik P, Toth P, Sirotiakova J, Lopez de Sa E, Bueno MG, Selles MM, Cabrera JA, Freire RB, Gonzalez Juanatey JR, Comin J, Soriano F, Lopez A, Vicho R, Lama MG, Schaufelberger M, Brunotte R, Ullman B, Hagerman I, Cizinsky S, Cherng WJ, Yu WC, Kuo CT, Chang KC, Lai WT, Kuo JY, Ural D, Badak O, Akin M, Yigit Z, Yokusoglu M, Yilmaz M, Abaci A, Ebinc H, Perlman R, Parish D, Bergin J, Burnham K, Brown C, Lundbye J, Williams C, Eisen H, Juneman E, Joseph S, Peberdy MA, Peura J, Gupta V, Habet K, French W, Mody F, Graham S, Hazelrigg M, Chung E, Dunlap S, Nikolaidis L, Najjar S, Katz R, Murali S, Izzo JL, Callister T, Phillips R, Lippolis N, Winterton J, Meymandi S, Heilman K, Oren R, Zolty R, Brottman M, Gunawardena DR, Adams K, Barnard D, Klapholz M, and Fulmer J
- Subjects
Male ,medicine.medical_specialty ,Cardiotonic Agents ,ASTRONAUT ,Diabetic Cardiomyopathies ,Administration, Oral ,Kaplan-Meier Estimate ,Placebo ,Diabete ,chemistry.chemical_compound ,Double-Blind Method ,Fumarates ,Internal medicine ,Diabetes mellitus ,Troponin I ,Renin ,Clinical endpoint ,medicine ,Humans ,Prospective Studies ,Heart Failure ,Ejection fraction ,business.industry ,Surrogate endpoint ,Aliskiren ,Middle Aged ,medicine.disease ,Amides ,Hospitalization ,Endocrinology ,Death, Sudden, Cardiac ,Treatment Outcome ,chemistry ,Heart failure ,Female ,Cardiology and Cardiovascular Medicine ,business ,aliskiren - Abstract
Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether alis- kiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post- discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B- type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P ¼ 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P ¼ 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P , 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldoster- one relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P ¼ 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
- Published
- 2013
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