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OBJECTIVE To elucidate the cardiovascular effects of escalating doses of phenylephrine and norepinephrine in dogs receiving acepromazine and isoflurane. ANIMALS 8 beagles aged 1 to 2 years (7.4 to 11.2 kg). METHODS All dogs received acepromazine 0.01 mg/kg, propofol 4 to 5 mg/kg, and isoflurane and were mechanically ventilated. Mean arterial pressure (MAP) from a femoral artery catheter and continuous electrocardiogram were recorded. Cardiac output (CO) was measured with transpulmonary thermodilution. Systemic vascular resistance (SVR), global end-diastolic volume (GEDV), and global ejection fraction (GEF) were subsequently calculated. Phenylephrine and norepinephrine were infused in random order at 0.07, 0.3, 0.7, and 1.0 μg/kg/min. All variables were measured after 15 minutes of each infusion rate. The effects of dose, agent, and their interaction on the change of each variable were evaluated with mixed-effect models. A P < .05 was used for significance. RESULTS Atrial premature complexes occurred in 3 dogs during norepinephrine infusion at doses of 0.3, 0.7, and 1 μg/ kg/min; no dysrhythmias were seen with phenylephrine administration. MAP increased during dose escalation (P < .0001) within each agent and did not differ between agents (P = .6). The decrease in HR was greater for phenylephrine (P < .0001). Phenylephrine decreased CO and GEF and increased GEDV and SVR (all P < .03). Norepinephrine decreased the SVR and increased CO, GEDV, and GEF (all P < .03). CLINICAL RELEVANCE Our results confirm that phenylephrine increases arterial pressures mainly through vasoconstriction in acepromazinepremedicated dogs while norepinephrine, historically considered a vasopressor, does so primarily through an increase in inotropism. [ABSTRACT FROM AUTHOR]

Abstract Background Glucagon is thought to increase heart rate and contractility by stimulating glucagon receptors and increasing 3′,5′-cyclic adenosine monophosphate (cAMP) production in the myocardium. This has been confirmed in animal studies but not in the human heart. The cardiostimulatory effects of glucagon have been correlated with the degree of cardiac dysfunction, as well as with the enzymatic activity of phosphodiesterase (PDE), which hydrolyses cAMP. In this study, the presence of glucagon receptors in the human heart and the inotropic and chronotropic effects of glucagon in samples of failing and nonfailing (NF) human hearts were investigated. Methods Concentration‒response curves for glucagon in the absence and presence of the PDE inhibitor IBMX were performed on samples obtained from the right (RA) and left atria (LA), the right (RV) and left ventricles (LV), and the sinoatrial nodes (SNs) of failing and NF human hearts. The expression of glucagon receptors was also investigated. Furthermore, the inotropic and chronotropic effects of glucagon were examined in rat hearts. Results In tissues obtained from failing and NF human hearts, glucagon did not exert inotropic or chronotropic effects in the absence or presence of IBMX. IBMX (30 µM) induced a marked increase in contractility in NF hearts (RA: 83 ± 28% (n = 5), LA: 80 ± 20% (n = 5), RV: 75 ± 12% (n = 5), and LV: 40 ± 8% (n = 5), weaker inotropic responses in the ventricular myocardium of failing hearts (RV: 25 ± 10% (n = 5) and LV: 10 ± 5% (n = 5) and no inotropic responses in the atrial myocardium of failing hearts. IBMX (30 µM) increased the SN rate in failing and NF human hearts (27.4 ± 3.0 beats min −1 , n = 10). In rat hearts, glucagon induced contractile and chronotropic responses, but only contractility was enhanced by 30 µM IBMX (maximal inotropic effect of glucagon 40 ± 8% vs. 75 ± 10%, in the absence or presence of IBMX, n = 5, P 0.05). Glucagon receptors were not detected in the human heart samples. Conclusions Our results conflict with the view that glucagon induces inotropic and chronotropic effects and that glucagon receptors are expressed in the human heart.

Background: Glucagon is thought to increase heart rate and contractility by stimulating glucagon receptors and increasing 3′,5′-cyclic adenosine monophosphate (cAMP) production in the myocardium. This has been confirmed in animal studies but not in the human heart. The cardiostimulatory effects of glucagon have been correlated with the degree of cardiac dysfunction, as well as with the enzymatic activity of phosphodiesterase (PDE), which hydrolyses cAMP. In this study, the presence of glucagon receptors in the human heart and the inotropic and chronotropic effects of glucagon in samples of failing and nonfailing (NF) human hearts were investigated. Methods: Concentration‒response curves for glucagon in the absence and presence of the PDE inhibitor IBMX were performed on samples obtained from the right (RA) and left atria (LA), the right (RV) and left ventricles (LV), and the sinoatrial nodes (SNs) of failing and NF human hearts. The expression of glucagon receptors was also investigated. Furthermore, the inotropic and chronotropic effects of glucagon were examined in rat hearts. Results: In tissues obtained from failing and NF human hearts, glucagon did not exert inotropic or chronotropic effects in the absence or presence of IBMX. IBMX (30 µM) induced a marked increase in contractility in NF hearts (RA: 83 ± 28% (n = 5), LA: 80 ± 20% (n = 5), RV: 75 ± 12% (n = 5), and LV: 40 ± 8% (n = 5), weaker inotropic responses in the ventricular myocardium of failing hearts (RV: 25 ± 10% (n = 5) and LV: 10 ± 5% (n = 5) and no inotropic responses in the atrial myocardium of failing hearts. IBMX (30 µM) increased the SN rate in failing and NF human hearts (27.4 ± 3.0 beats min−1, n = 10). In rat hearts, glucagon induced contractile and chronotropic responses, but only contractility was enhanced by 30 µM IBMX (maximal inotropic effect of glucagon 40 ± 8% vs. 75 ± 10%, in the absence or presence of IBMX, n = 5, P < 0.05; maximal chronotropic response 77.7 ± 6.4 beats min−1 vs. 73 ± 11 beats min−1, in the absence or presence of IBMX, n = 5, P > 0.05). Glucagon receptors were not detected in the human heart samples. Conclusions: Our results conflict with the view that glucagon induces inotropic and chronotropic effects and that glucagon receptors are expressed in the human heart. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the cardioactive glycosides oleandrin and ouabain, and compared them to digoxin in a model of cardiotoxicity induced by doxorubicin. Adult rats were distributed into four experimental groups. Each group was challenged with a single intraperitoneal application of doxorubicin at a dose of 12 mg/kg. Then, they were treated with saline solution and the glycosides oleandrin, ouabain, and digoxin at a dose of 50 µg/kg, for 7 days. They underwent echocardiography, electrocardiography, hematologic, biochemical tests, and microscopic evaluation of the heart. All animals presented congestive heart failure, which was verified by a reduction in the ejection fraction. Oleandrin and digoxin were able to significantly reduce (p < 0.05) the eccentric remodeling caused by doxorubicin. Oleandrin and digoxin were significantly lower (p < 0.05) than the control group in maintaining systolic volume and left ventricular volume in diastole. Other parameters evaluated did not show significant statistical differences. All animals showed an increase in erythrocyte count, and an increase in the duration of the QRS complex on the ECG and myocardial necrosis at the histopathological analysis. It is concluded that the glycosides oleandrin, ouabain, and digoxin in the used dosage do not present therapeutic potential for the treatment of congestive heart failure caused by doxorubicin. [ABSTRACT FROM AUTHOR]

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank–Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank–Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise. [ABSTRACT FROM AUTHOR]

The review deals with the release of endothelium-derived dopamine and 6-nitrodopamine (6-ND) and its effects on isolated vascular tissues and isolated hearts. Basal release of both dopamine and 6-ND is present in human isolated umbilical cord vessels, human popliteal vessels, nonhuman primate vessels, and reptilia aortas. The 6-ND basal release was significantly reduced when the tissues were treated with N ω -nitro-l-arginine methyl ester and virtually abolished when the endothelium was mechanically removed. 6-Nitrodopamine is a potent vasodilator, and the mechanism of action responsible for this effect is the antagonism of dopamine D 2 -like receptors. As a vasodilator, 6-ND constitutes a novel mechanism by which nitric oxide modulates vascular tone. The basal release of 6-ND was substantially decreased in endothelial nitric oxide synthase knockout (eNOS -/- ) mice and not altered in neuronal nitric oxide synthase knockout (nNOS -/- -adrenoceptor antagonists at concentrations that do not affect the effects induced by noradrenaline, adrenaline, and dopamine, indicating that blockade of the 6-ND receptor is the major modulator of heart chronotropism and inotropism. The review proposes that endothelium-derived catecholamines may constitute a major mechanism for control of vascular tone and heart functions, in contrast to the overrated role attributed to the autonomic nervous system.1 -adrenoceptor antagonists at concentrations that do not affect the effects induced by noradrenaline, adrenaline, and dopamine, indicating that blockade of the 6-ND receptor is the major modulator of heart chronotropism and inotropism. The review proposes that endothelium-derived catecholamines may constitute a major mechanism for control of vascular tone and heart functions, in contrast to the overrated role attributed to the autonomic nervous system.

The purpose of the present study was to identify the cardiac vagal nerve (CVN) of the turtle, to characterize its fiber composition, and to correlate this composition with cardioinhibitory functions. Turtles (Ocadia sinensis) were anesthetized with sodium pentobarbital. The CVN was identified anatomically as a thoracic vagal branch going to the heart. Transection or reversal block of this branch completely abolished the negative chronotropic and inotropic effects produced by ipsilateral cervical vagal stimulation. Electron microscopic examination of the CVN revealed that it is comprised of 500 to 1800 axon fibers. Among these, 86% were unmyelinated and 14% were myelinated fibers. Compound action potentials of the CVN consisted of A, B, and C groups. A decrease in the heart rate or a reduction of ventricular contractility was observed with electrical stimulation of the cervical vagus at an intensity which activates the B-fiber group. When the stimulus intensity increased to recruit both the B- and C-fiber groups, maximal cardioinhibitory effects were observed. The negative chronotropic effect of the right vagus was greater than that of the left vagus with low-frequency stimulation. In contrast, stimulation of the left vagus produced greater negative inotropic effect. These data indicate that the turtle heart is innervated by a single pair of CVN. The cardioinhibitory functions are subserved by small myelinated and large unmyelinated fibers. Functionally distinct vagal neurons may be distributed unevenly in the turtle brain, such that the right vagal nerve contains more chronotropic while the left more inotropic motor fibers. [ABSTRACT FROM AUTHOR]

Background: Age-related differences concerning cardiorespiratory responses and myocardial function during exercise have not been extensively investigated in healthy populations.Aims: To compare cardiorespiratory performance and myocardial function during maximal exercise in healthy/unmedicated men (older, n = 24, 63-75 years; young, n = 22, 19-25 years) and women (older, n = 18, age = 63-74 years; young, n = 23, 19-25 years).Methods: Oxygen uptake (VO2), ventilation minute (VE), heart rate (HR), stroke volume (SV), cardiac output (Q), O2 pulse (O2p), preejection period (PEP), and left ventricular ejection time (LVET) were assessed during cycle incremental exercise.Results: HR and SV remained equivalent between age groups until 75 and 50% peak workload, respectively. Q increased by 2.5 and 4.5 times in older and young groups, respectively. However, Q/VO2 ratio was always similar across age and sex groups (∼0.50). The energetic efficiency ratio (W/VO2) was also alike in older and young men, but slightly lower in women. At maximal exercise, cardiorespiratory responses were lower in older than young men and women: VO2 (−40 to 50%), VE (−35 to 37%), HR (−23%), SV (−26 to 29%), Q (−43 to 45%), and O2p (−15 to 20%). Cardiac and SV indices were lower in older than young groups by approximately 42 and 25%, respectively. LVET was longer in the older individuals, while PEP was similar across age groups. Hence, PEP/LVET was lowered among older vs. young men and women.Conclusion: Submaximal work capacity was preserved in healthy and unmedicated older individuals. Age-related lessening of maximal performance in both sexes was due to poor chronotropic and, particularly, inotropic properties of the heart. [ABSTRACT FROM AUTHOR]

Varying temperature affects cardiac systolic and diastolic function and the left ventricular (LV) pressure-time curve (PTC) waveform that includes information about LV inotropism and lusitropism. Our proposed half-logistic (h-L) time constants obtained by fitting using h-L functions for four segmental phases (Phases I-IV) in the isovolumic LV PTC are more useful indices for estimating LV inotropism and lusitropism during contraction and relaxation periods than the mono-exponential (m-E) time constants at normal temperature. In this study, we investigated whether the superiority of the goodness of h-L fits remained even at hypothermia and hyperthermia. Phases I-IV in the isovolumic LV PTCs in eight excised, cross-circulated canine hearts at 33, 36, and 38 °C were analyzed using h-L and m-E functions and the least-squares method. The h-L and m-E time constants for Phases I-IV significantly shortened with increasing temperature. Curve fitting using h-L functions was significantly better than that using m-E functions for Phases I-IV at all temperatures. Therefore, the superiority of the goodness of h-L fit vs. m-E fit remained at all temperatures. As LV inotropic and lusitropic indices, temperature-dependent h-L time constants could be more useful than m-E time constants for Phases I-IV. [ABSTRACT FROM AUTHOR]

En este reporte se expone el caso de una cachorra de raza Springer Spaniel que presentaba taquipnea, ascitis, intolerancia al ejercicio, leve cianosis y baja condición corporal. A la auscultación cardiaca se evidenció un soplo 5/6 mitral que irradiaba a ambos hemitórax. En la ecocardiografía se apreció una disminución de la función contráctil del ventrículo izquierdo, hipertrofia excéntrica del atrio y ventrículo izquierdo, e insuficiencia mitral.Este relatório descreve o caso de uma cachorra da raça Springer spaniel de baixa condição corporal que tinha taquipnéia, ascite, intolerância ao exercício, cianose leve. Na ausculta cardíaca foi mostrado um fôlego 5/ 6 mitral que irradiava ambos hemitórax. Em ecocardiografia revelou uma diminuição na função contrátil do ventrículo esquerdo, excêntrica hipertrofia do ventrículo direito e átrio esquerdo e insuficiência mitral.This is a case of a Springer spaniel puppy which presented tachypnea, ascitis, exercise intolerance, mild cyanosis and a poor body condition. At cardiac auscultation a 5/6 mitral murmur was detected that irradiated to both hemithorax. Echocardiography revealed diminished left ventricular contractility, eccentric hypertrophy of the left atrium and ventricle and mitral insufficiency.

Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them ( 1b,c,e ) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation. [ABSTRACT FROM AUTHOR]

It has been reported that star fruit can lead to a fatal outcome in uremic patients. The intoxication syndrome consists of hiccups, mental confusion, dizziness, and vomiting. On the other hand, folk medicine uses teas and infusions of carambola leaves to treat headache, vomiting, cough, insomnia, and diabetes. This motivated us to determine if Averrhoa carambola can act on the contractility and automaticity of the guinea pig heart. We measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria. The carambola leaf extracts (1.5 mg/ml) abolished the contractile force in a concentration-dependent manner. Among the crude, methanolic, ethanolic, aqueous, and acetic extracts, the aqueous one was the most potent (EC50 = 520 ± 94 µg/ml; flavonoids and tannins are the main constituents; Na+ and K+ contents in 1.0 mg/ml of aqueous extract were 0.12 ± 0.016 and 1.19 ± 0.15 mM, respectively). The aqueous extract abolished the positive Bowditch staircase phenomenon and reduced the inotropic response to CaCl2 (0.17-8.22 mM), events that are dependent on the cellular Ca2+ inward current. The adrenergic, muscarinic or opioid membrane receptors do not seem to participate in the mechanism of action of the cardioactive substance(s). In spontaneously beating atria, the aqueous extract promoted a negative chronotropic effect that was antagonized by 0.1 µM isoproterenol bitartrate. With this agonist, the EC50 of the aqueous extract increased from 133 ± 58 to 650 ± 100 µg/ml. These data regarding the effect of A. carambola on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.

The hypothalamic neuropeptide Nesfatin-1 is present in both mammals and teleosts in which it elicits anorexigenic effects. In mammals, Nesfatin-1 acts on the heart by inducing negative inotropism and lusitropism, and cardioprotection against ischemic damages. We evaluated whether in teleosts, Nesfatin-1 also influences cardiac performance. In the goldfish ( Carassius auratus ), mature, fully processed Nesfatin-1 was detected in brain, gills, intestine and skeletal muscle, but not in the cardiac ventricle. However, on the isolated and perfused working goldfish heart, exogenous Nesfatin-1 induced a positive inotropic effect, revealed by a dose-dependent increase of stroke volume (SV) and stroke work (SW). Positive inotropism was abolished by inhibition of adenylate cyclase (AC; MDL123330A) and cAMP-dependent kinase (PKA; KT5720), suggesting a cAMP/PKA-mediated pathway. This was confirmed by the increased cAMP concentrations revealed by ELISA on Nesfatin-1-treated hearts. Perfusion with Diltiazem, Thapsigargin and PD98059 showed the involvement of L-type calcium channels, SERCA2a pumps and ERK1/2, respectively. The role of ERK1/2 and phospholamban in Nesfatin-1-induced cardiostimulation was supported by Western blotting analysis. In conclusion, this is the first report showing that in teleosts, Nesfatin-1 potentiates mechanical cardiac performance, strongly supporting the evolutionary importance of the peptide in the control of the cardiac function of vertebrates. [ABSTRACT FROM AUTHOR]

Background Reactive oxygen species, such as superoxide, are being increasingly recognized as key components of a vast array of signaling pathways. Angiotensin II is a well-recognized stimulus for superoxide production through NADPH oxidase activation and opening of the mitochondrial ATP-sensitive potassium channels (mK ATP ). A role for this mechanism has been proposed to explain several physiological effects of the peptide. The aim of this study was to evaluate the involvement of this mechanism in the inotropic response to 100 nmol/L angiotensin II. Methods Sarcomere shortening and intracellular pH (BCECF-epifluorescence technique) were evaluated in isolated cat ventricular myocytes placed in a perfusion chamber on the stage of an inverted microscope. Myocardial superoxide production was evaluated by the lucigenin quimioluminiscence method. Results Angiotensin II (100 nmol/L) increased~70% sarcomere shortening, effect that was only partially prevented by NADPH oxidase inhibition, mK ATP channel blockade or inhibition of the cardiac Na + /H + exchanger (NHE-1). Moreover, angiotensin II stimulates NHE-1 activity by a NADPH oxidase-dependent mechanism. Myocardial superoxide production was also increased by angiotensin II, and this action was completely prevented either by NADPH oxidase inhibition or mK ATP channel blockade. Conclusions The positive inotropic response to 100 nmol/L angiotensin II is due to both ROS/NHE-1 dependent and independent pathways, this being a point of divergence with the signaling previously described to be triggered by lower concentrations of angiotensin II (i.e.: 1 nmol/L). [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) has recently emerged as an important mediator of mammalian cardiovascular homeostasis. In nonmammalian vertebrates, little is known about the cardiac effects of H2S. This study aimed to evaluate, in the avascular heart of the frog, Rana esculenta, whether and to what extent H2S affects the cardiac performance, and what is the mechanism of action responsible for the observed effects. Results were analyzed in relation to those obtained in the rat heart, used as the mammalian model. Isolated and perfused (working and Langendorff) hearts, Western blot analysis, and modified biotin switch (S-sulfhydration) assay were used. In the frog heart, NaHS (used as H2S donor, 10-12/10-7 M) dose-dependently decreased inotropism. This effect was reduced by glibenclamide (KATP channels blocker), NG-monomethyl- L-arginine (NOS inhibitor), 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin- 1-one (guanylyl cyclase inhibitor), KT5823 (PKG inhibitor), and it was blocked by Akt1/2 (Akt inhibitor) and by detergent Triton X-100. In the rat, in addition to the classic negative inotropic effect, NaHS (10-12/10-7 M) exhibited negative lusitropism. In both frog and rat hearts, NaHS treatment induced Akt and eNOS phosphorylation and an increased cardiac protein S-sulfhydration that, in the rat heart, includes phospholamban. Our data suggest that H2S represents a phylogenetically conserved cardioactive molecule. Results obtained on the rat heart extend the role of H2S also to cardiac relaxation. H2S effects involve KATP channels, the Akt/NOS-cGMP/PKG pathway, and S-sulfhydration of cardiac proteins. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Dobutamine stress echocardiography (DSE) is performed to detect subtle ischemic regions in the myocardium in patients suffering from stenosed coronary artery disease. While in a clinical and veterinary context DSE is performed daily, in the preclinical context, a very limited application has been described in the literature. In the drug development process, the safety of new chemical entities on the cardiovascular system is a primary requirement for the development of new agents/drugs for administration in humans. There are limited tools to evaluate the impairment of myocardial performance and cardiac contractility in preclinical species and particularly in rodents. In this present paper a possible imaging application is presented. Methods: Anesthetised male Crl:CD(SD) rats (n =14) were given single intravenous doses of vehicle (5% w/v Dextrose solution) and dobutamine hydrochloride at 10μg/kg/min. Echocardiography was performed, starting immediately before the infusion and animals were monitored up to 5min after the end of infusion. Standard and non-standard echocardiography parameters were evaluated to detect test article related changes compared to vehicle infused animals. Results: Thickening of left ventricle walls and interventricular septum and increased velocity of circumferential stress were observed in dobutamine infused animals compared to those receiving vehicle. These changes were considered to be a direct effect on myocardial contractility, as also confirmed by increased functional parameters (i.e., Ejection Fraction, End Diastolic Volume and decrease of the ratio between pre-ejection period and ejection time of the aortic flow). In dobutamine infused rats the “Tei index” increased up to approximately 32% compared to vehicle animals, showing a clear relationship with increased contractility. Discussion: As expected dobutamine infusion in the anaesthetised rat is capable of inducing a positive inotropic effect and echocardiography results are a reliable tool for the determination of changes in contractility induced by pharmacological stress testing in the rat. [Copyright &y& Elsevier]

Abstract: Adrenomedullin (AM) effects were studied in rabbit papillary muscles by adding increasing concentrations (10−10 to 10−6 M) either alone or after pre-treatment with l-NNA, indomethacin, AM22–52 (AM receptor antagonist), CGRP(8–37) (CGRP receptors antagonist), KT5720 (PKA inhibitor), as well as after endocardial endothelium (EE) removal. Passive length–tension relations were constructed before and after a single concentration of AM (10−6 M). AM concentration-dependently induced negative inotropic and lusitropic effects, and increased resting muscle length (RL). At 10−6 M, AT, dT/dt max and dT/dt min decreased 20.9±4.9%, 18.3±7.3% and 16.7±7.8%, respectively, and RL increased to 1.010±0.004 L/L max. Correcting RL to its initial value resulted in a 26.6±6.4% decrease of resting tension, indicating decreased muscle stiffness, also patent in the down and rightward shift of the passive length–tension relation. The negative inotropic effect of AM was dependent on its receptor, CGRP receptor, PKA, the EE and NO, while the effects of AM on myocardial stiffness were abolished by EE damage and NO inhibition. This latter effect represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AM is an important regulator of cardiac filling. [Copyright &y& Elsevier]

Abstract: Endogenous polyamines mediate acute metabolic effects and cardiac hypertrophy associated to β-adrenoceptor stimulation. The aim of this study is to characterize the role of polyamines on β-adrenoceptor system mediated responses. To this end, the functional interaction of polyamine modifying drugs on isoproterenol-elicited cardiotonic effect, in isolated left atria of male Wistar rats, and their effects on [3H]dihydroalprenolol (DHA) binding on β-adrenoceptors and on adenylyl cyclase activity of membrane heart were studied. Polyamines interact with β-adrenoceptors in rat heart, as shown by the displacement of [3H]DHA binding. Furthermore, putrescine (but not spermidine or spermine) increased adenylyl cyclase activity, elicited a positive inotropism and increased intracellular cAMP. The putrescine effect on adenylyl cyclase was not antagonized by the β-adrenoceptors blockers, alprenolol and ICI-118,551, and facilitated the isoproterenol effect. Neither alprenolol, atenolol nor ICI-118,551 antagonized putrescine-elicited positive inotropism. However, the effect was abolished in preparations with desensitized β-adrenoceptors. α-Difluoromethylornithine, an inhibitor of ornithine decarboxylase, antagonized the effect of isoproterenol on inotropism and cAMP increase. In addition, putrescine might elicit effects by mechanisms independent of β-adrenoceptor system, since in left atria with functional desensitized receptors an interaction with ouabain-elicited cardiotonic effect was observed. These results suggest that putrescine may act as a low affinity agonist on β-adrenoceptors and modulate acute responses mediated by β-adrenoceptors. These findings may be of importance in the physiology and in diseases involving cardiac β-adrenoceptors. [Copyright &y& Elsevier]

Endothelin (ET)-1 regulates the contractility and growth of the heart by binding G protein-coupled receptors of the ET type A receptor (ETA)/ET type B (ETB) receptor family. ETA, the predominant ET-1 receptor subtype in myocardium, is thought to localize preferentially within cardiac T tubules, but the consequences of mislocalization are not fully understood. Here we examined the effects of the overexpression of ETA in conjunction with T-tubule loss in cultured adult rat ventricular myocytes. In adult myocytes cultured for 3 to 4 days, the normally robust positive inotropic effect (PIE) of ET-1 was lost in parallel with T-tubule degeneration and a decline in ETA protein levels. In these T tubule-compromised myocytes, an overexpression of ETA using an adenoviral vector did not rescue the responsiveness to ET- 1, despite the robust expression in the surface sarcolemma. The inclusion of the actin polymerization inhibitor cytochalasin D (CD) during culture prevented gross morphological changes including a loss of T tubules and a rounding of intercalated discs, but CD alone did not rescue the responsiveness to ET-1 or prevent ETA downregulation. The rescue of a normal PIE in 3- to 4-day cultured myocytes required both an increased expression of ETA and intact T tubules (preserved with CD). Therefore, the activation of ETA localized in T tubules was associated with a strong PIE, whereas the activation of ETA in surface sarcolemma was not. The results provide insight into the pathological cardiac conditions in which ETA is upregulated and T-tubule morphology is altered. [ABSTRACT FROM AUTHOR]

Abstract: Angiotensin II is an octapeptide whose effects are mediated by two types of receptors. AT1 receptors are responsible for the vasoconstrictor, positive inotropic and growth promoting properties, while AT2 receptors have been linked to vasodilator and anti-mitogenic properties. In this study we investigated the effects of selective AT2 receptor stimulation on myocardial contractility and lusitropy. Effects of selective AT2 receptor activation were evaluated in rabbit right papillary muscles (n =96) by adding increasing concentrations of H-9395, an AT2 receptor agonist, alone or in presence of a selective AT1 receptor antagonist (ZD-7155), or alternatively, by adding increasing concentrations of angiotensin II in presence of ZD-7155. In the latter conditions, selective AT2 receptor activation was also performed in presence of NG-nitro-l-Arginine, indomethacin, proadifen, hydroxocobalamin, apamin plus charybdotoxin, Hoe-140 or PD-123,319, as well as, after endocardial endothelium removal. Selective AT2 stimulation induced a negative inotropic and lusitropic effect in the first three protocols. This effect was completely abolished after selective removal of the endocardial endothelium and blunted in presence of Hoe-140, hydroxocobalamin, apamin plus charybdotoxin and PD-123,319, but maintained in presence of NG-nitro-l-Arginine, indomethacin or proadifen. Selective AT2 receptor stimulation induces a negative inotropic and lusitropic effect, which is modulated by endocardial endothelium and mediated by bradykinin B2 receptors through NO release and calcium dependent potassium channels activation. Such findings may help to better understand the therapeutic effects of selective AT1 antagonists, which are increasingly used for treating cardiovascular diseases. [Copyright &y& Elsevier]

1. The acute effect of amiodarone on haemodynamics (mean arterial pressure and heart rate) and ventricular function (+dP/dtmax and –dP/dtmax) was investigated in conscious rats. In addition, the effects of amiodarone on dobutamine stress were determined. 2. Catheters were inserted in rats into the left ventricle and femoral artery and vein. Three groups of rats received 25 or 50 mg/kg, i.v., amiodarone or vehicle (a 1 : 1 : 8 mixture of Tween 80 : 99.5% ethanol : distilled water), followed by dobutamine (10 µg/kg). 3. The hypotensive effect of 50 mg/kg amiodarone was combined with marked bradycardia and attenuation of +dP/dtmax and –dP/dtmax. A slight, but significant, hypotension was caused by 25 mg/kg amiodarone, without affecting heart rate, +dP/dtmax and –dP/dtmax. However, although both doses of amiodarone attenuated the tachycardia caused by dobutamine, neither 25 nor 50 mg/kg amiodarone affected the increase in mean arterial pressure or the enhanced response of +dP/dtmax and –dP/dtmax. 4. In conclusion, amiodarone caused hypotension, bradycardia, negative inotropic (+dP/dtmax) and lusitropic (–dP/dtmax) effects in conscious rats. In addition, amiodarone attenuated the tachycardia without affecting the hypertensive, contractile (+dP/dtmax) and lusitropic (–dP/dtmax) responses to dobutamine stress. [ABSTRACT FROM AUTHOR]

Fluvoxamine (FLV), a selective serotonin reuptake inhibitor (SSRI) antidepressant, caused a dose-dependent decrease in rate and contractile force of the isolated guinea-pig atria. These effects significantly blocked by DPCPX, a specific A1receptor antagonist. Theophylline, an A1/A2A receptor antagonist, also prevented the inotropic and chronotropic effect of FLV. The atrium was dissected out and suspended in modified Krebs solution under physiologic conditions. Drug was added to the solution. The changes in rate and contractions were measured using a physiograph. The data indicate that DPCPX and theophylline prevent the inotropic and chronotropic effects of FLV on atria, but these effects were not prevented by atropine and DMPX, an A2 receptor antagonist. Adenosine A1 receptor blockade attenuates FLV effects in isolated guinea-pig atria. [ABSTRACT FROM AUTHOR]

Abstract: We analyzed the influence of endothelin-1 and endocardial endothelium on the myocardial effects of angiotensin-II. Angiotensin-II (10−9–10−5 M) was tested in rabbit right papillary muscles in absence (Protocol-A) or presence of PD-145065 (10−7 M; Protocol-B), BQ-123 (10−7 M; Protocol-C) or losartan (10−6 M; Protocol-E), as well as, after removing the endocardial endothelium with Triton X-100 0.5% (Protocol-D). In Protocol-F increasing concentrations of endothelin-1 (10−10–10−8 M) were added in presence of angiotensin-II (10−7 M) after selective removal of the endocardial endothelium. In Protocol-A, angiotensin-II had dose-dependent positive inotropic and lusitropic effects, maximal at 10−6 M increasing 122±13% active tension, 117±16% dT/dt max and 86±9% dT/dt min. In Protocols B, C and D the inotropic and lusitropic effects of angiotensin-II were significantly attenuated. The same concentration (10−6 M) of angiotensin-II increased respectively 48±11%, 59±27% and 72±16% active tension; 54±14%, 54±20% and 32±9% dT/dt max; and 39±8%, 48±19% and 59±11% dT/dt min; and 40±10%. EC50 for active tension significantly increased from −7.8±0.1 logM in Protocol A to −7.1±0.3, −6.7±0.4 and −6.8±0.3 logM in Protocols B, C and D respectively, while E max decreased from 106±14% in Protocol A to 50±14 and 51±19% in Protocols B and C respectively, but did not significantly change in Protocol D (114±25%). Losartan completely blocked the inotropic and lusitropic effects of angiotensin-II, while the attenuation of these effects after the selective removal of the endocardial endothelium was blunted by concomitant administration of endothelin-1 (Protocol F). In conclusion, angiotensin-II has a dose-dependent positive inotropic effect that depends, to a great extent, on endothelin ETA receptor activation and intact endocardial endothelium. [Copyright &y& Elsevier]

Recent data from our laboratory suggest that sex steroids promote contractile function in cardiac muscle of rainbow trout (Oncorhynchus mykiss Walbaum), and there are sex differences in hormone signaling and cardiac function. The current study investigated whether steroid-induced inotropism in electrically paced (0.5 Hz, 14°C) ventricle strips at 90% Lmax (1) has a metabolic requirement for exogenous glucose and (2) is associated with enhanced intracellular Ca2+ storage and release from the sarcoplasmic reticulum (SR). We also explored whether sex differences exist in extracellular Ca2+ (Ca2+o) or cardiac sensitivity to Ca2+o. In the absence or at low concentrations (1 or 2 mmol l-1) of exogenous glucose, resting tension and relaxation time were increased selectively in cardiac tissue from females. Increasing glucose promoted twitch force in a bell-shaped manner, with 5 mmol l-1 representing the optimal concentration for both sexes. The positive inotropic effects of physiological concentrations of testosterone (T) and 17β-estradiol (E2) in male and female trout ventricle strips, respectively, developed slowly (10–45 min) and were not apparent in glucose-free medium, in medium containing iodoacetate (IAA), an inhibitor of glycolysis, or medium containing 5 mmol l-1 lactate or pyruvate. Male ventricle strips had increased inotropic responses to glucose and T compared with female strips exposed to glucose and E2. Furthermore, sexually maturing males showed a greater inotropic response than immature males or females. Pretreatment with ryanodine (a specific blocker of SR Ca2+ release) also eliminated the inotropic effects of sex steroids and exogenous glucose and reduced the post-rest potentiation of contractile force (a marker of SR Ca2+ storage). By contrast, the inotropic effects of epinephrine (Epi) or elevated Ca2+o were faster (developing within 1–3 min) and were not diminished by the presence or absence of glucose or by pretreatment with IAA or ryanodine. Sex differences were also found in responsiveness to caffeine (males > females) and the relationship between Ca2+ concentration and force development above baseline. The Ca2+50 was lower in female cardiac tissue than males, suggesting greater Ca2+ sensitivity, and although plasma albumin was higher in females, total and ionized plasma Ca2+ did not differ between the sexes. For the first time, our study highlights the importance of extracellular glucose, glycolytic activity and SR Ca2+ storage and release for sex steroid-induced inotropism in the trout ventricle. Conversely, the inotropes Epi and elevated [Ca2+o] do not require the presence or metabolism of exogenous glucose or the SR for signaling their positive effects on contractility. These results also demonstrate novel sex-related differences in cardiac reliance on exogenous glucose, Ca2+ sensitivity and SR function and thus should be considered in future studies. [ABSTRACT FROM AUTHOR]

We previously reported that intramyocardial injection of bone marrow-derived mesenchymal stem cells overexpressing Akt (Akt-MSCs) inhibits ventricular remodeling and restores cardiac function measured 2 wk after myocardial infarction. Here, we report that the functional improvement occurs in < 72 h. This early remarkable effect cannot be readily attributed to myocardial regeneration from the donor cells. Thus, we hypothesized that paracrine actions exerted by the cells through the release of soluble factors might be important mechanisms of tissue repair and functional improvement after injection of the Akt-MSCs. Indeed, in the current study we demonstrate that conditioned medium from hypoxic Akt-MSCs markedly inhibits hypoxia-induced apoptosis and triggers vigorous spontaneous contraction of adult rat cardiomyocytes in vitro. When injected into infarcted hearts, the Akt-MSC conditioned medium significantly limits infarct size and improves ventricular function relative to controls. Support to the paracrine hypothesis is provided by data showing that several genes, coding for factors (VEGF, FGF-2, HGF, IGF-I, and TB4) that are potential mediators of the effects exerted by the Akt-MSC conditioned medium, are significantly up-regulated in the Akt-MSCs, particularly in response to hypoxia. Taken together, our data support Akt-MSC-mediated paracrine mechanisms of myocardial protection and functional improvement. [ABSTRACT FROM AUTHOR]

Abstract: A mechanism underlying the increase in rat heart contractility modulated by BmK I, an α-like scorpion neurotoxin, was investigated using whole-cell patch-clamp and fluorescence digital imaging techniques. Results showed that (a) L-type Ca2+ current could not be modified by 500nM BmK I; (b) The inactivation process of Na+ current was significantly delayed with no change of its amplitude; (c) The overall intracellular Na+ and Ca2+ concentration could be augmented in the presence of BmK I; (p<0.05); (d) The increase of free intracellular Ca2+ concentration induced by BmK I was inhibited completely by 5mM NiCl2 (p<0.05), an inhibitor of Na+–Ca2+ exchanger; (e) The spontaneous Ca2+ release induced by 10mM caffeine from sarcoplasmic reticulum could not be modulated by 500nM BmK I in the absence of external Ca2+. These results indicate that cardiac voltage-gated Na+ channels are also targets of BmK I. Na+ accumulation through Na+ channels can trigger sarcoplasmic reticulum Ca2+ release in rat cardiac myocytes via reverse-mode Na+–Ca2+ exchanger. Furthermore, Ca2+ release from sarcoplasmic reticulum induced by BmK I most likely involves a Ca2+-induced release mechanism. [Copyright &y& Elsevier]

Cardiomyocytes (CMCs) adapt to physiological or pathological stimuli by undergoing molecular changes which differentiate according to the specificity of the stimulus and eventually generate a phenotype with peculiar molecular characteristics. Here, we review the literature on the molecular mechanisms activated in the CMC during physiologic adaptation to stress, as opposed to maladaptation. The critical role of the IGF-1 receptor/PI3K/Akt signaling pathway during this process is described, including effector targets regulating inotropism and cell size. [Copyright &y& Elsevier]

The purpose of this study was to determine whether steroid hormones modulate cardiac function in rainbow trout (Oncorhynchus mykiss Walbaum). We assessed the effects of exogenously administered steroids on isolated ventricle strips and report that physiological concentrations of androgens, 17Β-estradiol and cortisol rapidly (<10 min) enhance inotropism (30–40%) in a sex-specific manner. These effects were specific to the hormones studied, absent if animals were anesthetized chemically and dependent upon steroid concentration and contraction frequency. Based on the use of specific steroid receptor antagonists and key enzyme inhibitors, it appears that testosterone, 11-ketotestosterone and cortisol each act through specific intracellular receptors in males and that the positive inotropism requires the synthesis of polyamines and nitric oxide. Cortisol and 17Β-estradiol, but not androgens, had similar effects in females and also involved similar signaling pathways. Androgen and cortisol effects were additive in males but cortisol and 17Β-estradiol were not additive in females, suggesting sex differences in the pathways through which these hormones stimulate inotropism. In summary, gonadal steroids and cortisol promote ventricular contractility in a sex-dependent manner through mechanisms that appear multifaceted. Ultimately, steroid-mediated improvements in cardiac performance might involve non-genomic pathways and be physiologically important during migration, spawning or stressful periods. [ABSTRACT FROM AUTHOR]

AKT is a serine-threonine kinase involved in several different cellular functions, including the control of cell size and the regulation of survival and metabolism. Many studies have demonstrated that AKT also plays a critical role in the homeostasis of the cardiomyocyte. In these cells, AKT is activated by upstream molecules such as β-adrenergic receptor, insulin-like growth factor-I or insulin receptor, through PI3Kα; whereas its activation is inhibited by the PTEN molecule, Downstream targets of AKT in the cardiomyocyte include glycogen-synthase kinase-3β and S6 kinase. Major effects of AKT activation in the cardiomyocyte are increase in cell size, prevention of apoptosis, and regulation of glucose metabolism. Interestingly, the AKT-dependent hypertrophic pathway is distinct from that activated by MAPKs. In fact, overexpression of AKT does not lead to MAPK activation. Our group has shown, moreover, that AKT exerts a positive effect on both inotropism and relaxation. In fact, mice overexpressing the E40K mutant of AKT in the heart showed improved cardiac function. Thus, AKT increases both cell size through the S6 kinase pathway and inotropism through the functional regulation of critical Ca2+-handling proteins. Therefore, AKT is a critical mediator of physiological hypertrophy. [ABSTRACT FROM AUTHOR]

Putrescine, spermidine and spermine are natural compounds found in up to millimolar concentrations in eukaryotic and prokaryotic cells. At physiologic pH, the polyamines are protonated (+2, +3 and +4 charges), their polycationic properties lead to the assumption that they could affect physiological systems by binding to anionic sites of the cellular membrane and/or by modulating ion channels. At the cardiovascular level, their effects are not completely understood. However, these compounds may be able to exert the induction of synthesis and release of cellular mediators. In an attempt to explore this possibility, we used the isolated and perfused rat heart, Langendorff, model in order to evaluate the inotropic effects of these polyamines, putrescine, spermidine and spermine. Dose–response curves (0.1–0.6 mM) for putrescine, spermidine and spermine were constructed; with the finding that spermine had the largest negative effect. The obtained effects were not blocked by nitric oxide synthesis inhibitors (l-NAME), H1 and H2 receptor antagonists (Brompheniramine and Cimetidine) or by Glibenclamide, an antagonist of ATP-sensitive K+ channels.We found that spermine-induced and increased ATP concentration in cardiac effluents. Reactive Blue, a P2y purinoreceptor antagonist and Aminophylline, an unspecific adenosine receptor antagonist, blocked the spermine-induced effects. These results showed that ATP, at least in part, is responsible of the spermine cardiovascular effects. Adenosine was shown to also play an important role on those effects. [Copyright &y& Elsevier]

Idarubicin (IDA) is a member of an important class of anticancer agents, the anthracycline antibiotics. Although the clinical efficacy of anthracyclines is limited by a high incidence of severe cardiac toxicity, our understanding of IDA transport into the heart is still limited. In a previous study, we demonstrated that IDA is transported into the heart by a saturable mechanism. Based on in vitro data suggesting an enhancement by methylxanthines of IDA influx in leukemia cells, this study was designed to test the hypothesis that a commonly used methylxanthine, caffeine, might influence the myocardial uptake of IDA. In the Langendorff rat heart, after infusion of 0.5 mg IDA during 10 min, the presence of caffeine (1 µM) in perfusate enhanced the residual amount of IDA in the heart by 30% due to a 2.7-fold increase in the maximal uptake rate Vmax. Theophylline (3 µM), in contrast, did not influence the uptake process but caused a slight decrease of fractional myocardial sequestration rate (19% reduction). Caffeine reversed the cardiodepressive action of IDA (49% decrease in left ventricular developed pressure at the end of infusion) to a positive inotropic effect (18% increase of basal level). Theophylline significantly attenuated the negative inotropic effect of IDA (only 21% decrease) and led to positive inotropism in the washout phase (21% increase at the end of experiment). We speculate that co-administration of caffeine may enhance the chronic cardiotoxicity of IDA by increasing its accumulation in the heart. [ABSTRACT FROM AUTHOR]

The effect of aqueous crude extract (ACE) of Eugenia uniflora L. (Myrtaceae) was studied on rat''s perfused ventricles. This plant is used in South American traditional medicine as an antihypertensive and we already demonstrated previously its hypotensive properties. In this paper, maximal left intraventriclular pressure (P) of rat''s hearts beating at 0.2 Hz firstly increased to 162.1±11.1% of basal value during 1–3 min of perfusing ACE 0.6%. Maximum rate of contraction (+P) also increased to duplicating +P/P ratio. Both types of effect were significantly decreased by either propranolol 0.35 μM, and pre-treatment with reserpine (5 mg/kg), suggesting that they were caused by a compound that releases cathecolamines with β-adrenergic action. Nevertheless, after 20 min of perfusing ACE, ventricles decreased P to about 50% of their basal value, suggesting a negative-inotropic compound present in the extract. The perfusion of 1.2% ACE decreased P in a pressure–[Ca]o curve (0.5–2 mM) in a non-competitive manner, suggesting that an irreversible Ca-blocking compound is also present in the extract. In summary, E. uniflora ACE has a dual effect on the heart related to its hypotensive action and is probably responsible for the therapeutic or adverse effects in patients under cardiac risk. [Copyright &y& Elsevier]

The electrophysiological and mechanical effects of HNS-32, a novel azulene-1-carboxamidine derivative with antiarrhythmic activity, were studied in isolated guinea-pig myocardial preparations. HNS-32 (10[sup –6] –10[sup –4] mol/l) concentration-dependently decreased the maximum rate of rise (V[sub max] ) of action potential in isolated papillary muscle; the potency was the same or slightly higher than that of disopyramide. At 10[sup –4] mol/l, HNS-32 also shortened the action potential duration (APD) and depolarized the resting membrane potential; these effects were similar to those of 10[sup –5] mol/l verapamil. HNS-32 (10[sup –7] –10[sup –4] mol/l), as well as verapamil (10[sup –8] –10[sup –5] mol/l) and disopyramide (10[sup –6] –10[sup –3] mol/l), had concentration-dependent negative chronotropic and negative inotropic effects on isolated right atrial and right ventricular papillary muscle preparations, respectively. The concentration-response relationship for the positive chronotropic effect of isoproterenol was not affected by HNS-32 (10[sup –5] mol/l). In isolated ventricular myocytes, HNS-32 (10[sup –6] –10[sup –4] mol/l) concentration-dependently inhibited the peak amplitude of the L-type Ca[sup 2+] current. These results suggest that NHS-32 has V[sub max] reducing activity on myocardial tissue, which may be responsible for antiarrhythmic effect. The drug may also have additional effect on the Ca[sup 2+] channel at higher concentrations.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

SUMMARY 1. Many diseases are associated with elevated endothelin (ET)-1 plasma concentrations. In order to understand the consequence of this elevation, in the present study the effects of exogenous ET-1 on the entire organsim were investigated, in particular with respect to the role of ETA and ETB receptors in the cardiovascular system. In open-chest rabbits, left ventricular (LV) pressure (LVPmax, LVPed), dP/dtmax and dP/dtmin were recorded in ejecting and isovolumically beating hearts to determine cardiac function. In addition, heart rate (HR), aortic pressure (AoP) and aortic flow (AoF) were measured. Total peripheral resistance (TPR) was calculated from mean AoP and AoF. 2. In the first series of experiments (n = 11), ET-1 (0.5 nmol/kg; bolus) produced a non-significant reduction in HR. Systolic function, in terms of AoF, LVPmax and dP/dtmax, was improved; for example, LVPmax was increased significantly (69 ± 10 vs 106 ± 20 mmHg for control and ET-1, respectively; P < 0.05). Similarly, early relaxation (dP/dtmin) was improved. In parallel, TPR rose significantly (0.25±0.07 vs 0.35±0.1 mmHg/min per mL for control and ET-1, respectively; P < 0.05). Isovolumic measurements showed corresponding responses. 3. In the second series of experiments (n = 7), animals were pretreated with an ETA receptor antagonist (330 nmol/min per kg FR 139317). After ETA receptor blockade, the administration of ET-1 had no significant effect on cardiac function or vasomotion. 4. In the third series of experiments (n = 6), animals were pretreated with an ETB receptor antagonist (10 nmol/min per kg BQ 788). In this series of experiments, the effects of ET-1 on cardiac function and vasomotion were the same as in the first series of experiments, except for the effect on HR, which decreased by 35% after ET-1. 5. In our experimental model, exogenous ET-1 exerted a clear-cut positive inotropic effect, together with the anticipated peripheral vasoconstriction via ETA receptors. [ABSTRACT FROM AUTHOR]

The effects of theophylline upon cardiovascular function were studied in 8 male subjects, aged 22-33 years, before and during concomitant administration of metoprolol (50 mg every 6 h) and propranolol (40 mg every 6 h). Theophylline, as aminophylline (6.7-7.3 mg/kg) was given over 30 min. The theophylline level five minutes after completion of the aminophylline infusion was 15.9±1.8 µg/ml in the absence of beta blockade, 16.1±1.7 µg/ml during metoprolol, and 15.1±1.6 µg/ml during propranolol. Theophylline produced a 7% increase in mean arterial pressure which was not attenuated by either metoprolol or propranolol. Heart rate was not changed by theophylline. The QS Index (QSI), a sensitive indicator of inotropism, was shortened from 488±16 to 476±16 msec ( p<0.01) by theophylline alone. After administration of metoprolol or propranolol, theophylline produced no shortening of the QSI. Theophylline has a mild inotropic effect in healthy subjects. This effect is prevented by pretreatment with beta-adrenergic antagonists. [ABSTRACT FROM AUTHOR]

We compared the oxygen cost of increasing ventricular contractility using Emax (slope of the ventricular end-systolic pressure-volume relation) as the index of ventricular contractility. Contractility was enhanced by calcium and epinephrine in paired experiments on dog left ventricles. Firstly, we obtained left ventricular oxygen consumption (Vo) and systolic pressure-volume area (PVA, a measure of total mechanical energy) of contractions at different volumes in the control contractile state to determine a reference Vo-PVA relation. PVA was obtained as the area in the pressure-volume (P-V) diagram which was bounded by the end-systolic P-V line, end-diastolic P-V curve and systolic P-V trajectory of individual contractions. Secondly, we gradually enhanced Emax with calcium and epinephrine in two consecutive runs at a fixed ventricular volume. Both Vo and PVA increased with enhanced Emax. From these Vo-PVA data, we calculated the PVA-independent Vo values at the respective enhanced Emax levels and determined the oxygen cost of Emax as the slope of the relation between the PVA-independent Vo and Emax. The cost per beat and per 100g was 0.00158ml O/ (mmHg/ml) for calcium and 0.00166 ml O/(mmHg/ml) for epinephrine on average, values not significantly different from each other ( P < 0.05). We conclude that epinephrine and calcium have similar oxygen costs of contractility over a wide range of Emax despite their different pharmacological mechanisms of positive inotropism. [ABSTRACT FROM AUTHOR]

To investigate the controversial effects of hypothermia on cardiac contractile performance, we have carried out ventricular volume-loading experiments in 23 perfused, paced (2 Hz), isolated rat hearts, contracting isovolumically at various temperatures. A water-filled, unstressed latex balloon was inserted into the left ventricle and its volume was controlled with a microsyringe. Left ventricular pressure (LVP), its first derivative (d P/d t) and coronary flow were recorded. One group of hearts ( n=7) were perfused at 37°C over 2 h. Another group of hearts ( n=16) were cooled in a stepwise manner from 37°C to 21°C, with 10-min perfusion at each of seven different temperatures, and then rewarmed to 37°C. E, an index of contractility, calculated as the slope of the regression line of the end-systolic pressure-volume relationship, was found to increase as temperature fell (3.9, 4.6, 4.9, 5.5, 5.5, 6.2, and 6.3 cm HO/µl at 37°, 34°, 31°, 29°, 27°, 24° and 21°C, respectively) while it remained constant over the 2-h perfusion in the normothermic perfusion group. By contrast, peak positive d P/d t/ peak-developed pressure (+d P/d t/DP) progressively decreased during cooling without any change in the normothermic perfusion group. The results indicate that hypothermia can be designated as a positive inotropic intervention in terms of forcegeneration (E) but as a negative inotropic intervention in terms of shortening velocity of contractile element in Hill's model (+d P/d t/DP). [ABSTRACT FROM AUTHOR]