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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]

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]

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 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]

The responsiveness to ouabain of hypertrophied rat hearts has been investigated either in vivo using an isolated Langendorff rat heart perfused at various external calcium concentrations, or in vitro on purified sarcolemma vesicles. (i) The physiological study shows that at 0.25 mM CaCl, the positive inotropic effect of 10 M ouabain was diminished in hypertrophied hearts ( p<0.02). At 0.5 mM CaCl, the drug has no effect in controls, but it has a slight positive inotropic effect in hypertrophied hearts. At 2.50 mM CaCl, ouabain has a negative inotropic effect accompanied by extrasystoles in controls, but in hypertrophied hearts it still has a positive inotropic effect and is not arrhythmogenic. (ii) After the pretreatment of the hearts with 2.5 mM CaCl, the responsiveness of the (Na, K)-ATPase activity to ouabain was studied: the sarcolemma from hypertrophied heart contains half as many low affinity forms of (Na, K)-ATPase for ouabain (35%±6) than in controls (80%±2). Assuming that the low affinity forms are responsible for the toxic effect, these data correlate well with some of the physiological findings and suggest that the diminished toxicity for ouabain in hypertrophied hearts rather reflects a modification of the properties of the (Na, K)-ATPases than a change in the myocardial calcium metabolism. [ABSTRACT FROM AUTHOR]

The agonist (−)-denopamine was used as a tool to study relationships between pharmacological effects and adenylate cyclase stimulation mediated through β-adrenoceptors. [ABSTRACT FROM AUTHOR]

Recently it has been reported that some dihydropyridine calcium channel antagonists (nifedipine, nimodipine, nitrendipine) are able to produce positive inotropic effects in isolated perfused guinea pig hearts. We studied the effects of nifedipine in isolated perfused paced rat hearts under constant pressure and constant flow perfusion conditions. We found that nifedipine is able to produce a positive inotropic effect under constant pressure conditions but not under constant flow conditions. We conclude that nifedipine does not have partial calcium channel agonistic properties and that the positive inotropic effect seen under constant pressure conditions is a result of the vasodilating properties of the drug. Positive inotropic effects caused by vasodilatation can be explained by the 'garden-hoseeffect'. [ABSTRACT FROM AUTHOR]

The chronotropic and inotropic effects of isoproterenol, adrenaline and phenylephrine were examined in isolated right and left rabbit atria. [ABSTRACT FROM AUTHOR]

Three β-adrenoceptor-related parameters were measured for 23 agonists on kitten ventricular myocardium: inotropic potencies (EC's) on papillary muscles, intrinsic activities for stimulation of the adenylyl cyclase in membrane particles, and affinities for β-adrenoceptors labelled with H-(−)-propranolol in membrane particles. For catecholamines a dissociation between inotropic potencies and β-adrenoceptor affinities was observed. Inotropic potencies are 1.3-1.8 orders of magnitude higher than affinities. This dissociation between inotropic activation and binding is similar for (+)- and (−)-enantiomers of catecholamines, despite the higher affinities of the latter. The dissociation is considerably smaller for dopamine and dobutamine, which suggests a role of the β-OH group in the phenomenon. The effect is also smaller with resorcinols than with catechols; it decreases further, or is not observed at all, when one of the ring hydroxyl groups is replaced or absent. With most agonists the degree of dissociation appears to be directly proportional to the degree of adenylyl cyclase stimulation. About 1/4 of maximum adenylyl cyclase stimulation suffices to activate the inotropic processes fully. It is suggested that both the magnitude of the dissociation and the degree of adenylyl cyclase activation are indicators of the degree of change induced by agonist in the conformation of the β-adrenoceptor. The production of marked inotropic effects by noradrenaline and adrenaline with low β-adrenoceptor occupancy and little adenylyl cyclase stimulation may permit the regulation of heart function. Conditions of desensitization that reduce maximum activation of the adenylyl cyclase may not necessarily reduce maximum inotropic effects of these catecholamines. The agonist (±)-hydroxybenzylpindolol caused positive inotropic effects only at high β-adrenoceptor occupancy. This is consistent with the idea that sufficient conformational change occurs only near receptor saturation. [ABSTRACT FROM AUTHOR]

Melting points measured with the capillary method were 150.5°C, 150.5°C and 224.0°C for hydrochlorides of (+)-bupranolol, (−)-bupranolol and (±)-bupranolol, respectively. The large difference in melting points of 73.5°C prompted us to determine possible contaminations of (+)-bupranolol with traces of (−)-bupranolol using differential scanning calorimetry. We detected as little as 0.001% (−)-bupranolol in a standard mixture of (+)-bupranolol and (−)-bupranolol. A batch of (+)-bupranolol not measurably contaminated with (−)-bupranolol (optically purity>99.999%) was used in pharmacological and biochemical assays. The affinities of (−)-bupranolol and (+)-bupranolol were determined functionally by the blockade of isoprenaline stimulation of spontaneously beating rat right atria and electrically driven kitten papillary muscles; and directly by the inhibition of binding of H-(−)-propranolol to kitten ventricle membrane particles. In all 3 systems the enantiomeric (−)/(+) affinity ratio was 50-120 for bupranolol. These experiments prove that (+)-bupranolol itself binds to the β-adrenoceptors of mammalian myocardium. [ABSTRACT FROM AUTHOR]

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