Ro 40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction.

Ro 40-5967 is a new calcium antagonist that binds to the same binding site as verapamil but that has been shown to have a much lesser negative inotropic effect than verapamil. The goal of the present study was to compare the effects of Ro 40-5967 and diltiazem on left ventricular contractility in vitro and in vivo in normal rats and in rats with chronic myocardial infarction induced by ligating the left coronary artery. Left ventricular contractility was assessed in vitro in isolated perfused hearts and in vivo in conscious rats by measuring left ventricular dP/dtmax + and dP/dt at P 40. In vitro, both Ro 40-5967 and diltiazem did not decrease cardiac contractility up to a dose producing complete atrioventricular block. In vivo, diltiazem decreased dP/dtmax + and dP/dt at P 40. Ro 40-5967 was less negative inotropic than diltiazem. We conclude that if these results were confirmed in clinical trials. Ro 40-5967 might be a safer drug than diltiazem, especially in patients with left ventricular dysfunction.     

Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart

Levosimendan is a novel calcium sensitizer that increases contraction force without change in intracellular calcium ([Ca2+]i); milrinone is a phosphodiesterase inhibitor that exerts a positive inotropic effect by increasing [Ca2+]i. The effects of levosimendan and milrinone on oxygen consumption in the isolated guinea-pig heart were studied. Isolated guinea-pig hearts were paced (280 beats/min) and perfused according to the Langendorff technique. Levosimendan (0.01-1 microM) or milrinone (0.1-10 microM) were added cumulatively and changes from baseline for diastolic and systolic pressure (LVEDP and LVSP), contractility and relaxation (+dP/dt and -dP/dt), and coronary flow and oxygen consumption (CF and VO2) were calculated. Levosimendan was found to be 10 to 30 times more potent than milrinone as an inotropic agent. The effect on VO2 was markedly lower in levosimendan-perfused hearts than in milrinone-perfused hearts (P = 0.031 between the concentration-dependent effects of the two drugs). The maximum increase in VO2 was 10 +/- 4% in the levosimendan group and 38 +/- 15% in the milrinone group. The economy of the contraction was more advantageous in levosimendan-perfused hearts (P 相似文献   

The effects of aging on the electrophysiologic and hemodynamic responses to nifedipine in isolated perfused hearts.

Age effects on responses to calcium channel blockade with nifedipine were studied in isolated Langendorff-perfused Fischer 344 rat hearts. Responses to 25 min of perfusion with nifedipine concentrations of 0, 25, 50, 75, and 100 ng/ml were studied in hearts from 11 mature (6 months) and 13 senescent (23-27 months) male F344 rats. Nifedipine produced significant increases in the atrial cycle length (p less than 0.001), paced atrioventricular (AV) conduction time (p less than 0.001), AV Wenckebach cycle length (p less than 0.001), left ventricular (LV) diastolic pressure (p less than 0.001), and decreases in LV systolic pressure (p less than 0.001) and peak dP/dt (p less than 0.001) in hearts from both mature and senescent rats. Greater decreases in the atrial rate (p less than 0.05) and depression of peak dP/dt (p less than 0.05) were detected in senescent vs. mature rat hearts. No age difference in responses of AV conduction parameters were detected although increases in the AV Wenckebach cycle length appeared to be greater in senescent hearts at concentrations greater than 75 ng/ml.     

Cardioplegic arrest of the myocardium with calcium blocking agents.

This study was designed to compare the effects of the calcium slow channel blocking agents verapamil (0.15 mg/kg), diltiazem (0.15 mg/kg), and nifedipine (50 micrograms/kg) on the myocardium after global ischemia and reperfusion in the in situ canine model. Animals were subjected to 120-min normothermic global ischemia, followed by 45-min reperfusion. Cardioplegic arrest of the myocardium was achieved by administering one of the three calcium antagonists in a multidose fashion. Superior preservation (p less than 0.01) of left ventricular (LV) systolic function was achieved in group I (verapamil cardioplegia). dP/dt, at an intraventricular balloon volume of 25 cc, was 83% of control after reperfusion in group I. Group II (diltiazem) and group III (nifedipine) achieved only 55 and 63% of their preischemic dP/dt values. LV chamber stiffness was increased in hearts protected with nifedipine. The exponential constant m was increased from 0.04 +/- 0.01 to 0.08 +/- 0.01. Coronary blood flow after reperfusion increased from 120 to 184 cc/100 gr/min in group I (p less than 0.01). The hyperemic response in group III was negligible. The O2 consumption of the reperfused myocardium was not significantly altered in any of the treatment groups. Lactate metabolism during ischemia and after reperfusion was similar in all groups. ATP values were markedly reduced in all groups (p less than 0.05). Immediately after ischemia, ATP was 50, 28, and 44% of control in group I, II, and III, respectively. The excellent preservation of systolic function and a physiologic hyperemic response by verapamil could not be correlated with improved preservation of high-energy compounds or with significant changes in myocardial O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

The positive inotropic effect of glucagon in the chronically failed right ventricle as demonstrated in the isolated cat heart.

Previous in vitro studies had provided evidence to show that papillary muscles obtained from cats with chronic right ventricular failure had lost their ability to develop a positive inotropic response to glucagon. Since it is difficult to extrapolate from the isolated papillary muscle to the intact heart, studies were done to assess the effects of glucagon in the perfused isovolumically beating heart obtained from cats four months after surgical banding of the pulmonary artery for the experimental production of chronic right ventricular failure (CRVF). At the peak of the dose-response curve, glucagon increased right ventricular isovolumic pressure 25% (39.00 +/- 4.37 to 49.67 +/- 5.15 mm Hg; p less than 0.001) and right ventricular dP/dt 63% (522.2 +/- 93.9 to 852.6 +/- 159.9 mm Hg/sec; p less than 0.001) in 6 normal hearts. Similar dose related increases in right ventricular isovolumic pressure and dP/dt were obtained in 6 hearts taken from cats with chronic right ventricular failure. The respective increases in right ventricular isovolumic pressure and dP/dt were 43% (30.33 +/- 4.01 to 43.67 +/- 6.25 mm Hg; p less than 0.025) and 73% (317.50 +/- 30.29 to 550.83 +/- 89.04 mm Hg/sec; p less than 0.025). These results provide evidence that glucagon possesses the capacity to augment myocardial contractility in the heart with experimentally induced chronic right ventricular failure.     

The effect of external calcium concentration on the negative inotropic action of dantrolene in isolated hyperthyroid and euthyroid heart

The effect of altering external calcium concentration [Ca2+]o on the negative inotropic action of dantrolene was tested in Langendorff-perfused hearts from euthyroid and hyperthyroid rats. Elevated contractility was demonstrated in the hyperthyroid hearts at all the [Ca2+]o tested. At a [Ca2+]o of 1.25 mM (physiological), dantrolene (5 x 10(-5) M) significantly reduced contractility (dP/dtmax) in hyperthyroid but not in euthyroid hearts (-42% and -4% of zero-time values at 12 min perfusion, respectively). When hearts from both groups were paced at 375 beats/min, dantrolene again exerted a greater negative inotropic action in the hyperthyroid preparations, showing that the effect was not heart rate related. Elevating the [Ca2+]o did not further affect the time course of dantrolene action in hyperthyroid hearts. In euthyroid hearts, however, raising the [Ca2+]o to 2.5 and 3.75 mM caused a progressive increase in the negative inotropic action of dantrolene (-15% and -56% of zero-time values at 12 min perfusion, respectively). Our results demonstrate that dantrolene exerts a negative inotropic action which at physiological [Ca2+]o is greater in the hyperthyroid than in the euthyroid heart thus indicating that calcium handling by the myocardium is altered in the hyperthyroid state. However, dantrolene action in the rat myocardium is more complex than was at first believed; as in euthyroid hearts, its negative inotropic action appears to be increased rather than reduced by increases in [Ca2+]o.     

Effects of platelet-activating factor on myocardial contraction and myocardial relaxation of isolated perfused guinea pig hearts.

Platelet-activating factor (PAF) is an important mediator of cardiovascular shock owing to immunologic reactions, including anaphylaxis and endotoxaemia. Previous studies have shown that PAF is a potent cardio-depressive agent causing a marked coronary constriction and a sustained impairment of myocardial contractility. In this study, we attempted to characterize further the prolonged PAF effects on coronary circulation and myocardial contractile force in isolated guinea pig hearts perfused at constant pressure (60 cm H2O) or constant flow which was adjusted to a level of 100% above basal flow. In addition, the PAF-induced changes of ventricular systolic and diastolic function were distinguished. In the hearts perfused at constant pressure, PAF induced a dose-dependent (0.57, 5.7, and 57 pmol/min) decrease of coronary flow rates, left ventricular pressure (LVP), LV contraction (peak positive dP/dt) and LV relaxation (peak negative dP/dt). The decrement of peak negative dP/dt was more pronounced than that of peak positive dP/dt. Maintenance of coronary flow rates only attenuated, but did not suppress, the PAF-induced ventricular malfunction, and it improved ventricular relaxation less than it did ventricular contraction. Pretreatment with the PAF antagonist WEB 2086 (19.7 nmol/min) almost completely abolished the effects of the highest PAF dose on coronary circulation and ventricular contractile parameters. We conclude that the cardiodepressive effects of PAF are due to coronary constriction and direct contractile events. Furthermore, PAF impairs ventricular diastolic function more than ventricular systolic function.     

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.     

Ca(2+)-sensitizing effect is involved in the positive inotropic effect of troglitazone

1. Troglitazone, an insulin sensitizing agent, has a direct positive inotropic effect. However, the mechanism of this effect remains unclear. Thus, we examined the inotropic effect of troglitazone while focusing on intracellular Ca2+ handling. 2. Troglitazone significantly increased peak isovolumic left ventricular pressure (LVP(max)), peak rate of rise of LVP (dP/dt(max)), peak rate of fall of LVP (dP/dt(min)) in isolated rat hearts perfused at a constant coronary flow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein kinase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca(2+)-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). 3. Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. 4. Whole-cell patch clamp analysis revealed that troglitazone had no effect on inward Ca2+ currents in cardiomyocytes. 5. In fura-2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca2+ concentration. 6. These results suggest that neither the inward Ca2+ currents nor Ca2+ handling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effect without affecting the intracellular concentration of Ca2+. 7. In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.     

Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure.

To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.     

Effects of intracoronary Bay k 8644, a calcium channel agonist, in anesthetized dogs

Bay k 8644, a new dihydropyridine calcium channel activator has been shown to have positive inotropic and vasoconstrictor properties following intravenous (i.v.) administration. In the present study, intracoronary administration of Bay k 8644 was used to isolate drug effects on regional myocardial blood flow and contractility independent of systemic hemodynamic actions in beta-adrenoceptor-blocked anesthetized dogs. Intracoronary infusion of Bay k 8644 (1.5, 3.7, 7.4, 14.8 micrograms/min) produced significant increases in contractility (percentage of segment shortening) in the drug-perfused region. Peak positive dP/dt, an index of global contractility, was increased in parallel with increases of regional contractility. No other changes in systemic hemodynamics occurred. Transmural tissue blood flow distribution as measured by radioactive microspheres was also unchanged by Bay k 8644. Intracoronary infusion of KB-944, a nondihydropyridine calcium channel blocking agent, increased coronary blood flow and decreased regional segment shortening and peak positive dP/dt. KB-944 inhibited increases in contractility produced by Bay k 8644. Thus, Bay k 8644 was shown to have a direct positive inotropic effect in vivo which was inhibited by calcium channel blockade.     

Effects of OPC-8212, a new positive inotropic agent, and dobutamine on left ventricular global and ischemic regional functions and coronary hemodynamics under coronary artery stenosis

We have investigated the effects of OPC-8212, a new positive inotropic agent, and dobutamine, a known cardioselective inotropic agent, on global left ventricular (LV) and ischemic regional functions in 14 excised canine hearts with a flow-limiting stenosis of the left circumflex coronary artery (LCX) (i.e., 20-25% of control flow). OPC-8212 infusion (n = 7) under LCX stenosis improved cardiac depression [i.e., peak LV dP/dt increased from 1,295 +/- 143 mm Hg/s to 2,669 +/- 266 mm Hg/s (mean +/- SEM) (p less than 0.001)], while myocardial ischemic injury, assessed by myocardial CO2-tension and electrocardiogram (ECG)-ST changes, improved (i.e., delta CO2-tension and ECG-ST deviation decreased from 21.1 +/- 3.6 mm Hg and 3.8 +/- 0.6 mV to 13.3 +/- 2.8 mm Hg (p less than 0.01) and 2.0 +/- 0.7 mV (p less than 0.05), respectively). On the other hand, dobutamine infusion (n = 7) further increased myocardial CO2-tension and ECG-ST deviation [i.e., delta CO2-tension and ECG-ST deviation increased from 14.4 +/- 4.2 mm Hg and 2.5 +/- 1.2 mV to 29.0 +/- 6.0 mm Hg (p less than 0.01) and 4.9 +/- 1.0 mV (p less than 0.01), respectively]. At the same time, peak LV dP/dt clearly improved, but to a lesser degree; from 1,425 +/- 153 mm Hg/s to 2,393 +/- 245 mm Hg/s (p less than 0.001). There was also an increase in percent systolic segment shortening of each corresponding area as with OPC-8212.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative cardiac effects of KT-362 and verapamil in isolated heart--correlation to calcium channel current depression.

Direct cardiac effects of KT-362 (5-[3 [[-2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a drug that may inhibit intracellular calcium mobilization as well as extracellular calcium influx was compared to verapamil. Guinea pig hearts (n = 19) were used to examine the changes in atrial rate, atrioventricular conduction time (AVCT), coronary flow, myocardial oxygen consumption (MVO2), and isovolumetric left ventricular pressure (LVP). Both drugs concentration-dependently and reversibly decreased atrial rate, contractility, and MVO2; AVCT increased during spontaneous rhythm. The increases in AVCT and the incidence of AV dissociation were accentuated during cardiac pacing. Verapamil significantly increased coronary flow, while KT-362 did not. Median effective concentration (EC50) was about 25 times lower for verapamil in depressing LVP and about three times lower in depressing atrial rate and AV conduction. The changes in calcium channel current in voltage-clamped single canine Purkinje cells (n = 6) were also examined. Verapamil (0.3 microM) and KT-362 (7 microM) decreased peak Ca2+ channel current at maximum activation (+10 mV) by 38.1 +/- 8% and 28.6 +/- 6%, respectively, without shifting the current-voltage relationship. This study indicates that verapamil is more potent than KT-362 in depressing contractile function, heart rate, and AV conduction in isolated hearts and calcium current in isolated cardiac Purkinje cells. Moreover, there was a much greater difference between the EC50 for verapamil and that for KT-362 for the depression of indices of contractility (23-30-fold) than for the depression of sinoatrial and atrioventricular nodal function (2.5-4-fold).     

Hemodynamic effects of different calcium antagonists in the heart-lung preparation of the guinea pig

The present study was performed with the aim to demonstrate and quantify the influence of several different calcium antagonists (CA) on hemodynamic parameters in the guinea pig heart lung preparation (HLP). In paced HLP the following parameters were recorded: dp/dt max; cardiac output (CO); left ventricular pressure (LVP), and aortic pressure (AoP). In separate experiments the influence of the CA on heart rate (HR) was established in spontaneously performing HLP. All CA studied reduced or depressed dp/dt max, CO, LVP, AoP and HR. Nifedipine and verapamil showed the strongest depressant influence on dp/dt max and CO, whereas diltiazem caused a moderate reduction of these parameters. Lidoflazine, flunarizine and bepridil proved considerably less potent than nifedipine, verapamil and diltiazem. Bepridil proved least potent with respect to the influence on LVP and AoP. The strongest reduction on HR was caused by nifedipine greater than verapamil greater than diltiazem, and to a lesser degree by lidoflazine. Bepridil and flunarizine only caused a mild reduction of HR. From the calculated ratio EC20(HR)/EC20(dp/dt max) it is obvious that nifedipine, verapamil and bepridil display a much stronger influence on contractility than on HR. dp/dt max proved the most sensitive indicator for contractility in the HLP as used in our experiments.     

Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats

Calcium channel antagonists (CCAs) have been proposed to prevent cardiac events after myocardial infarction (MI). However, unwanted effects, such as negative inotropy, limit their use in many cases. The aim of this study was to compare the effects of long-term treatment with the CCAs, mibefradil, verapamil, and amlodipine, administered before and after chronic MI on myocardial remodeling and cardiac function. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Infarcted animals were treated with placebo, mibefradil (10 mg/kg/d po), verapamil (8 mg/kg bid po), or amlodipine (4 mg/kg/d po). Treatment was started 7 days before or 3 h after MI induction. Six weeks after MI, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), and cardiac contractility (dP/dt(max)) were measured. Morphometric parameters such as infarct size (IS), left ventricular dilation (LVD), septal thickness (ST), and cardiac fibrosis were determined in picrosirius red-stained hearts. Six weeks after MI, MAP and dP/dt(max) were decreased, whereas LVEDP and HR were increased in placebo-treated controls. The hearts featured an IS of 45%, left ventricular dilation, cardiac fibrosis, and septal thinning. MAP of all CCA-treated animals was increased, whereas LVEDP was decreased and dP/dt(max) increased 7-day pre- and 3-h post-MI started in mibefradil- and amlodipine-treated animals, but not in verapamil-treated animals. In contrast to amlodipine treatment, before and after MI started mibefradil and verapamil treatment decreased HR. Pretreatment with all CCA reduced IS and increased ST, whereas only mibefradil and amlodipine pretreatment prevented LVD and cardiac fibrosis. After MI started treatment with mibefradil and amlodipine reduced IS and cardiac fibrosis, and increased ST. Long-term treatment with the CCAs mibefradil, verapamil, and amlodipine reduced myocardial remodeling and improved cardiac function in MI-induced heart failure in rats.     

The Ca2+ -antagonist and binding properties of the phenylalkylamine, anipamil.

1. Isolated, Langendorff-perfused rat hearts, isolated membranes, and pharmacological and receptor binding techniques were used to study the properties of the newly developed verapamil derivative, anipamil. 2. When added acutely to isolated, spontaneously beating or electrically paced hearts, anipamil (0.01-0.15 microM) exerted a dose-dependent negative inotropic effect which developed slowly and persisted after 60 min washout. 3. When added acutely (0.05-0.1 microM) to isolated hearts, or when given intravenously (2 mg kg-1 body weight 1 h before the animals were killed), anipamil displaced the dose-response curves for the positive inotropic effect of (0.10-3.0 mM) Ca2+ and (10-50 nM) Bay K 8644 to the right. 4. When added to freshly isolated cardiac membranes, 0.1 microM anipamil increased the dissociation constant (KD) of the phenylalkylamine (-)-[3H]-desmethoxyverapamil ((-)-[3H]-D888) from 1.22 +/- 0.2 to 2.91 +/- 0.46 nM, without any significant change in density (Bmax; control: 163 +/- 17; anipamil: 117 +/- 20 fmol mg-1 protein). Bound (-)-[3H]-D888 was displaceable by (-)-D888 (Ki 1.7 +/- 0.4 nM) greater than (-)-D600 (Ki 12 +/- 0.5 nM) greater than verapamil (Ki 55 +/- 11 nM) greater than (+)-D600 (Ki 108 +/- 12.2) greater than anipamil (Ki 471 +/- 52 nM). 5. In cardiac membranes isolated from rats pretreated with anipamil (2 mg kg-1 i.v.) 1h before they were killed, the KD of (-)-[3H]-D888 binding was increased (P less than 0.05) from 1.59 +/- 0.18 to 3.28 +/-0.65 nM with no significant change in density, compared to the placebo-treated (control) rats. 6. These results establish that anipamil interacts in a competitive manner with the phenylalkylamine binding sites in cardiac membranes, and that it resembles other Ca2+ antagonists in displacing the dose-response curve for the positive inotropic effect of Ca2+ to the right. The results also show that although anipamil binds tightly to the cardiac membranes, it binds to the (-)-[3H]-D888 recognition sites less potently than (-)-D888, (-)-D600 or verapamil.     

Effect of chlorpromazine on myocardial damage in the calcium paradox

Prevention of myocardial cell death is an important goal in the treatment of myocardial infarction. The potential benefit of chlorpromazine in myocardial injury was assessed in the isolated rabbit heart under conditions of the calcium paradox. A period of 20 min of calcium-free perfusion followed by reintroduction of calcium was associated with myocardial damage, as indicated by severe impairment in left ventricular contractile function and marked loss of protein and enzymes (aspartate aminotransferase) from the myocardium. Chlorpromazine, 15 or 25 mg/kg, was given intravenously 30 min before excision of the heart. Chlorpromazine was associated with significant (p less than 0.05) improvement in left ventricular function, as indicated by larger developed pressure, greater peak positive and negative dP/dt, and lower left ventricular end-diastolic pressures. Chlorpromazine pretreatment was associated with significant (p less than 0.05) reduction in the amount of enzyme and protein lost from the myocardium. Thus, chlorpromazine can reduce the severity of myocardial cell injury.     

Mibefradil is more effective than verapamil for restoring post-ischemic function of isolated hearts of guinea pigs with acute renal failure

The deleterious intracellular Ca(2+) overload in the ischemic-reperfusion injury of the heart can be even more expressed in subjects with acute renal failure in whom maintenance of intracellular Ca(2+) has already been disturbed in normoxia. To study the influence of acute renal failure in ischemic-reperfusion injury on the heart, we used isolated Langendorff's hearts of guinea pigs with gentamicin-induced acute renal failure. We examined arrhythmias, heart contractility and myocardial cell damage during reperfusion. Two specific Ca(2+) channel antagonists, mibefradil (0.1 and 1 microM) and verapamil (0.1 microM), were used to test the possible involvement of T-type and L-type Ca(2+) channels in these processes. We exposed hearts to 50 min of zero-flow global ischemia and 60 min of reperfusion. During reperfusion, unrecoverable ventricular fibrillation appeared more often in hearts of animals with acute renal failure than in control hearts (80% vs. 0%, respectively). Mibefradil, but not verapamil, applied either pre- or post-ischemically, terminated ventricular fibrillation in all hearts of animals with acute renal failure. Mibefradil (0.1 microM only) improved contractility in hearts of animals with acute renal failure during reperfusion by 30%. During reperfusion, lactate dehydrogenase (LDH) release rate increased less in hearts of guinea pigs with acute renal failure than in control hearts and only verapamil decreased it additionally. Thus, our results suggest a more important role of T- than of L-type Ca(2+) channels in ischemic-reperfusion injury in isolated guinea pig hearts with acute renal failure.     

Hemodynamic and cardiac effects of nicardipine in patients with coronary artery disease

The hemodynamic and cardiac effects of the calcium antagonist nicardipine, alone (n = 10 patients) or combined with propranolol (0.1 mg/kg i.v.; n = 9 patients), were assessed in patients with coronary artery disease. In the absence of beta-blockade, nicardipine (5 or 10 mg i.v.) increased heart rate (+23 and +15 beats/min after 5 and 10 mg, respectively; p less than 0.01) and cardiac output (from 4.7 +/- 1.1 to 7.4 +/- 1.3 L/min after 5 mg and from 5.1 +/- 1.1 to 8.6 +/- 1.6 L/min after 10 mg; p less than 0.005). Systemic vascular resistance decreased with both doses (-46 and -57%; p less than 0.005), whereas mean aortic pressure decreased by 14 mm Hg after 5 mg and by 28 mm Hg after 10 mg (p less than 0.004); left ventricular end-diastolic pressure was unchanged. Nicardipine also decreased significantly end-systolic left ventricular volume and increased ejection fraction (from 63 to 71% after 5 mg and from 54 to 63% after 10 mg; p less than 0.008) and velocity of shortening. Peak (+) dP/dt and (dP/dt)/DP40 (value of dP/dt at a developed pressure of 40 mm Hg) were unchanged, and Emax, the maximal left ventricular pressure/volume ratio, improved slightly (+8%; p less than 0.05). After beta-blockade, nicardipine (2.5 mg i.v.) still decreased mean aortic pressure (-16 mm Hg; p less than 0.05) and systemic vascular resistance, and improved the ejection phase indices; cardiac output and ventricular relaxation, both depressed after propranolol administration, were also normalized after infusion of nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous endothelin on hemodynamics and cardiac contractility in conscious Milan normotensive rats.

The effects of endothelin-1 (ET-1) on hemodynamics and cardiac contractility were compared with the responses to angiotensin I (AI) and phenylephrine (PE) in Milan normotensive rats. Intravenous (i.v.) injection of ET-1 (0.8 nmol/kg) initially decreased mean blood pressure (MBP), total peripheral resistance (TPR), and dP/dt (-28 +/- 2, -34.8 +/- 3.7, and -9.4 +/- 1.3%, p less than 0.01, respectively), and increased heart rate (HR), cardiac output (CO), and the velocity of myocardial anterior wall shortening (dL/dt) (11.8 +/- 2.1, 10.4 +/- 2.9, and 28.3 +/- 8.3% p less than 0.05, respectively). These effects were followed by a sustained increase in MBP and TPR and a decrease in CO. As compared with AI (0.25 nmol/kg) and PE (35 nmol/kg), which produced a similar degree of increase in TPR, the reduction in CO induced by ET-1 was more prominent (-25 +/- 2 by ET-1 vs. -14 +/- 2 by AI and -14 +/- 3% by PE, p less than 0.05, respectively). Moreover, ET-1 induced a significant decrease in dP/dt, shortening fraction (SF), and dL/dt (-6.1 +/- 1.6, -35.0 +/- 3.8, and -38.6 +/- 5.5%, p less than 0.01, respectively), whereas these indexes of left ventricle performance were not affected by either AI or PE. Furthermore, the reduction in SF induced by ET-1 was mainly due to the decrease in myocardial diastolic segment length, suggesting reduction in diastolic filling volume.(ABSTRACT TRUNCATED AT 250 WORDS)