EFFECTS OF NEUROPEPTIDE Y ON LEFT VENTRICULAR FUNCTION IN THE CONSCIOUS RABBIT

1. Changes in arterial pressure, heart rate and left ventricular contractility induced by intravenous injections of neuropeptide Y (NPY; 1-30 micrograms/kg) were studied in the conscious rabbit. 2. NPY has a brief pressor effect associated with a bradycardia, an increase in left ventricular end diastolic pressure, and a prolonged fall in peak left ventricular dP/dt (LVdP/dt). 3. The haemodynamic changes increase substantially with increasing doses up to 10 micrograms/kg. Beyond 10 micrograms/kg there are only slight effects on heart rate or peak LV dP/dt.     

Effects of neuropeptide Y on the heart and circulation of the conscious rabbit

The direct and reflex-mediated components of the cardiovascular response to administration of neuro-peptide Y (NPY) in intact conscious rabbits were determined by studies with cardiac beta adrenoceptor and vagal blockade, and during total autonomic blockade. Cardiac pacing was used to prevent bradycardia, and sinoaortic denervation (SAD) was used to remove afferent baroreflex input. In control animals, NPY (10 micrograms/kg bolus i.v.) caused arterial pressure to increase from 77.4 +/- 1.5 mm Hg (mean +/- SEM) to a maximum of 91.4 +/- 1.6 mm Hg (p less than 0.05). This pressor response was independent of autonomic effectors but was buffered by arterial baroreflexes. The fall in heart rate (HR) from 281 +/- 14 to 252 +/- 18 beats/min (p less than 0.05) was mediated in part through baroreceptor-dependent changes in cardiac autonomic efferent activity, but was in part independent of autonomic neural mechanisms. Peak left ventricular (LV)dP/dt fell from 5,551 +/- 342 to 4,182 +/- 394 mm Hg/s (p less than 0.05) following NPY in control rabbits. This reduction was maintained during pacing and following SAD, and was caused partly by a withdrawal of cardiac beta-adrenergic tone and partly through a non-beta-mediated myocardial depression. Small changes in cardiac output (CO) and in LV end-diastolic pressure (LVEDP) after NPY were secondary to bradycardia. Total autonomic blockade did not impair the NPY-induced rise in total peripheral resistance (TPR), suggesting a direct vasoconstrictor action that was independent of neural mechanisms.     

Haemodynamic profile of an inhibitor of phosphodiesterase III, adibendan (BM 14.478): comparison with nitroprusside and dobutamine in conscious dogs.

1. This study was performed to investigate whether cardiac positive inotropic as well as peripheral vasodilator properties of adibendan contribute to its overall haemodynamic profile in conscious dogs. 2. Haemodynamic measurements were carried out in conscious chronically instrumented dogs after administration of adibendan, sodium nitroprusside or dobutamine. 3. The cardiovascular changes induced by adibendan (0.01 and 0.03 mg kg-1) resembled those of dobutamine (1.0-4.0 micrograms kg-1 min-1): left ventricular dP/dt60 (LV dP/dt60), stroke volume (SV) and cardiac output (CO) increased to a similar extent, but mean arterial pressure (MAP) and heart rate (HR) remained unchanged. 4. In contrast to dobutamine, higher doses of adibendan (0.1-1.0 mg kg-1) decreased MAP and LVEDP. These effects were of a similar magnitude to those observed following nitroprusside administration (0.5-12.5 micrograms kg-1 min-1). In contrast to nitroprusside, adibendan still showed additional effects on LV dP/dt60 and CO. 5. From these results, it is concluded that both the peripheral vasodilator and the cardiac positive inotropic action of adibendan contribute to its overall haemodynamic profile.     

Cardiovascular Effects of the Novel Cardiotonic Agent DPI 201–10. in the Anaesthetized Rat

Abstract: DPI 201–10. (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole-2-carbonitrile) was given intravenously to anaesthetized male rats. DPI caused an increase in left ventricular dP/dt (LV dP/dt), giving a significant increase at 0.03 μmol/kg. At this dose DPI had no effect on either mean arterial pressure (MAP) or heart rate (HR). At higher doses, MAP decreased transiently. At 0.3 and 1 μmol/kg, HR was decreased. The results indicate that DPI produces positive inotropic and negative chronotropic effects in the anaesthetized rat.     

Cardiovascular effects of the novel cardiotonic agent DPI 201-106 in the anaesthetized rat

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole -2- carbonitrile) was given intravenously to anaesthetized male rats. DPI caused an increase in left ventricular dP/dt (LV dP/dt), giving a significant increase at 0.03 mumol/kg. At this dose DPI had no effect on either mean arterial pressure (MAP) or heart rate (HR). At higher doses, MAP decreased transiently. At 0.3 and 1 mumol/kg, HR was decreased. The results indicate that DPI produces positive inotropic and negative chronotropic effects in the anaesthetized rat.     

Hemodynamic and myocardial energetic effects of CK-3197, a selective positive inotropic agent.

CK-3197 was developed as a selective positive inotropic agent for the treatment of congestive heart failure. We compared the hemodynamic and myocardial energetic effects of CK-3197 to ouabain in the pentobarbital-anesthetized dog. Fifteen minutes after intravenous (i.v.) administration of CK-3197 (0.1, 0.3, and 1.0 mg/kg) to five dogs, mean left ventricular (LV) dP/dt increased by 24, 68, and 109% and mean arterial pressure (MAP) decreased by 4, 9, and 18%, respectively, from basal values. CK-3197 was 11 times more potent as a positive inotropic agent than as a vasodilator. Heart rate (HR) increased by 5, 14, and 24% after these doses of CK-3197, whereas LV end diastolic pressure (LVEDP) decreased by 4 mm Hg after the highest dose of compound. LV oxygen consumption (MVO2) and stroke MVO2 increased by 9, 25, and 102% and 1, 8, and 58%, respectively, at the peak of the increases in LV dP/dt. Ouabain (0.02 and 0.03 mg/kg, i.v.) increased MAP (12 and 22%), HR (2 and 20%), and LV dP/dt (19 and 36%), with a 14 and 16% increase in LV MVO2 and a 12 and -6% change in stroke MVO2. Thus, CK-3197 is a selective, positive inotropic agent with preload reducing activity in the dog. CK-3197, similar to ouabain, produced energy-efficient positive inotropic responses with either no increase in MVO2 or increases in myocardial oxygen consumption that were less than the expected 1:1 ratio with LV dP/dt. Therefore, CK-3197 may have significant utility in the clinical treatment of congestive heart failure.     

Beta-adrenergic influence on cardiac dynamics during shock-avoidance in dogs

The role of beta-adrenergic receptors in the mediation of the cardiodynamic effects of a shock-avoidance task was evaluated in conscious dogs with the cardioselective beta-adrenergic antagonist practolol. The animals were chronically instrumented for the measurement of peak rate of change of left ventricular pressure (LV dP/dt), heart rate (HR), cardiac output (CO), systolic (SPB) and diastolic (DBP) blood pressure and total peripheral resistance (TPR), and were each subjected to brief bouts of shock-avoidance with and without practolol pretreatment (2-4 mg/kg). Shock-avoidance evoked reliable increases of LV dP/dt, HR, CO, SBP and DBP, and decreases of TPR. Beta-adrenergic blockade virtually eliminated LV dP/dt increases, attenuated HR and CO increase as well as the vasodilatation, diminished SBP increases in certain animals but did not affect DBP increases. Stable interindividual differences in the magnitude of LV dP/dt and HR increases during shock-avoidance were demonstrated; these differences were abolished by beta blockade. These findings indicate that a beta-adrenergic mechanism accounted for most of the rise of LV dP/dt during avoidance but contributed proportionally less to the elevations of HR and CO. Inter-individual differences in myocardial reactivity were however completely ascribable to beta-adrenergic factors.     

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.     

Celiprolol: a positive inotropic beta-adrenoceptor blocking agent in conscious dogs.

1. beta-Adrenoceptor blocking agents are used to manage various cardiovascular disorders. A limiting factor in their use is the suppression of the cardiac contractile state. In our study, we examined the cardiac effects of celiprolol, a new beta-adrenoceptor blocking agent with reported positive inotropic effects. 2. Dogs were instrumented by use of sterile surgical techniques for the study of myocardial inotropic state, heart rate and internal left ventricular dimensions. Following complete recovery from surgery, experiments were conducted in the conscious state. 3. Intravenous injection of celiprolol (3 mg kg-1) in nine dogs, increased LV dP/dt by 13 +/- 2.6%, velocity of shortening (LV dD/dt) by 9.2 +/- 3.4%, and heart rate by 19 +/- 4.6% and decreased LV end-diastolic diameter by 1.8 +/- 0.8%, all significantly (P less than 0.05). Celiprolol blocked the inotropic actions of isoprenaline (0.5 micrograms kg-1) but only partially reduced its hypotensive effects. Propranolol, in contrast, reduced LV dP/dt by 17 +/- 3.3% and heart rate by 8.1 +/- 2.7% (P less than 0.05) while totally abolishing the hypotension, tachycardia and increase in LV dP/dt caused by isoprenaline. Following beta-adrenoceptor blockade with propranolol and with heart rate held constant by electrical pacing, celiprolol increased LV dP/dt by 16 +/- 4.0%, LV dD/dt by 12 +/- 3.0% and reduced LV end-diastolic diameter by 3.5 +/- 0.5% (P less than 0.05). 4. Thus, in conscious dogs, celiprolol increases inotropic state and reduces preload independently of beta 1-adrenoceptor mechanisms and the Bowditch phenomenon, while effectively blocking beta 1-receptors in the heart. These properties would make celiprolol useful in patients where a conventional beta-adrenoceptor blocking agent might lead to pump failure.     

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.     

The role of angiotensin II AT1 receptor in the maintenance of hemodynamics in a canine model of coronary microembolization-induced heart failure

The purpose of this study was to determine whether Angiotensin II (Ang II) contributes to the regulation of resting hemodynamics via Ang II type 1 (AT1) receptors in awake dogs with coronary microembolization-induced heart failure. Six dogs were surgically instrumented for measurement of systemic hemodynamics and for coronary microembolization. The acute hemodynamic effects of a selective AT1-receptor antagonist, GR138950 (1 mg/kg, i.v.), were determined before and after congestive heart failure (CHF). GR138950 had no effects on hemodynamics before CHF Daily coronary microembolizations (through the previously implanted coronary catheter) resulted in CHF, as documented by hemodynamic measurements, a slight but significant increased Ang II plasma level (17.4 +/- 1.6 vs. 23 +/- 1.0 pg/ml; p < 0.05), and characteristic clinical signs of CHF. After CHF, GR138950 significantly increased left ventricular dP/dt(max) (LVdP/dt(max)) from 1,754 +/- 68 to 2,347 +/- 114 mm Hg/s and decreased LV systolic pressure (LVSP) from 118 +/- 5 to 101 +/- 7 mm Hg; meanwhile, heart rate (from 132 +/- 4 to 102 +/- 6 beats/min) and LV end-diastolic pressure (LVEDP; from 17 +/- 3 to 9 +/- 1.5 mm Hg) were significantly decreased. Mean arterial pressure (MAP) was not affected. The peak effects occurred 90 min after administration. Thus Ang II contributes significantly to resting hemodynamics via AT1 receptors in this CHF model; that is, the specific AT1 blocker inhibits the negative inotropic actions of Ang II in the CHF state.     

Effects of acute hypoxemia on responses to dopamine and dobutamine in neonatal swine

The effects of acute hypoxemia on cardiovascular responses to dopamine (DA) and dobutamine (DB) were studied in 2-4 day (n = 21) and 13-17 day (n = 27) old swine under sodium pentobarbital anesthesia. Sequential 10-min infusions of 2, 5 and 15 mu/kg/min of DA or DB or normal saline were administered under conditions of normoxemia and repeated during hypoxemia. Data are presented as mean percent of baseline value +/- SE. During normoxemia, DA increased aortic pressure, cardiac output, heart rate, LV dP/dt max and renal resistance and decreased mesenteric resistance in both ages, while DB increased heart rate, LV dP/dt max and cardiac output in both age groups and decreased total arterial resistance and renal resistance in the youngest. Increases in LV dP/dt max were larger with DA as compared to DB (p less than 0.05) with the highest dose in younger (152 +/- 5% vs. 124 +/- 4%) and older (201 +/- 29% vs. 157 +/- 9%) animals. Hypoxemia reduced heart rate responses to DA and DB in older piglets, contractility responses to DB in older animals, aortic pressure responses to DA in all animals and renal resistance responses to DA in older animals. Hypoxemia had little or no effect on cardiac output and total arterial, mesenteric and carotid resistance responses to DA and DB. Thus, in the newborn: 1) DA is a stronger inotropic agent during normoxemia and hypoxemia while the chronotropic effects of the two drugs did not differ. 2) Changes in cardiac output with both drugs did not differ significantly during normoxemia and were not affected by hypoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiovascular pharmacology of 7-propyl-theo-phylline-dopamine (D4975); comparison with dopamine and dobutamine.

1 The effects of a newly developed dopamine-xanthine derivative, 7-propyl-theophylline-dopamine (D4975), have been examined in cats anaesthetized with sodium pentobarbitone. When administered intravenously (in doses as low as 0.5 to 1.0 micrograms/kg) it increased systemic arterial pressure, left ventricular (LV) dP/dtmax, dP/dt at fixed ventricular isovolumic pressures and cardiac output. Heart rate effects were minimal. 2 D4975 was about 5 times more active than dopamine or dobutamine in elevating LV dP/dtmax or dP/dt at common peak isovolumic pressures (CPIP) and about 10 times more active than dopamine at increasing systemic arterial blood pressure. The effects of D4975 were also more prolonged than those of the other two agents. 3 The effects of D4975 on LV dP/dtmax were greatly reduced by the prior administration of propranolol. D4975 has no effect on peripheral beta 2-adrenoceptors. 4 It is suggested that the effects of D4975 on the myocardium involve both beta 1-adrenoceptor stimulation and inhibition of phosphodiesterase and that the marked and prolonged pressor response is due to resistance to enzymatic breakdown by monoamine oxidase. 5 The results suggest that D4975 might prove valuable in the treatment of the hypotension and reduced myocardial contractility of shock, especially as it is possible to select a dose that increases LV dP/dtmax without increasing either heart rate of systemic arterial pressure.     

Hemodynamic response to intracoronary infusion of atrial natriuretic factor in patients with normal or altered left ventricular function.

To assess the effects of atrial natriuretic factor (ANF) on cardiac function, synthetic human ANF was infused directly into the left main coronary artery of eight patients with congestive heart failure (CHF) and six subjects with normal left ventricular (LV) function (controls) who underwent cardiac catheterization. ANF infusion at the incremental rates of 60, 125, 400, and 800 ng/min induced a dose-related increase in plasma ANF concentrations in the coronary sinus, from 1,223 +/- 590 to 3,923 +/- 1,123 pg/ml in patients with CHF (p less than 0.01) and from 1,041 +/- 605 to 2,710 +/- 1,741 pg/ml in controls (p less than 0.01). Peripheral plasma ANF concentrations (femoral artery) increased from 538 +/- 278 to 752 +/- 262 pg/ml (p less than 0.01) in patients with CHF and from 193 +/- 63 to 401 +/- 147 pg/ml (p less than 0.01) in controls. The increase in peripheral or coronary sinus plasma ANF concentrations did not differ between patients with CHF and controls. At the three lowest ANF infusion rates, cardiac index (CI), systemic vascular resistance (SVR), and LV contractility assessed by peak positive dP/dt remained unchanged both in patients with CHF and in controls. At the highest ANF infusion rate, CI increased from 2.18 +/- 0.53 to 2.54 +/- 0.49 L/min/m2 (p less than 0.01) and SVR decreased from 14.6 +/- 3.6 to 12.8 +/- 4.5 mm Hg.min/L (p less than 0.01) in patients with CHF. There was no associated change in heart rate (HR), mean arterial blood pressure (MAP), cardiac filling pressures, or peak positive dP/dt.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines

1. The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8-12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2-4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the beta-adrenoceptor blocking drug alprenolol.2. The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.3. Over the 2-3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.4. The predominant delayed effect of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess-20 mEq/litre). Arterial pO(2) and pCO(2) were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.5. The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2-3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.     

Effects of the partial beta 1-adrenergic agonist, xamoterol, on hemodynamics and regional myocardial function during acute coronary occlusion in dogs.

Xamoterol is a partial beta 1-adrenergic agonist that has combined beta 1-stimulating and beta 1-blocking actions. We studied the effects of xamoterol on hemodynamics and regional left ventricular (LV) function after circumflex coronary artery occlusion in eight anesthetized dogs. Left ventricular systolic wall thickening (%WT: sonomicrometry) was measured in nonischemic, marginal, and ischemic zones. Xamoterol (350 micrograms/kg i.v.) increased the maximum LV pressure (dP/dt) by 62% and aortic flow (AOF) by 52% and decreased LV end-diastolic pressure (EDP) but did not change heart rate (HR) and peak LV pressure (LVP). Xamoterol increased %WT in nonischemic (23.6 +/- 2.3 to 35.1 +/- 2.6%, p less than 0.05) and marginal (5.0 +/- 0.6 to 12.0 +/- 1.5%, p less than 0.05), but not in the ischemic region [-5.7 +/- 0.7 to -2.7 +/- 0.3%, not significant (NS)]. The beta 1-blocking action of xamoterol was evaluated. Xamoterol significantly attenuated the increase in HR and maximum dP/dt caused by isoproterenol (0.1 microgram/kg/min). %WT in each region was maintained at the level caused by xamoterol after isoproterenol. Thus, xamoterol improved cardiac function, yet prevented excessive stimulation by catecholamine in the presence of acute myocardial ischemia.     

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. II. Studies with dopamine and ouabain in the barbiturate-anesthetized dog

To test the hypothesis that selective increases in inotropic state without concomitant acceleration of heart rate would not augment acute ischemic injury in the non-failing heart of the anesthetized dog, we carried out studies in 16 dogs subjected to serial 10-min occlusions of the left anterior descending coronary artery. The severity of ischemic injury was determined by mass spectrometric measurement of the rise in intramural carbon dioxide tension (delta PmCO2) in the ischemic zone, and inotropic stimulation was provided by either dopamine or ouabain. In Group I dogs (n = 9), dopamine [4 +/- 1 (SD) micrograms/kg/min] was infused before the final occlusion to increase left ventricular (LV) dP/dt without changing heart rate; delta PmCO2 was not significantly different between control (64 +/- 21 mm Hg) and postdopamine (67 +/- 22 mm Hg) occlusions. In Group II dogs (n = 7), ouabain (0.03 mg/kg) was administered 15 min before the final occlusion, resulting in a significant increase in LV dP/dt and a slight decrease in heart rate (average 13 beats/min); delta PmCO2 was slightly decreased in the occlusion after ouabain (60 +/- 12 mm Hg) compared with the preceding occlusion without inotropic stimulation (67 +/- 13 mm Hg), p less than 0.05. Throughout the studies in both groups, there were no significant changes in collateral blood flow to the central ischemic zone, or in heart rate-systolic arterial pressure product, an estimate of myocardial oxygen consumption. Analyses of individual responses revealed that when LV dP/dt increased by 50% or more after dopamine or ouabain, ischemia was more likely to intensify.(ABSTRACT TRUNCATED AT 250 WORDS)     

Negative inotropic and lusitropic effects of intravenous amiodarone in conscious rats

1. The acute effect of amiodarone on haemodynamics (mean arterial pressure and heart rate) and ventricular function (+dP/dt(max) and -dP/dt(max)) 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 microg/kg). 3. The hypotensive effect of 50 mg/kg amiodarone was combined with marked bradycardia and attenuation of +dP/dt(max) and -dP/dt(max). A slight, but significant, hypotension was caused by 25 mg/kg amiodarone, without affecting heart rate, +dP/dt(max) and -dP/dt(max). 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/dt(max) and -dP/dt(max). 4. In conclusion, amiodarone caused hypotension, bradycardia, negative inotropic (+dP/dt(max)) and lusitropic (-dP/dt(max)) effects in conscious rats. In addition, amiodarone attenuated the tachycardia without affecting the hypertensive, contractile (+dP/dt(max)) and lusitropic (-dP/dt(max)) responses to dobutamine stress.