Direct coronary vasodilation induced by intracoronary vasoactive intestinal peptide.

Vasoactive intestinal peptide (VIP) is a neurotransmitter that has been identified in epicardial coronary arteries. To evaluate the direct effect of VIP on coronary hemodynamics and blood flow, graded doses of VIP (0.01, 0.03, 0.10, and 0.30 micrograms/min) were infused into the left coronary artery of 7 patients at the time of diagnostic cardiac catheterization for chest pain syndromes. None of the patients had coronary stenoses greater than 50% during subsequent angiography. Coronary sinus VIP concentrations increased during each infusion (22 +/- 28 pg/ml at baseline to 109 +/- 22 pg/ml at 0.30 micrograms/min; p less than 0.05), but arterial VIP was elevated (39 +/- 29 pg/ml) only at the maximal dose of 0.30 micrograms/min. During all dosages of VIP, heart rate, right atrial and left ventricular end-diastolic pressure, and the heart rate x blood pressure product did not change. Moreover, neither mean aortic pressure nor left ventricular peak + dP/dt changed significantly at doses less than 0.30 micrograms/min; at 0.30 micrograms/min, mean aortic pressure decreased (97 +/- 15 to 90 +/- 15 mm Hg; p less than 0.05) and LV peak + dP/dt increased (1,621 +/- 230 to 1,801 +/- 226 mm Hg/s; p less than 0.05). Compared to baseline, the arterial-coronary sinus O2 content difference and myocardial O2 extraction diminished progressively at the 0.03, 0.10, and 0.30 micrograms/min doses of VIP (118 +/- 12 ml O2/L vs. 94 +/- 15, 70 +/- 9, and 61 +/- 26 ml O2/L, respectively, and 0.64 +/- 0.05 vs. 0.53 +/- 0.10, 0.38 +/- 0.06, and 0.34 +/- 0.15, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Antagonism of vasopressin-induced coronary artery constriction by the vasopressin antagonist d(CH2)5Tyr(Me)-AVP

d(CH2)5Tyr(Me)-AVP is a potent inhibitor of the systemic vasoconstrictor action of vasopressin (AVP). In order to examine the effectiveness of this agent in blocking AVP-induced coronary vasoconstriction, 11 pentobarbital-anesthetized mongrel dogs were instrumented for the measurement of left circumflex (LCX) coronary blood flow, systemic arterial blood pressure, heart rate, lead II electrocardiogram, left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular +/- dP/dt. Direct injection of AVP (0.01-1 microgram) into the LCX produced a dose-dependent decrease in coronary artery blood flow (maximum reduction: 60.5 +/- 8.1% after 1 microgram), - dP/dt (maximum reduction: 41.8 +/- 5.3% after 1 microgram), and +dP/dt (maximum reduction: 14.6 +/- 5.3%), whereas a dose-dependent increase in left ventricular end-diastolic pressure was observed (maximum increase: 62.6 +/- 20.2%). No significant changes occurred in heart rate, mean blood pressure, or left ventricular developed pressure. Intravenous administration of d(CH2)5Tyr(Me)-AVP reduced (1 microgram/kg) or abolished (5 micrograms/kg) the effects of AVP on coronary blood flow +/-dP/dt and left ventricular end-diastolic pressure. In addition, doses of 1,2, and 5 micrograms/kg of d(CH2)5Tyr(Me)-AVP alone produced increases of LCX blood flow of 5.1 +/- 1.5, 2.0 +/- 0.7, and 6.8 +/- 1.7 ml/min, respectively (p less than 0.05). We conclude that d(CH2)5Tyr(Me)-AVP is effective in preventing the coronary artery constriction and hemodynamic sequelae of intracoronary administered AVP.     

Cardiac sympathectomy with phenol acutely blunts the postsynaptic adrenergic response

Studies were performed in anesthetized dogs to determine if topical application of phenol to the heart acutely alters postsynaptic function in addition to destroying efferent sympathetic nerves. Left ventricular dP/dt max as well as segment length shortening (%SL) and maximal rate of shortening (dL/dt max) in the circumflex perfusion territory were measured. Responses to left stellate ganglion stimulation (LSS) and intracircumflex injection of norepinephrine (NE, 0.10-0.50 m?g) were recorded before and after application of 85% phenol to the atrioventricular junction and to the circumflex artery and its branches (stage 1) as well as to the myocardial surface (stage 2). Responses of dP/dt max, %SL, and dL/dt max to the various dosages of NE were reduced by 40-64%, 69-75%, and 44-61%, respectively, 1 hr after stage 1, indicating that application of phenol to the coronary arteries and arterio-ventricular junction attenuated the postsynaptic response to adrenergic stimulation. No further changes occurred 1 hr after stage 2. Responses of dP/dt max and dL/dt max to LSS were reduced by 36% and 57%, respectively, after stage 1 and by 75% and 71% after stage 2. Because of high variability, the response of %SL to LSS were not affected by stage 1 or stage 2 application of phenol. In a secondo of 5 dogs, only stage 2 application of phenol was used. The blunting of the LSS response was similar to that seen with stage 1 followed by stage 2, but the NE response was unaffected. These data indicate that application of phenol to the coronary Vessels and to the atrioventricular junction acutely blunts both the postsynaptic response to afferent nerve stimulation, while application of phenol to the myocardial surface blunts only the response to efferent nerve stimulation. Thus, in acute animal studies, application of phenol to the myocardial surface may provide more reliable result on the effects of ventricular denervation.     

EFFECTS OF NEUROPEPTIDE Y ON BAROREFLEX CONTROL OF HEART RATE AND MYOCARDIAL CONTRACTILITY IN CONSCIOUS RABBITS

1. The effects of intravenous (i.v.) neuropeptide Y (NPY, 10 micrograms/kg bolus) on the stimulus-response curves relating changes in heart period (HP) and in peak left ventricular (LV) dP/dt to acute changes in mean arterial pressure (MAP) were determined in conscious, normotensive rabbits. 2. The relationship between increases and decreases in MAP and the subsequent changes in HP were represented by a sigmoid-shaped curve described by a logistic function. Following NPY administration there was a baroreflex-dependent increase in the maximum slope (sensitivity) at the midpoint of this MAP-HP curve from 7.0 +/- 0.5 to 10.6 +/- 1.3 ms/mmHg (P less than 0.05). NPY caused an upward shift in the whole curve which reflected the NPY-induced bradycardia and was independent of baroreflexes. 3. The relationship between increases in MAP and decreases in peak LV dP/dt was determined during fixed-rate atrial pacing to prevent the effects of the accompanying bradycardia. Increases in MAP and the corresponding reductions in peak LV dP/dt were represented by an exponential function. The slope of the curve, measured at its origin 5-15 min after NPY administration, was reduced from -0.9 +/- 0.2 to -0.4 +/- 0.1 units (P less than 0.05). 4. The effects of NPY are consistent with an action on efferent connections of the arterial baroreceptor reflex, mediated through a reduction in cardiac beta-adrenergic tone. They would also be explained through actions on the afferent or central neural connections of the baroreflex.     

Myocardial contractile behavior of a new sotalol derivative.

The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)     

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 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)     

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.     

Coronary and systemic hemodynamic effects of tetramethylpyrazine in the dog

The hemodynamic effects of tetramethylpyrazine were examined in 27 anesthetized open chest dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and ascending aorta. Tetramethylpyrazine, 2-15 mg/kg i.v., caused prominent systemic and coronary vasodilation, with a maximum reduction of mean aortic pressure from 92 +/- 5 mm Hg during control conditions to 62 +/- 7 mm Hg (p less than 0.01), a peak increase in cardiac output from 3.0 +/- 0.4 to 4.1 +/- 0.7 L/min (p less than 0.05), and a peak reduction of systemic vascular resistance from 2,450 +/- 400 to 1,210 +/- 329 dyne X s X cm-5 (p less than 0.01). Simultaneously, heart rate increased from 143 +/- 9 to 174 +/- 8 beats/min (p less than 0.01), and maximum left ventricular dP/dt increased from 2,410 +/- 120 to 4,020 +/- 60 mm Hg/s (p less than 0.01). Dose-related increases of coronary blood flow occurred from 37.3 +/- 3.7 to a maximum of 74.1 +/- 6.6 ml/min (p less than 0.01), while mean coronary vascular resistance decreased from 1,770 +/- 240 to 700 +/- 260 dyne X s X cm-3 (p less than 0.01). Myocardial oxygen consumption increased in proportion to the increase in coronary blood flow. Following beta-adrenergic blockade with propranolol (1 mg/kg, i.v.), ganglionic blockade with hexamethonium, or catecholamine depletion with reserpine (1.0 mg/kg, i.p.), the systemic and coronary vasodilator effects of tetramethylpyrazine persisted, but the increases in heart rate, maximum left ventricular dP/dt, and myocardial oxygen consumption were markedly attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning

We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.     

Measurement of cardiac left ventricular pressure in conscious rats using a fluid-filled catheter.

A fluid-filled catheter consisting of 100 cm of PE50 polyethylene tubing welded to 7 cm of PE10 polyethylene tubing (PE50/PE10) was constructed for the purpose of measuring the rate of left ventricular pressure development (+dP/dt) in conscious, freely moving rats. Prior to in vivo experiments, four PE50/PE10 catheters were randomly selected, and their natural frequencies and damping ratios were determined using a square wave impact. The mean (n = 4), natural frequency of these catheters was shown to be 35.0 +/- 5.5 Hz, and the mean damping ratio was 0.83 +/- 0.10. Natural frequency plotted against increasing PE50 tubing length was shown to have a slope of -0.44 Hz/cm with a correlation coefficient of 0.99. The effect of the 7-cm PE10 tubing segment on the catheter damping ratio was also demonstrated. One of the four PE50/PE10 type catheters exhibited a damping ratio of 0.74 +/- 0.09. When the 7-cm PE10 tube was removed, the damping ratio was reduced to 0.31 +/- 0.04. Left ventricular +dP/dt obtained in conscious rats with a PE50/PE10 catheter (n = 7; 6300 +/- 300 mmHg/sec) was significantly less than the +dP/dt obtained using a 100-cm PE50 catheter (n = 6; 9400 +/- 400 mmHg/sec). The results of this study make it clear that the PE50/PE10 catheter is suitable for the measurement of left ventricular +dP/dt in the conscious rat, and that catheter design has a profound influence on both the catheter natural frequency and damping ratio.     

Comparisons of the inotropic effects of the beta 1-adrenoceptor partial agonists SL 75.177.10 and ICI 118,587 with digoxin on the intact canine heart

The effects of the beta 1-adrenoceptor partial agonists ICI 118,587 (xamoterol) and SL 75.177.10 on the left ventricular inotropic state and relaxation rate were compared with those of digoxin in open-chest dogs. These agents were administered to three separate groups of dogs (5, 6, and 7 dogs, respectively). In each animal, the inotropic effects were assessed at fixed heart rate (atrial pacing) and at similar end-diastolic left ventricular diameter. Under these controlled conditions, ICI 118,587 (200 micrograms/kg) increased peak (+) dP/dt by 3176 +/- 363 mm Hg/s (p less than 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p less than 0.01). These changes were significantly greater than after digoxin (100 micrograms/kg) which increased these indexes, respectively, by 2132 +/- 248 mm Hg/s (p less than 0.003) and by 31 +/- 4% (p less than 0.05). SL 75.177.10 (200 micrograms/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 +/- 105 mm Hg/s; p less than 0.007); the increase in end-systolic pressure/diameter slope was not different from that observed after digoxin. In contrast to ICI 118,587 which accelerated isovolumic relaxation (-7.6 ms in time constant of isovolumic pressure fall; p less than 0.01), neither SL 75.177.10 nor digoxin modified this phase of the cardiac cycle. Finally, at the dose used in the study, digoxin induced ventricular arrhythmias in all animals, a side effect which was never observed after ICI 118,587 or SL 75.177.10.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dilatation of coronary stenosis as the salutary effect of nitroglycerin in relief of myocardial ischemia in the dog

To clarify the role of coronary responses to nitroglycerin (NTG) in relieving myocardial ischemia, we examined the effects of NTG in canine models of dynamic and fixed coronary stenoses. Application of coronary stenosis in the proximal left circumflex artery decreased resting coronary blood flow by approximately 40% and caused a significant depression of left ventricular (LV) dP/dt. During fixed coronary stenosis created with an externally applied constrictor device, intravenous NTG, 5 micrograms/kg, reduced mean aortic pressure by 12 +/- 1.1 mm Hg (mean +/- SEM, p less than 0.01) and coronary blood flow by 9 +/- 1.0% (p less than 0.01) but did not affect stenosis resistance and LV dP/dt. During dynamic coronary stenosis produced with an intraluminal microballoon occluder, intravenous NTG caused a marked increase in coronary blood flow by 40 +/- 8.3% (p less than 0.01) and a decrease in stenosis resistance by 62 +/- 9.3% (p less than 0.01), as compared with postocclusion values, concomitant with a significant improvement in LV dP/dt. Intracoronary infusion of NTG, 1.0 microgram/kg/min, had few systemic and coronary hemodynamic effects during fixed coronary stenosis, whereas intracoronary NTG increased coronary blood flow and reduced stenosis resistance, depending on its dose, during dynamic coronary stenosis. These results indicate that NTG is capable of increasing coronary blood flow and alleviating myocardial ischemia due to direct stenosis-dilating effects related to the vasomobility of the coronary stenosis.     

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)     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

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.     

Myocardial and ventricular mechanics as influenced by disopyramide

The effects of disopyramide (D) on the mechanics of isolated myocardium as well as on the whole ventricle were examined in the rat model. Moreover bipolar leads of the apex and an area at the base of the left ventricle were set up to get indications for changes in the spread of excitation. D in concentrations of 10(-8) to 10(-4) mol/l did not affect the diastolic elastic properties of isolated myocardium. Isometric contraction amplitude was nearly unaltered, while rate of isometric contraction and relaxation were slightly increased. In the whole ventricle in situ D (2 to 10 mg/kg b.w. administered i.v.) induced a dose-dependent decrease in left ventricular isovolumetric peak pressure (16%), max.pos. dP/dt (40%) and max.neg. dP/dt (30%; for highest doses respectively), while time to peak pressure and relaxation time 90% were prolonged. Therapeutic dose of D (2 mg/kg b.w.i.v.) induced no decrease in essential systolic parameters of the whole ventricle under auxotonic conditions. Left ventricular pressure, dP/dt max.pos. and neg., left ventricular end-diastolic pressure and cardiac output were nearly unaltered. Heart rate showed a tendency to decrease, while total time of contraction and left ventricular ejection time increased. Higher doses of D led to marked cardiac depressant effects. The time interval between the excitation of the apex and an area at the base of the heart was increased. It was concluded that the negative dromotropic effect of D and thereby an altered pattern of left ventricular contraction are essential components in the elimination of the pressure gradient between left ventricle and aorta, observed in patients with muscular subaortic stenosis, and are presumably involved in the cardiac depressant effect of the drug in over-therapeutic doses.     

Hemodynamic effects of a new inotropic compound,PST-2744, in dogs with chronic ischemic heart failure

Inotropic agents for acute decompensated heart failure are associated with a lack of efficacy or increased mortality. New compounds are needed to support patients with acute exacerbations of heart failure. This study examined the hemodynamic effects of a new inotropic agent (PST-2744) in dogs with chronic ischemic heart failure. Eight mongrel dogs at low risk for postmyocardial infarction (MI) sudden death entered the protocol. Dogs were studied after ischemic left ventricular dysfunction was induced by repeated injections of latex microspheres into the circumflex artery until the ejection fraction reached 35%. Hemodynamic parameters were measured at baseline and peak drug effect (PST-2744 5 microg.kg-1.min-1). In 5 animals, PST-2744 effects were compared with dobutamine. Heart rates, PR intervals and QT intervals were unchanged following PST-2744 administration. PST-2744 increased contractility (+dP/dt) by 56% from 1881 +/- 282 mm Hg/s to 2939 +/- 734 mm Hg/s (P < 0.01). The inotropic effect of PST-2744 was equal to that produced by 5-microg.kg-1.min-1 dobutamine (56% increase in +dP/dt), but peak heart rates were significantly higher with dobutamine (129 +/- 24 bpm PST-2744 versus 160 +/- 6 bpm 5-microg.kg-1.min-1 dobutamine, P < 0.002). No arrhythmias or conduction delays were seen with either compound. PST-2744 is an effective inotropic agent without positive chronotropic effect in subjects with stable moderate left ventricular dysfunction.