Kevin C. Preuss

Time course of recovery of “stunned” myocardium following variable periods of ischemia in conscious and anesthetized dogs☆

Persistence of regional contractile dysfunction after restoration of blood flow to transiently ischemic myocardium has been well described. To date, most studies have been performed in anesthetized animals. The present investigation compared the time course of recovery of regional segment shortening (percentage of segment shortening) in anesthetized versus conscious dogs subjected to a brief period of total occlusion of the left anterior descending coronary artery. Periods of occlusion lasting 5, 10, and 15 minutes were followed by 3 hours of reperfusion. Dogs anesthetized with sodium pentobarbital (30 mg/kg intravenously) had a significantly higher heart rate and blood pressure and lower dP/dt than conscious dogs. Coronary artery occlusion resulted in similar degrees of regional dyskinesis or akinesis, indicative of severe myocardial ischemia, in all experiments. During reperfusion, a gradual return of contractile function toward baseline was observed. At the end of the first 15 minutes of reflow, dogs subjected to 5 minutes of coronary occlusion demonstrated approximately 70% of control segment shortening in the previously ischemic zone. Animals subjected to 10- and 15-minute periods of coronary artery occlusion showed approximately 60% and 40% of control segment shortening at the same time point, respectively. The remainder of the 3-hour reperfusion period was characterized by a more gradual recovery of regional segment function. No differences were observed between anesthetized and conscious animals. It is concluded that the time course of functional recovery of postischemic reperfused myocardium is directly related to the duration of coronary occlusion and is similar in conscious and anesthetized dogs.

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 β-adrenergic receptor blockade. Nicorandil (25–300 μg/kg/min) and nitroglycerin (5–60 (μg/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 β-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 β-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75–300 μg/kg/min) produced a dose-related increase in trans-mural 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.

Slow channel calcium activators, a new group of pharmacological agents

Specific calcium channels in myocardium and vascular smooth muscle and pharmacologic agents which possess the ability to block them have been the subject of intense research over the past several years. Many studies have utilized dihydropyridine derivatives (e.g. nifedipine, nitrendipine, nisoldipine) which have been shown to be efficacious inhibitors of calcium influx through voltage sensitive slow channels. Administration of these agents results in vascular smooth muscle relaxation and negative inotropic effects. Recently, novel dihydropyridines such as Bay k 8644, CGP 28 392 and YC-170, with actions diametrically opposed to those of compounds typified by nifedipine have been synthesized. These agents demonstrate vaso-constrictor and positive inotropic effects - actions which might be expected of compounds capable of stimulating the transmembrane influx of calcium into vascular smooth muscle and myocardium. Actions of Bay k 8644 and CGP 28 392 studied in vitro and in vivo have also shown that pharmacological blockade of beta or alpha adrenergic receptors does not influence the direct effects of these agents. Future analogs, with similar but more selective actions on myocardial calcium channels, may prove useful in the management of pathologic states characterized by insufficient contractile function of the heart.

Cardiovascular effects of the nifedipine analog, CGP 28 392, in the conscious dog.

The cardiovascular profile of the nifedipine analog, CGP 28 392, was studied in instrumented conscious dogs. CGP 28 392 (25, 50, 100, and 150 μg/kg) was administered intravenously, and systemic and coronary hemodynamics monitored with and without prior treatment with nifedipine, phentolamine, propranolol, or atropine. CGP 28 392 increased arterial blood pressure and coronary vascular resistance in a dose-related manner and reduced heart rate. No positive inotropic actions were observed. All hemodynamic effects of CGP 28 392 were blocked by nifedipine but were unaltered by phentolamine. The decrease in heart rate was attenuated by atropine and propranolol. These data demonstrate that the actions of CGP 28 392 are diametrically opposed to those of the dihydropyridine slow channel calcium entry blockers and are specifically blocked by nifedipine. The cardiovascular actions of this compound (with the exception of bradycardia) are not mediated through the autonomic nervous system, and interactions with other pharmacological agents suggest that CGP 28 392 has calcium channel activating properties.

A microcomputer-based package for determination of regional and global cardiac function and coronary hemodynamics

A multichannel data acquisition package for reduction of systemic and coronary hemodynamic data that utilizes a personal microcomputer is described. The system provides a printout of heart rate, maximal rate of left ventricular pressure development (+dP/dt), maximal rate of ventricular relaxation (-dP/dt), absolute and normalized myocardial segment lengths, the degree of shortening of the segment over the cardiac cycle, systolic, diastolic, and mean coronary blood flow velocities, left ventricular systolic and end diastolic pressures, and systolic, diastolic, and mean aortic blood pressure from six channels of input data. Obtained values are precisely linked to the cardiac cycle. To illustrate the output of this system, data obtained by reading strip-chart records are compared to microcomputer-derived values in conscious, instrumented dogs.

Positive inotropic actions of the calcium channel stimulator, Bay k 8644, in awake, unsedated dogs

SummaryThe hemodynamic effects of the dihydropyridine derivative Bay k 8644, a new calcium agonist with positive inotropic actions, were studied in instrumented conscious dogs before and after beta adrenergic blockade with propranolol. Intravenous Bay k 8644 (2, 4, 8 and 20 μg/kg/min) produced dose-related increases in arterial and left ventricular systolic pressures and myocardial contractility (+dP/dt; % segment shortening). Coronary blood flow velocity was increased at higher doses. Prior administration of propranolol produced no significant alteration of the hemodynamic effects of Bay k 8644. Increases in arterial and left ventricular pressures produced by Bay k 8644 were controlled by intravenous infusion of sodium nitroprusside with resulting enhancement of positive inotropic effects. The results demonstrate that the hemodynamic responses to this novel calcium agonist with positive inotropic properties are not mediated via beta adrenergic mechanisms and control of increases in arterial pressure lead to enhanced regional contractility.

Comparative Effects of Inotropic Agents on Coronary and Systemic Hemodynamics of Conscious Dogs: Actions of Milrinone, Dopamine, Ouabain and MCI-154

The hemodynamic actions of a new inotropic agent, MCI-154, were compared to dopamine, ouabain and milrinone in conscious, chronically instrumented dogs. MCI-154 and milrinone produced similar hemodynamic changes: increases in heart rate, diastolic coronary blood flow velocity and peak positive dP/dt. Neither agent had significant effects on arterial pressure while both drugs reduced left ventricular end-diastolic pressure in a dose-related fashion and myocardial segment length, indicating a decrease in diastolic left-ventricular size. MCI-154 was found to be approximately twice as potent as milrinone. In contrast, dopamine and ouabain produced little change in left ventricular end-diastolic pressure or myocardial segment length during diastole, while both drugs produced increases in arterial and left ventricular systolic pressures. An increase in left ventricular afterload was not observed with either MCI-154 or milrinone, highlighting an important advantage of the latter compounds.

Cardiovascular actions of a new dihydropyridine calcium antagonist, 8363-S: comparison with nifedipine and nicardipine in awake, unsedated dogs.

The systemic and coronary hemodynamic actions of a new dihydropyridine. 8363-S, were compared with nifedipine and nicardipine in conscious, instrumented dogs following intravenous and oral administration. All agents produced similar reductions in arterial and ventricular pressures and increases in heart rate, dP/dt. and coronary blood flow velocity, following intravenous infusion. Following oral administration, all agents had qualitatively similar actions; however, there was a marked difference in potency. 8363-S was found to he most potent in that 0.25 mg/kg produced equivalent or larger changes from control than 0.5 mg/kg nifedipine or 1.0 mg/kg nicardipine. Furthermore. 8363-S had a longer duration of action following oral administration. The results suggest that important differences in bioavailability exist amongst dihydropyridines which may have important therapeutic implications.

Determination of in utero fetal rat heart rate by ultrasound

A technique for in utero determination of rat fetal heart rat in conscious and anesthetized animals is described. Fetal heart rate was analyzed using echocardiography by recording two-dimensional ultrasound images along with the derived M-mode tracing. This method allows for the simultaneous and sequential analysis of both maternal and fetal heart rate after exposure to therapeutic or environmental agents. When compared to other techniques, this noninvasive approach can clearly yield a more accurate assessment of drug effects on the fetal cardiovascular system. The method eliminates the influence of surgical manipulation on cardiac activity. More importantly, this approach can avoid the use of cardiodepressant anesthetic drugs and their potential interaction with agents under investigation. This method is thereby more sensitive and specific for determining the effects of compounds under study than previously described techniques. To illustrate this system, fetal heart rates are compared after maternal propranolol administration in conscious and anesthetized animals.

STIMULATION OF MYOCARDIUM DURING REPERFUSION INJURY BY A NEW INOTROPE-VASODILATOR AGENT, MCI-154

Summary— The systemic and coronary hemodynamic actions of a newly synthesized inotropic agent structurally related to milrinone and amrinone, MCI‐154 (0.5‐4.0 μg/kg/min IV), were studied in 2 groups of conscious, chronically instrumented dogs with normal or depressed postischemic, reperfused myocardium after a 15‐min coronary artery occlusion. In an additional group of control experiments, the time course of recovery of postischemic, reperfused myocardium was studied to verify the constancy of regional segment shortening in the previously ischemic zone during the time corresponding to drug infusion. Similar inotropic actions of MCI‐154 were observed in both normal and postischemic, reperfused hearts, indicating significant contractile reserve to be present in ‘stunned’ myocardium. Global contractility as measured by peak positive dP/dt was significantly increased in both groups. In postischemic, reperfused myocardium 90 min after initiation of reflow, regional segment function remained depressed at 44% of control but improved to 93% of control after administration of MCI‐154. In addition, MCI‐154 produced significant dose‐related decreases in mean arterial pressure, left ventricular end‐diastolic pressure, end‐diastolic segment length, and diastolic coronary vascular resistance. The data demonstrate that in addition to producing beneficial hemodynamic changes, MCI‐154, a new non‐sympathomimetic inotropic agent, markedly enhances regional contractility of postischemic, reperfused myocardium.