Antiischemic effects of pirsidomine, a new nitric oxide donor.

The antiischemic effect of pirsidomine (CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl))-sydnon imine), a new nitric oxide donor, was investigated in a model of myocardial infarction in the dog. Dogs were anaesthetised, thoracotomized, and the left descending coronary artery was occluded for 6 h. Pirsidomine was given intraduodenally (i.d.) at the dose of 1.0 mg/kg to 11 dogs 30 min prior to coronary occlusion. Eleven dogs received the solvent i.d. and served as controls. Pirsidomine administration completely prevented the increase in left ventricular end-diastolic pressure and pulmonary artery pressure induced by the coronary occlusion and resulted in a marked decrease in systolic and diastolic blood pressure, cardiac output, left ventricular contractility, left ventricular work and left ventricular oxygen consumption. Additionally, pirsidomine completely prevented the occlusion-induced increase in flow in the non-occluded circumflex coronary artery. Regional blood flow measurements (with radioactive microspheres) revealed that pirsidomine induced a significant reduction in blood flow in the non-ischemic areas (both epi- and endocardial) but in the course of the ischemia, significantly increased flow in the ischemic epicardial areas. Infarct-size (triphenyltetrazolium chloride technique) in control dogs was 45% of the area at risk, but only 26% (P < 0.05) in pirsidomine-treated dogs. Thus, pirsidomine had a marked antiischemic effect in this model. This was probably due to the hemodynamic unloading of the heart as well as to redistribution of blood from the non-ischemic to the ischemic areas of the myocardium.

Protection by carbocromene and molsidomine against arrhythmias occurring during coronary artery occlusion and reperfusion in dogs.

We studied the effects of carbocromene (4 mg/kg plus 40 micrograms/kg/min i.v.) and molsidomine (0.1 mg/kg plus 2 micrograms/kg/min i.v.) on arrhythmias occurring during 90-min occlusion and 30-min reperfusion of the left anterior descending coronary artery in anesthetized dogs. Both drugs reduced the incidence of left ventricular (LV) premature depolarization during ligation (39% after carbocromene and 33% after molsidomine vs. 80% in controls; both p less than 0.05) and tachycardia (44% after carbocromene and 38% after molsidomine vs. 85% in controls; p less than 0.05). During reperfusion, the incidence of LV fibrillation was reduced in the carbocromene- (6 vs. 38% in controls; p less than 0.05) and molsidomine-treated dogs (10 vs. 38% in controls; p less than 0.05). The high incidence of ectopic activity and the ST segment elevation occurring after coronary ligation in control animals were prevented by both drugs. The hemodynamic deterioration after coronary occlusion, i.e., increase in blood pressure, LV systolic and end-diastolic pressures, LV dP/dtmax, and tachycardia observed in controls, was prevented by carbocromene. Molsidomine reduced blood pressure and LV pressure by 18 and 27% (p less than 0.05), respectively, during coronary occlusion. During reperfusion, no hemodynamic alterations occurred in the drug-treated animals. We conclude that carbocromene reduced the electrophysiologic consequences of acute ischemia by hemodynamic and anti-ischemic effects on heart metabolism. Molsidomine protected the jeopardized heart by a similar attenuation of hemodynamic derangement after coronary occlusion and perhaps by influencing prostanoid release from the ischemic myocardium.

Treatment of haemodynamic and electrocardiographic side-effects resulting from imipramine toxicity in rats and dogs.

This study was designed to analyze the effects of carbocromene and dipyridamole on the haemodynamic and electrocardiographic side-effects resulting from imipramine infusion in anaesthetised rats and dogs. Imipramine was infused at 1 mg/kg/min until cardiac failure and vascular collapse terminated the experiment at 21 +/- 2.3 min in rats and at 29.5 +/- 2.1 min in dogs. This was characterized by hypotension, bradycardia, intraventricular conduction delay, cardiac tachyarrhythmia and A-V block. Carbocromene (4 mg/kg i.v., followed by 80 micrograms/kg/min) protected the animals against heart failure. This was associated with delayed hypotension and negative inotropy, and lower incidence of heart block. Survival time increased to 37 +/- 1.5 min (P less than 0.05), and 54.2 +/- 2.6 min (P less than 0.02) in rats and dogs, respectively. Dipyridamole (0.5 mg/kg i.v., followed by 80 micrograms/kg/min) failed to decrease imipramine toxicity as judged by the haemodynamic and electrocardiographic parameters and did not alter survival time of imipramine controls. These results suggest that carbocromene is an effective treatment for imipramine-induced cardiovascular collapse and cardiac arrhythmias, the beneficial effects being largely due to metabolic and membrane stabilizing effects. Carbocromene has both therapeutic and prophylactic value and appears to be superior to dipyridamole therapy.

Comparison of the effects of molsidomine, nitroglycerin and isosorbide dinitrate on experimentally induced coronary artery thrombosis in the dog.

Platelet activation and aggregation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Molsidomine (M), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) have been found to inhibit platelet aggregation in vitro. In the present study, the activity of these compounds was investigated in a model of coronary artery thrombosis in vivo. Dogs were anesthetized, thoracotomized, and their heart was exposed. An electrode was inserted into the left circumflex coronary artery and set to rest on the intima. Electrical stimulation (9 V, 150 microA) lasted for 6 h. Compounds (each in 2 dose levels) were given as an i.v. infusion starting 30 min after the beginning of the stimulation and lasting for the duration of the experiment. All control (saline-treated) animals underwent thrombotic occlusion of the coronary artery as assessed by flow measurement. On the other hand, 2/8 dogs treated with the lower M dose and 4/8 dogs treated with the higher M dose did not have a coronary occlusion. Neither ISDN nor NTG, at both doses, prevented the coronary occlusion. In control animals thrombus wet weight was 74.43 +/- 11.25 mg. M reduced the thrombus weight in a dose-related manner, while ISDN (marginally) and NTG (significantly at the higher dose) increased this parameter. Following the coronary thrombosis, all control animals developed myocardial infarcts as assessed by the tetrazolium technique. Similarly all animals treated with ISDN and with NTG (at both doses) showed infarcts. However, 3/8 M-dogs did not have a myocardial infarction in the lower as well as in the higher dose groups. The hemodynamic changes induced by the 3 compounds were similar in magnitude. Thus M but not ISDN or NTG showed in this in-vivo study antithrombotic and consequently antiischemic activity.

Effect of molsidomine on spontaneous ventricular fibrillation following myocardial ischemia and reperfusion in the dog.

The effect of the novel antianginal agent molsidomine on the incidence of spontaneous ventricular fibrillation during myocardial ischemia and reperfusion was investigated in the anesthetized dog. Molsidomine was administered as an intravenous bolus at the dose of 0.05 mg/kg. Twenty minutes later, the left anterior descending coronary artery was occluded for 90 min. During the occlusion period, molsidomine was given as a continuous intravenous infusion at the dose of 0.5 micrograms/kg per ml per min. After release of the occlusion, the animals that survived were monitored for another 30 min. Control animals received saline. In the control animals, coronary occlusion was accompanied by an increase in heart rate, heart contractility, left ventricular end-diastolic pressure, and blood pressure as well as by ventricular arrhythmias. Molsidomine either abolished or reduced both hemodynamic and electrical changes. During the reperfusion period, 10 out of 12 control animals died, and the deaths were from ventricular fibrillation; one out of eight molsidomine-treated animals also died of ventricular fibrillation. It is postulated that the protective effect of molsidomine rests on its hemodynamic effects resulting in a shift in blood flow toward the ischemic zones and, consequently, in an increase in ventricular electrical stability.

Comparison of various methods for assessing infarct-size in the dog.

Various methods used for the assessment of infarct-size were compared in a canine model of coronary artery occlusion. The ability of molsidomine (an antianginal agent) to reduce infarct-size was also investigated. Open-chest dogs underwent occlusion of the left anterior descending coronary artery and starting 30 min after the occlusion received either molsidomine (n=8) as an infusion at the rate of 1 microgram/kg/min for 30 min and at a rate of 0.75 microgram/kg/min for 2 h, or saline (controls, n=8). Three hours after the occlusion methylene blue was injected into the left atrium for the assessment of the area at risk in vivo (ARV). The animals were then sacrificed, the heart removed and coronary arteriograms made after injection into the left coronary ostium of a BaSO4-gelatin mass to delineate the post-mortem area at risk (ARPM). The hearts were then cut in sections and the infarct's (I) area visualized with nitroblue tetrazolium C1. The left ventricle (LV) and I were also weighed, ARV, ARPM as well as LV and I areas were determined by planimetry. Body weight and LV mass were similar in both groups, I mass however, was markedly lower in molsidomine than in control dogs. Percentages I/LV mass and area were also significantly lower in the treated than in the control animals, and there was a significant correlation between the mass and planimetric methods for determining I size. ARPM/LV % was similar in both groups and I/ARPM % was smaller in molsidomine than in control animals, however this difference was not statistically significant. Molsidomine markedly reduced ARV/LV % which resulted in similar I/ARV ratios both in the treated and control groups. It is concluded: (1) that the direct measurement of I (mass) or the percentages I/LV mass or area are similarly useful for the detection of a pharmacological effect of I size. ARPM is unaffected by drug treatment and thus provides a valid reference point for the assessment of I. ARV may be altered by a pharmacological intervention and thus may give false negative results when used as the basis for expressing I size. (2) Molsidomine is a potent agent for reducing I size.

Effects of intravenous carbocromene on infarct size following acute coronary artery occlusion and reperfusion in the dog.

The effects of the antianginal drug carbocromene on hemodynamics, infarct size, and arrhythmias after 90 min of coronary artery occlusion and following 30 min reperfusion were investigated in anesthetized, open-chest dogs. Carbocromene led to only slight pressure and rate alterations after ligation and reperfusion whereas untreated animals gave evidence of significant changes in these parameters. Furthermore, contractility remained unaffected by carbocromene but was significantly augmented in the control group after both experimental procedures. Preload (end-diastolic pressure) increased after occlusion and reperfusion in both groups, and this augmentation was permanently higher in the controls than in the carbocromene group. Increases in oxygen consumption and in ST-segment elevation were small after drug treatment but significant in control animals. Infarcted areas were significantly smaller in the carbocromene group than in the controls. Hemorrhage occurred in both groups but the amount was significantly smaller in the drug group. The onset of arrhythmias was delayed in the carbocromene group after ligation and reperfusion so that the mortality was significantly lower as compared to that in the non-treated control animals. Carbocromene possibly exerts metabolic effects on the heart, in addition to its coronary dilating properties, which confer the cardioprotective effects observed in acute canine experiments.