The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.

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The effects of carbocromene, 4 mg/kg intravenously, prior to coronary artery occlusion plus 40 μg/kg/min during coronary artery occlusion and reperfusion on ventricular fibrillation threshold (VFT) were studied in pentobarbital-anesthetized open-chest dogs and compared to controls receiving saline. Coronary artery occlusion decreased VFT by 46 ± 4% (mean ± SEM, p < 0.02) in controls and by 22 ± 3 % in drug-treated animals. Reperfusion of the occluded artery decreased VFT by 83 ± 7% (p < 0.01) in controls and by 47 ± 5% in carbocromene-treated hearts (p < 0.02). Hemodynamics did not change in the drug group during coronary artery occlusion. In controls, blood pressure and dP/dt_max decreased while heart rate, end-diastolic pressure and ST-T segments increased significantly during both coronary artery occlusion and reperfusion. The underperfused, ischemic region was assessed by staining with Evans blue and involved 34 ± 3% of the left ventricular mass in controls but only 27 ± 3% in carbocromene-treated hearts (p < 0.05). These results indicate protective effects of carbocromene on ventricular vulnerability in canine hearts during coronary artery occlusion and subsequent reperfusion.

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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.