Protection of Reperfused Ischemic Pig Myocardium by Nexopamil, a New Combined Ca2+ and Serotonin Antagonist

Abstract

We investigated the ability of a newly developed calcium and serotonin (5-HT2) antagonist, nexopamil, to protect the heart from ischemia- and reperfusion-induced myocardial injury. Anesthetized open-chest minipigs were subjected to 1 h left anterior descending coronary artery (LAD) occlusion and 3-h reperfusion. Thirty minutes before occlusion, one group of pigs (n = 7) received nexopamil (0.1 mg/kg intravenously, i.v.) and another group (n = 9) received vehicle. Nexopamil reduced infarct size (IS: tetrazolium stain) from 47 +/- 4% (vehicle) to 21 +/- 7% of the ischemic area (p < 0.05). In nexopamil-treated pigs, this was paralleled by reduced release of creatine kinase (CK) into coronary venous blood. In addition, nexopamil prevented reperfusion-associated myocardial contracture. Nexopamil decreased left ventricular peak pressure (LVPP) and pressure rate index (PRI) immediately before coronary occlusion by 11 and 18%, respectively. Coadministration of methoxamine (2 mg/kg, n = 6) with nexopamil increased LVPP and PRI to values of vehicle-treated pigs but did not prevent reduction in infarct size or CK activity in plasma. During reperfusion, neutrophil granulocytes showed increased formation of reactive oxygen metabolites (chemiluminescence) after stimulation with zymosan. Neutrophil counts in coronary venous blood were significantly reduced at 3 h reperfusion. Both changes were attenuated in nexopamil-treated pigs. Coronary occlusion resulted in increased platelet reactivity in coronary venous blood (collagen-induced aggregation) that was prevented by nexopamil. Nexopamil significantly increased the transcardiac (coronary venous-arterial) concentration gradients of 6-oxo-prostaglandin F1 alpha (PGF1 alpha) without changing thromboxane (B2 (TBX2) concentrations, indicating a selective increase in cardiocoronary PGI2 formation. Nexopamil reduces myocardial injury in reperfused ischemic myocardium. Besides calcium channel blocking activity, inhibition of ischemia-induced neutrophil activation and enhanced endogenous PGI2 formation may be factors contributing to the beneficial effects of nexopamil.