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.