The effects of calcium channel antagonist treatment and oxygen radical scavenging on infarct size and the no-reflow phenomenon in reperfused hearts

Abstract

Calcium antagonists reduce ischemic injury, and anti-free-radical interventions may reduce reperfusion injury. However, the effects of treatment with both interventions have never been investigated. In the present study, anesthetized rabbits underwent 30 minutes of coronary artery ligation, which was followed by 5.5 hours of reflow. Eight animals in each group received: (1) the calcium antagonist gallopamil during ischemia, (2) the oxygen radical scavenger superoxide dismutase during reperfusion, (3) combined treatment with gallopamil and superoxide dismutase, and (4) saline solution. All groups were similar with respect to collateral flow during ischemia and extent of risk region. Infarct size averaged 60.2% ± 5.5% of risk region in controls and was significantly smaller ( p < 0.001) in rabbits that were treated with either gallopamil (28.1% ± 3.4%) or superoxide dismutase (29.3% ± 3.2%). Little further reduction in infarct size was observed with combination therapy (22.9% ± 3.2% of risk region; p = NS). Superoxide dismutase had no effects on hemodynamics, whereas gallopamil significantly reduced heart rate, mean arterial pressure, and rate-pressure product. However, the reduction in infarct size that was observed in gallopamil-treated rabbits significantly exceeded the expected value in this group after corrections were made for changes in these determinants of ischemic injury. Therefore we investigated whether other factors may have contributed to the beneficial effects of gallopamil. In vitro the drug had no oxygen radical scavenging activity, nor did it exert antioxidant effects. In addition, gallopamil did not affect neutrophil function. In conclusion, in this acute model myocardial cell necrosis was significantly reduced either by administration of a calcium antagonist during ischemia or by removing oxygen radicals during reperfusion. However, superoxide dismutase administration did not further reduce infarct size when given to animals that had been treated with gallopamil. Since gallopamil has no direct effect on several mechanisms of reperfusion injury, these data suggest that calcium antagonists, by decreasing myocardial oxygen demand during ischemia, may indirectly reduce oxygen radical damage during subsequent reperfusion.