The protective effects of D-600 and propranolol on reperfusion injury in the anaesthetized rabbit

Abstract

The ability of a calcium channel blocker (D-600) and a β-adrenergic antagonist (propranolol) to modify the chemical, biochemical, functional, and ultrastructural manifestations of reperfusion injury following circumflex coronary artery ligation has been examined using an open chest, anaesthetized rabbit model of acute myocardial ischaemia. A 40-min ligation period followed by 60 min of reperfusion produced a decrease in mitochondrial azide-sensitive ATPase activity which could be prevented by pretreatment with either agent. While both drugs caused an equivalent (approximately 50%) reduction in myocardial Ca2+ accumulation associated with reperfusion, only D-600 preserved Mg2+ and Na+ levels. The greater protective effects of D-600 on sarcolemmal integrity were also apparent from its superior ability (when compared with propranolol) to offer protection against the loss of sarcolemmal Na+–K+ ATPase activity which we have previously suggested may parallel the development of irreversible ischaemic injury. Further support for these biochemical data came from ultrastructural studies in which we demonstrated significant improvement in subcellular membrane integrity by both of the drugs. In contrast to the foregoing protective actions, D-600 and propranolol failed to prevent the marked decrease in myocardial contractile function and in cellular ATP content associated with reperfusion. In conclusion, our studies have shown that both D-600 and propranolol can limit the injury caused by ischaemia and reperfusion. The superior effectiveness of D-600 in our system cannot be explained on the basis of Ca2+ antagonism alone, but is more likely a result of its greater negative inotropism.