EFFECTS OF FELODIPINE ON THE ISCHEMIC HEART - INSIGHT INTO THE MECHANISM OF CYTOPROTECTION

To assess whether the administration of felodipine protects the myocar dium in a dose-dependent manner against ischemia and reperfusion, isol ated rabbit hearts were infused with three different concentrations of felodipine: 10-(10), 10(-9) and 10(-8) M. Diastolic and developed pre ssures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were h arvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (C P), and calcium were determined. The occurrence of oxidative stress du ring ischemia and reperfusion was also monitored in terms of tissue co ntent and release of reduced (GSH) and oxidized (GSSG) glutathione. Tr eatment with felodipine at 10(-10) and 10(-9) RM had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 +/- 2.6 to 30.0 +/- 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untrea ted hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of develop ed pressure was 100% at 10(-8) M, 55% at 10(-9) M, and 46% at 10(-10) M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also signi ficantly reduced. The effects of felodipine were dose dependent. Felod ipine inhibited the initial rate of ATP-driven calcium uptake but fail ed to affect the initial rate of mitochondrial calcium transport. It i s concluded that felodipine infusion provides dose-dependent protectio n of the heart against ischemia and reperfusion. Because this protecti on also occurred at 10(-9) M and 10-(10) M in the absence of a negativ e inotropic effect during normoxia and of a coronary dilatory effect d uring ischaemia, it cannot be attributed to an energy-sparing effect o r to improvement in oxygen delivery. From our data we can envisage two other major mechanisms-(1) membrane protection and (2) reduction in o xygen toxicity. The ATP-sparing effect occurring at 10-(8) M is likely to be responsible for the further protection.