EFFECT OF LACIDIPINE ON ISCHEMIC AND REPERFUSED ISOLATED RABBIT HEARTS

Lacidipine is a new developed dihydropyridine calcium-antagonist, show ing a slow onset and long lasting-selective activity. To assess whethe r the administration of lacidipine protects the myocardium in a dose-d ependent manner against ischaemia and reperfusion, isolated rabbit hea rt were infused with three different concentrations of lacidipine: 10( -10); 10(-9); 10(-8) M. Diastolic and developed pressures were monitor ed; coronary effluent was collected and assayed for CPK activity and f or noradrenaline concentration; mitochondria were harvested and assaye d for respiratory activity, ATP production and calcium content and tis sue concentration of ATP, creatine phosphate (CP) and calcium were det ermined. Occurrence of oxidative stress during ischaemia and reperfusi on was also monitored in terms of tissue content and release of reduce d (GSH) and oxidized (GSSG) glutatione. Treatment with lacidipine at 1 0(-10) and 10(-9) M had no effects on the hearts when perfused under a erobic condition, whilst the higher dose reduced developed pressure of 36%. The ischaemic-induced deterioration of mitochondrial function wa s attenuated. On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, repleni shment of ATP and CP stores and mitochondrial function. The reperfusio n-induced tissue and mitochondrial calcium overload, release of CPK an d of noradrenaline and oxidative stress were also significantly reduce d. The effects of lacidipine were dose-dependent. The lower concentrat ion (10(-10) M) failed to modify ischaemic and reperfusion damage. The dose of 10(-9) M was cardioprotective, but the best effect was found at 10(-8) M. It is concluded that lacidipine infusion provides a dose dependent protection of the heart against ischaemia and reperfusion. B ecause this protection occurred also at 10(-9) M, in the absence of ne gative inotropic effect during normoxia and of a coronary dilatory eff ect during ischaemia, it cannot be attributed to an energy sparing eff ect or to improvement of oxygen delivery. From our data we can envisag e two other major mechanism: -1) membrane protection -2) reduction of oxygen toxicity. The ATP sparing effect occurring at 10(-8) M is likel y to be responsable for the further protection.