PROTECTIVE EFFECTS OF ITF-296 IN THE ISOLATED RABBIT HEART SUBJECTED TO GLOBAL-ISCHEMIA

The anti-ischemic action of ITF 296 was evaluated in isovolumic, elect rically driven rabbit heart preparations subjected to temporary ischem ia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure. and LV dP/dt, which culminated in complete ve ntricular arrest within 3-4 min. Thereafter, LV end-diastolic pressure (LVEDP) progressively increased, suggesting a severe ischemic episode . Reperfusion with 20 ml Krebs solution/min after 40 min of low-flow p erfusion produced only minimal recovery from the rhythm disturbances a ssociated with cardiac mechanical activity. During reperfusion, loss o f myocardial elasticity was associated with a significant increase in coronary vascular resistance, as indicated by the augmentation of coro nary perfusion pressure. Injection of ITF 296 (0.3-10 mu M) into the p erfusion system dose-dependently inhibited the increase in LVEDP that took place during ischemia and progressively improved the recovery of a regular rhythm in the isolated heart. Isosorbide dinitrate (ISDN) at a concentration of 10 mu M exerted a protective action on the myocard ium similar to that obtained with ITF 296 (3 mu M). Treatment with ITF 296 (1 and 10 mu M) resulted in a dose-dependent increase in the rate of 6-keto-PGF(1 alpha) biosynthesis during both the ischemia and the reperfusion period (+157% over basal values). Similar results were obt ained when hearts were pretreated with ISDN (10 mu M). Infusion of a b uffer containing N-G-monomethyl-L-arginine (L-NMMA; NO synthase inhibi tor at 10 mu M) just before reduction of flow, markedly exacerbated th e effects of ischemia and reperfusion on the myocardium and increased coronary perfusion pressure. The effects of L-NMMA were clearly antago nized by ITF 296 (10 mu M) or L-arginine (100 mu M). Mechanical activi ty and sinus rhythm during reperfusion were rapidly and completely res tored, and coronary resistance values were close to the preischemic va lues. As with ISDN, ITF 296 significantly increased the rate of synthe sis of 6-keto-PGF(1 alpha) both under basal conditions and during repe rfusion.