THE NOVEL CALCIUM-ANTAGONIST RO-40-5967 LIMITS MYOCARDIAL INFARCT SIZE IN THE DOG

Objective: The aim was to compare the infarct limiting effect of Ro 40-5967 (Ro40), a new calcium antagonist with little negative inotropic activity, with that of verapamil and with ischaemic preconditioning, a potent endogenous cardioprotective mechanism. Methods: Dogs (n=53) of either sex were subjected to 60 min of coronary occlusion followed by 3 h of reperfusion. Drug treated dogs received either verapamil (1.0 mg.kg(-1)) or Ro40 (3.0 mg.kg(-1)) intravenously for 100 min starting 15 min prior to the occlusion. Control dogs received a saline infusion. Ischaemic preconditioning consisted of four 5 min cycles of ischaemia alternating with four 5 min cycles of reperfusion. After 3 h of reflow, hearts were excised and infarct size was measured using tripheyltetrazolium chloride macrochemistry and expressed as percent of the ischaemic area at risk (AAR). To control for variation in infarct size due to variation in collateral blood flow, infarct size among groups was compared using ANCOVA, in which infarct size and collateral blood flow, measured at 30 min of occlusion, were dependent and independent variables, respectively. Results: Transmural collateral blood flow and AAR were not significantly different between any of the groups. Mean infarct size (adjusted by ANCOVA for slight differences in collateral blood flow among groups) in control dogs (n=13) was 25.9(SEM 3.2)% of the AAR. Both verapamil (n = 11) and Ro40 (n = 9) limited infarct size [14.2(3.2)% AAR and 16.7(2.9)% AAR, respectively; both p < 0.05]. Preconditioning (n = 17) also significantly limited infarct size [8.1(1.8)%; p < 0.01]. Conclusions: The new calcium antagonist, Ro 40-5967, was as effective as verapamil in limiting Infarct size after 60 min of regional ischaemia followed by 3 h of reperfusion, although neither calcium antagonist was as effective as ischaemic preconditioning.