HOE-694 AFFORDS PROTECTION VERSUS VERATRINE CONTRACTURES IN RAT ATRIABY NA+ CHANNEL BLOCKADE

We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na+-H+ exchange, against veratrine-induced diastolic con tractures and action potentials recorded in rat isolated left atria. C oncentration-dependent protective effects against veratrine-contractur es, in the absence of negative inotropic responses, were observed with HOE 694 (IC50 = 20.1(7.6-27.0) mu M, n = 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with ami loride itself. Concomitant Na+-H+ exchange blockade by a high concentr ation of amiloride (100 mu M) failed to significantly modify the prote ctive effects of HOE 694. HOE 694 decreased V-max significantly at 10 mu M (166.7 +/- 21 vs 154.7 +/- 20 V/s, P < 0.05, n = 6) without any e ffect on resting potential or action potential duration. High concentr ations (100 mu M) of HOE 694 further decreased V-max and increased act ion potential duration. The protective effects of HOE 694 were compare d with three of the class 1 antiarrhythmic agents, quinidine, lidocain e and flecainide against veratrine contracture. These Na+ channel bloc kers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine con tractures at concentrations which presumably affect Na+-H+ exchange. H owever, the mechanism by which HOE 694 affords protection is apparentl y mediated by class 1-type Na+ channel blockade.