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We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na(+)-H+ exchange, against veratrine-induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration-dependent protective effects against veratrine-contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50 = 20.1(7.6-27.0) microM, n = 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na(+)-H+ exchange blockade by a high concentration of amiloride (100 microM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmax significantly at 10 microM (166.7 +/- 21 vs 154.7 +/- 20 V/s, P < 0.05, n = 6) without any effect on resting potential or action potential duration. High concentrations (100 microM) of HOE 694 further decreased Vmax and increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na(+)-H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1-type Na+ channel blockade.

An investigation has been made of the putative direct myocardial protective effects of the alpha 1-adrenoceptor antagonists, prazosin and WB4101, against tetanic contractures of rat isolated left atria following modified Na+ channel function and consequent Ca2+ loading elicited by veratrine. Veratrine evoked concentration-dependent, reversible, tetanic contractures which were critically dependent upon the external Ca2+ concentration. Tetrodotoxin (TTX), prazosin, WB 4101 and R 56865 (0.1-10 microM) prevented tetanic contracture elicited by veratrine (100 micrograms/ml) at concentrations which were significantly lower than those which decreased active tension development. The apparent Hill coefficients (nH) obtained for TTX, prazosin, WB 4101 and R 56865 were comparable (range 0.79-0.93), and are consistent with a single site of action. In contrast, the class 1 antiarrhythmic agents, quinidine and lidocaine, elicited no significant inhibition of veratrine-induced contracture at 30 microM, but almost completely abolished the contractures at 100 microM. The nH values for quinidine and lidocaine were found to be significantly greater than unity (3.1 and 2.6, respectively). The L-type Ca2+ channel blockers, diltiazem, nicardipine, nifedipine and verapamil only weakly prevented tetanic contracture, whilst markedly, and concentration-dependently, decreasing active tension development. Neither atropine (10 microM) nor propranolol (1 microM) significantly modified either veratrine-induced contractures or active tension development. In conclusion, evidence is presented of novel, direct protective effects of prazosin and WB 4101 against tetanic contracture following modified Na+ channel function and Ca2+ loading provoked by veratrine. The precise mechanisms involved are unclear at present, but appear to be distinct from blockade of atrial alpha 1-adrenoceptors or L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)