VERATRINE-INDUCED TETANIC CONTRACTURE OF THE RAT ISOLATED LEFT ATRIUM- EVIDENCE FOR NOVEL DIRECT PROTECTIVE EFFECTS OF PRAZOSIN AND WB-4101

An investigation has been made of the putative direct myocardial prote ctive effects of the alpha1-adrenoceptor antagonists, prazosin and WB4 101, 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, teta nic contractures which were critically dependent upon the external Ca2 + concentration. Tetrodotoxin (TTX), prazosin, WB 4101 and R 56 865 (0 .1-10 muM) prevented tetanic contracture elicited by veratrine (100 mu g/ml) at concentrations which were significantly lower than those whic h 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 a t 30 muM, but almost completely abolished the contractures at 100 muM. The nH values for quinidine and lidocaine were found to be significan tly greater than unity (3.1 and 2.6, respectively). The L-type Ca2+ ch annel blockers, diltiazem, nicardipine, nifedipine and verapamil only weakly prevented tetanic contracture, whilst markedly, and concentrati on-dependently, decreasing active tension development. Neither atropin e (10 muM) nor propranolol (1 muM) significantly modified either verat rine-induced contractures or active tension development. In conclusion , evidence is presented of novel, direct protective effects of prazosi n and WB 4101 against tetanic contracture following modified Na+ chann el function and Ca2+ loading provoked by veratrine. The precise mechan isms involved are unclear at present, but appear to be distinct from b lockade of atrial alpha1-adrenoceptors or L-type Ca2+ channels. A poss ible involvement of a TTX-sensitive, quinidine-insensitive site on, or associated with the Na+ channel is suggested.