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)