1. The putative direct protective effects of a series of chemically diverse alpha 1-adrenoceptor antagonists against
veratrine alkaloid-induced tetanic
contractures in rat isolated left atria have been investigated. 2. Atria were mounted in organ
baths containing normal, oxygenated physiological
salt solution (20 ml, pH 7.4), for isometric tension recording. Atria were electrically driven at 4 Hz and were maintained at 34 degrees C.
Veratrine (100 micrograms ml-1) was applied to the atria to elicit tetanic (diastolic)
contracture. 3. Concentration-dependent protective effects against
veratrine-
contractures, in the absence of negative inotropic responses, were observed with the
quinazoline congeners,
prazosin and
doxazosin and with the benzodioxane-related compounds,
WB 4101 and its thio analogue,
benoxathian. IC50 concentrations and apparent Hill coefficients of all four drugs ranged from 0.27 to 0.93 microM, and from 0.86 to 1.09, respectively, and are consistent with interaction at a single site. 4. In contrast, no protective activity versus
veratrine-
contractures was observed with
corynanthine,
5-methyl-urapidil,
phenoxybenzamine,
phentolamine or
chloroethylclonidine (10 microM). 5.
Contractures were prevented by
prazosin at concentrations 2-3 log units higher than those which antagonized
methoxamine-evoked inotropic responses. In addition, concomitant alpha 1-adrenoceptor occupancy by high concentrations of
methoxamine (100 microM),
phentolamine (10 microM, inactive per se in preventing
contracture), or both drugs together, failed, in each case, to modify significantly the protective effects of
prazosin or
WB 4101 against
veratrine-
contractures. 6. Our findings demonstrate that alpha 1-adrenoceptor antagonists which prevent
veratrine-
contractures belong to specific chemical classes of the
quinazoline- and benzodioxane-type. The mechanism by which these drugs afford protection is apparently independent of an interaction with defined alpha 1-adrenoceptors.