Prevention by specific chemical classes of alpha 1-adrenoceptor antagonists of veratrine-contractures in rat left atria independently of alpha 1-adrenoceptor blockade.
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.
Le Grand
B
B
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases II, Castres, France.
Marty
A
A
Vié
B
B
Patoiseau
J F
JF
John
G W
GW
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008729:Methoxamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D014702:Veratrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D014702:Veratrine; D008729:Methoxamine