Article date: May 1994
By: Bruno Le Grand, Aline Marty, Bruno Vié, Jean‐François Patoiseau, Gareth W. John, in Volume 112, Issue 1, pages 195-199
The putative direct protective effects of a series of chemically diverse α1‐adrenoceptor antagonists against veratrine alkaloid‐induced tetanic contractures in rat isolated left atria have been investigated.
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°C. Veratrine (100 μg ml−1) was applied to the atria to elicit tetanic (diastolic) contracture.
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 μm, and from 0.86 to 1.09, respectively, and are consistent with interaction at a single site.
In contrast, no protective activity versus veratrine‐contractures was observed with corynanthine, 5‐methyl‐urapidil, phenoxybenzamine, phentolamine or chloroethylclonidine (10 μm).
Contractures were prevented by prazosin at concentrations 2–3 log units higher than those which antagonized methoxamine‐evoked inotropic responses. In addition, concommitant α1‐adrenoceptor occupancy by high concentrations of methoxamine (100 μm), phentolamine (10 μm, 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.
Our findings demonstrate that α1‐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 α1‐adrenoceptors.
The putative direct protective effects of a series of chemically diverse α1‐adrenoceptor antagonists against veratrine alkaloid‐induced tetanic contractures in rat isolated left atria have been investigated.
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°C. Veratrine (100 μg ml−1) was applied to the atria to elicit tetanic (diastolic) contracture.
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 μm, and from 0.86 to 1.09, respectively, and are consistent with interaction at a single site.
In contrast, no protective activity versus veratrine‐contractures was observed with corynanthine, 5‐methyl‐urapidil, phenoxybenzamine, phentolamine or chloroethylclonidine (10 μm).
Contractures were prevented by prazosin at concentrations 2–3 log units higher than those which antagonized methoxamine‐evoked inotropic responses. In addition, concommitant α1‐adrenoceptor occupancy by high concentrations of methoxamine (100 μm), phentolamine (10 μm, 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.
Our findings demonstrate that α1‐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 α1‐adrenoceptors.
DOI: 10.1111/j.1476-5381.1994.tb13051.x
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