A COMPARISON OF THE EFFECTS OF TMB-8 AND NIFEDIPINE ON PRESSOR-RESPONSES TO ALPHA(1)-ADRENOCEPTOR AND ALPHA(2)-ADRENOCEPTOR AGONISTS IN PITHED RATS

TMB-8 has been characterized as an inhibitor of the release of Ca2+ from intracellular pools. We have studied the modification of the pressor responses to selective alpha(1)-adrenoceptor agonists (methoxamine and phenylephrine), and to selective alpha(2)-adrenoceptor agonists (B-HT 920 and B-HT 933) in pithed rats, produced by TMB-8. We have compared this modification with that produced by the calcium antagonist nifedipine. Nifedipine (100 mu g/kg, 300 mu g/kg, and 1000 mu g/kg) inhibited in a dose-dependent manner the presser responses to the alpha(1)- and alpha(2)-adrenoceptor agonists, the dose-response curves to the alpha(2)-adrenoceptor agonists being shifted further to the right. TMB-8 at a dose of 3000 mu g/kg did not modify the presser effects of the alpha(1)-adrenoceptor agonists, and neither did it reinforce the inhibition of such responses produced by nifedipine. By contrast, TMB-8 pretreatment (0.03 mu g/kg, 0.3 mu g/kg, 3 mu g/kg, 30 mu g/kg, 300 mu g/kg and 3000 mu g/kg) inhibited the responses to both a,-adrenoceptor agonists, the inhibition being more pronounced with B-HT 920. A similar effect was obtained with 0.03 mu g/kg TMB-8 and 0.3 mu g/kg TMB-8, particularly in the case of B-HT 920. It was stronger with higher doses, but similar for all doses over 3 mu g/kg. The inhibition of the presser responses mediated by the stimulation of alpha(2)-adrenoceptors by TMB-8 was less in rats treated with the Ca2+ entry promoter BAY K 8644 (300 mu g/kg), and could also be reduced by the continuous infusion of CaCl2 (0.25 mu g/min). These results suggest that in pithed rats TMB-8 may also behave as an inhibitor of the Ca2+ influx into vascular smooth muscle.