Non-competitive antagonism of the α-adrenoceptor-mediated fast component of contraction of rat aorta, by doxazosin and prazosin

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Abstract
1 α-Adrenoceptor antagonists have been compared for their effects on dose-response curves of fast and slow components of contraction of the rat aorta to noradrenaline (NA). 2 All agents caused a competitive antagonism of the slow component of contraction to NA. The order of potency was: prazosin > WB4101 = doxazosin > tiodazosin > phentolamine > corynanthine > trimazosin > rauwolscine. 3 For the fast component, doxazosin, prazosin, tiodazosin and WB4101 caused some depression of the maximum response. Doxazosin (25 nm) and prazosin (25 nm) produced a complete and unsurmountable antagonism of the maximum fast component. Phentolamine, corynanthine, trimazosin and rauwolscine all competitively antagonized the fast component. 4 The degree of antagonism of the fast component by prazosin and its analogues appeared to be directly related to the potency of individual agents for the slow component. WB4101, which was equipotent with doxazosin and more potent than tiodazosin was less effective than either in reducing the fast component. 5 The antagonism of the fast component by prazosin or doxazosin was easily reversed by washing and prevented by phentolamine (2.5 μm). 6 Neither prazosin nor doxazosin in concentrations of up to 2.5 μm had any effect on contractions of the aorta to 5-hydroxytryptamine (5-HT, 0.25–250 μm) or caffeine (20 mm). 7 It is concluded that the ability of some α-adrenoceptor antagonists to produce a non-competitive antagonism of the fast component of contraction is (a) dependent upon blockade of α-adrenoceptors; (b) unrelated to selectivity for α1-adrenoceptors; (c) related to potency and structure. 8 EGTA (3.0 mm) caused a selective suppression of the slow component of contraction to NA. Both doxazosin and prazosin caused a non-competitive antagonism of EGTA-resistant contractions to NA whereas corynanthine showed competitive antagonism. These observations, together with those above imply that prazosin and doxazosin non-competitively antagonize α-adrenoceptor-induced release of calcium in the rat aorta, but competitively antagonize α-adrenoceptor-induced calcium entry.