title: Non-competitive antagonism of the alpha-adrenoceptor-mediated fast component of contraction of rat aorta, by doxazosin and prazosin.
abstract: alpha-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). All agents caused a competitive antagonism of the slow component of contraction to NA. The order of potency was: prazosin greater than WB4101 = doxazosin greater than tiodazosin greater than phentolamine greater than corynanthine greater than trimazosin greater than rauwolscine. 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. 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. The antagonism of the fast component by prazosin or doxazosin was easily reversed by washing and prevented by phentolamine (2.5 microM). Neither prazosin nor doxazosin in concentrations of up to 2.5 microM has any effect on contractions of the aorta to 5-hydroxytryptamine (5-HT, 0.25-250 microM) or caffeine (20mM). It is concluded that the ability of some alpha-adrenoceptor antagonists to produce a non-competitive antagonism of the fast component of contraction is (a) dependent upon blockade of alpha-adrenoceptors; (b) unrelated to selectivity for alpha 1-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 alpha-adrenoceptorinduced release of calcium in the rat aorta, but competitively antagonize alpha-adrenoceptor-induced calcium entry.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D011799:Quinazolines; D014665:Vasodilator Agents; D017292:Doxazosin; D002118:Calcium; D009638:Norepinephrine; D011224:Prazosin