Antinoradrenergic activity of thymoxamine and its metabolites in rats

The alpha-adrenoceptor blocking activity of thymoxamine and its two metabolites deacetylthymoxamine and N-demethyldeacetylthymoxamine was determined on the norepinephrine-induced contraction of rat vas deferens and thoracic aorta and the blood pressure increase induced by intravenously administered norepinephrine in anesthetized normotensive and pithed rats. In isolated rat vas deferens, the three drugs act as competitive antagonists (thymoxamine pA2 = 6.75;l deacetylthymoxamine pA2 = 6.57; N-demethyldeacetylthymoxamine pA2 = 6.20). At the level of the thoracic aorta, the three drugs act as antagonists with a dual mode of action (thymoxamine pA2 = 6.55--pD2' = 4.70; deacetylthymoxamine pA2 = 6.53--pD2' = 4.70; N-demethyldeacetylthymoxamine pA2 = 5.61--pD2' = 4.63). In anesthetized normotensive or pithed rats, thymoxamine and deacetylthymoxamine produce an antagonism of the hypertensive response to norepinephrine. Thymoxamine and deacetylthymoxamine present nearly the same alpha-blocking activity in vitro and in vivo. N-demethyldeacetylthymoxamine is less active.