| Abstract: | Acute intravenous prazosin (0.05 mg/kg) caused marked falls in mean arterial pressure and postsynaptic alpha 1-adrenoceptor blockade in rabbits. During chronic oral dosing (3--21 days), tolerance developed and blood pressure returned to base-line pretreatment levels. This did not appear to be related to changes in plasma renin activity, body weight, prazosin kinetics, or alpha 2-adrenoceptor responsiveness. However, pressor responses to the alpha 1-adrenoceptor agonist phenylephrine and the mixed alpha 1/alpha 2-agonist noradrenaline increased during chronic prazosin therapy. Despite the development of apparent "tolerance," the response to bolus injections of prazosin was unchanged. No changes in the maximum number of prazosin binding sites or their dissociation constant were observed in the heart, spleen, forebrain, or hindbrain after 21 days treatment. It appears that although compensatory mechanisms develop during chronic prazosin treatment, they are not mediated by alterations in alpha 1-receptor binding but are related to changes in alpha 1-adrenoceptor responsiveness beyond the drug-receptor binding site. |
