The alpha 1-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology.

The antihypertensive efficacy of the new alpha 1-adrenoceptor antagonist doxazosin is described, and its selectivity for alpha 1-adrenoceptors is reported from both in vivo and in vitro studies. Groups of beagle dogs with chronic perinephritic hypertension were given doxazosin orally, and systolic blood pressure was recorded indirectly from an exteriorized carotid loop. Dogs given doxazosin 0.5 mg kg-1 daily for 10 days showed consistent daily falls in systolic pressure in addition to a progressive reduction in daily pre-dose pressures. A clear indication of antihypertensive action in excess of 24 h post dose was evident. Heart rate changes were minimal. In pentobarbitone anaesthetized dogs pretreated with desimipramine, doxazosin 10-500 micrograms kg-1 i.v. reduced responses of the nictitating membrane to electrical stimulation of the vagosympathetic-depressor nerve trunk (an alpha 1-adrenoceptor response) but had no effect on the chronotropic response of the heart to electrical stimulation of the ansa subclavia. In contrast, the prejunctional alpha 2-adrenoceptor antagonist activity of yohimbine 10-100 micrograms kg-1 i.v. was manifest as a marked dose-related increase in both the heart rate and nictitating membrane responses. The lack of effect of doxazosin on postjunctional alpha 2-adrenoceptors in vivo was demonstrated in the anaesthetized cat. Doxazosin at 50 and 100 micrograms kg-1 i.v. inhibited pressor responses to injected phenylephrine (an alpha 1-adrenoceptor agonist) but had no effect on pressor responses to either alpha-methylnoradrenaline (an alpha 2-adrenoceptor agonist) or angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)