To clarify the hypotensive mechanism of adrenergic .alpha. blockers, effects of several .alpha. blockers on systemic blood pressure and on Ca-contracture of isolated cat aortic strips were studied. The effects of known adrenergic .alpha. blockers, phentolamine, phenoxybenzamine and a newly synthesized adrenergic .alpha. blocker (2-(N-(n-Butyloyl)homopiperazine-N''-yl)-4-amino-6,7-dimethoxy quinazoline; E-643) were compared with those of nitroglycerine and verapamil. Systemic blood pressure was decreased by administration (2 .times. 10-8 mol/kg i.v.) of all drugs except phenoxybenzamine. The order of maximal fall of diastolic blood pressure after the injection was nitroglycerine > E-643 > phentolamine > verapamil > phenoxybenzamine. Adrenaline [epinephrine] reversal was observed after 2 .times. 10-7 mol/kg phenoxybenzamine, i.e., a 10-fold increase in the dose of phenoxybenzamine; there was no decrease in systemic blood pressure with this dose. All the drugs in a concentration of 2 .times. 10-6 M inhibited the Ca-contracture (phasic and tonic) of the depolarized aortic strips. The order of inhibition of phasic and tonic contracture was nitroglycerine > E-643, verapamil > phentolamine > phenoxybenzamine. The pA2 [effective concentration of agonist to antagonist] values for phentolamine and E-643 in antagonizing contractions produced by noradrenaline [norepinephrine] of cat aortic strips were 7.8 and 8.2, respectively. Hypotensive effects of the drugs (except phenoxybenzamine), paralleled the inhibitory effects on the Ca-contracture of the aortic strips. .alpha. Blockers such as phentolamine and E-643 exert a systemic hypotensive effect not through their .alpha.-blocking action but by an inhibitory action on the contractile Ca-mechanism.