In this study the role of the endothelium was evaluated in the relaxation of rat aortic rings induced by a number of alpha adrenergic antagonists. Phentolamine, a nonselective alpha adrenergic antagonist, relaxed rat aortic rings that were previously contracted with an EC80 dose of phenylephrine, in a concentration-dependent manner. Removal of the endothelium significantly reduced the sensitivity but not the amplitude of the response. The presence of endothelium also enhanced the vascular relaxation induced by yohimbine, a specific alpha-2 adrenergic antagonist (10(-8)-10(-6) M), and by prazosin, a specific alpha-1 adrenergic antagonist (10(-11)-10(-9) M). Both methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, and eicosatetraynoic acid (3.2 X 10(-5) M) blocked the endothelial augmentation of vascular relaxation to phentolamine. Vessels precontracted with potassium chloride were slightly relaxed by phentolamine (10(-8)-10(-6) M) only with the endothelium was intact. Both methylene blue and eicosatetraynoic acid also inhibited the response to phentolamine in the intact vessels precontracted with potassium chloride. Prazosin (10(-9)-10(-7) M) and yohimbine (10(-8)-10(-6) M), unlike phentolamine, failed to induce relaxation in potassium chloride-precontracted vessels. When the vessels were precontracted with the thromboxane analog U46619 none of the three alpha antagonists induced vascular relaxation. These results indicate that the endothelium has a significant role in promoting relaxation induced by the three alpha adrenergic antagonists tested.