A ouabain sensitive, Mg2+ dependent, Na+, K+ stimulated adenosinetriphosphatase (ATPase) isolated from canine mesenteric arteries was activated by the following vasodilators: hydralazine, diazoxide, PGE1, PGE2, PGA2, and minoxidil. Epinephrine, norepinephrine, and isoproterenol also stimulated the ATPase, but, PGF2α was ineffective. Since these vasodilators activate the adenylate cyclase of vascular smooth muscle, the effects of cyclic adenosine monophosphate (AMP) and theophylline on the Na+, K+ ATPase were studied, both substances caused a concentration dependent increase in enzymatic activity. Propranolol blocked the catecholamine induced stimulation of Na+, K+ ATPase, and polyphloretin phosphate antagonized the effects of the prostaglandins. It is concluded that vasodilatation in response to these substances is associated with the stimulation of the Na+, K+ ATPase of vascular smooth muscle probably mediated through cyclic AMP.