Mechanisms of action of OPC-28326, a selective hindlimb vasodilator

The unique cardiovascular profile of OPC-28326 [4-(N-methyl-2-phenylethylam ino)-1-(3,5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monoh ydrate] provides insight into basic mechanisms of this new drug as determin ed by experiments in dogs and rats. In anesthetized open-chest dogs, an i.v . administration of a low dose (0.3 and 1.0 mu g/kg) of OPC-28326 selective ly increased femoral artery blood flow with only minimal action on systemic blood pressure, heart rate and coronary, carotid, vertebral, renal, and me senteric blood flows. Biochemical study suggests that OPC-28326 had no effe ct on phosphodiesterase-3 and -5. OPC-28326 dose-dependently inhibited phen ylephrine-induced increases in blood pressure in spinally anesthetized dogs . The potency of OPC-28326 was, however, about 180 times lower than that of prazosin. Although binding studies have revealed an affinity of OPC-28326 to serotonin 5-HT2 receptors, the drug is without effect, except at very hi gh concentrations, on serotonin-induced contraction in an isolated canine f emoral artery preparation. The potency of OPC-28326 on the increase in femo ral artery blood flow was about 14 times higher than that of prazosin but w as at about the same level as that obtained with yohimbine in canine autope rfused femoral artery preparations. In perfused rat hindlimb preparations, OPC-28326 inhibited the decrease in perfusion flow induced by brimonidine, a selective alpha(2)-adrenoceptor agonist. The potency of OPC-28326 was at least 10 times less than that of yohimbine. Taken together, the results sho w that at low doses, OPC-28326 selectively exerts a potent vasodilating eff ect on the femoral arterial bed, in part due to an alpha(2)-adrenoceptor-bl ocking activity.