Nitric oxide release mediates vasodilator responses to endomorphin 1 but not nociceptin/OFQ in the hindquarters vascular bed of the rat

We have recently shown that endomorphin1, an endogenous ligand for the mu-o pioid receptor, and nociceptin (Orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have substantial vasodilator activity in the hindquarte rs vascular bed of the rat. In the present study, the role of nitric oxide, vasodilator prostaglandins, and the opening of K+ATP channels in mediating vasodilator responses to endomorphin 1, PL017, and DAMGO was investigated in the regional vascular bed in the rat. Under constant-flow conditions, in jections of the mu-selective agonists endomorphin 1, PL017 ([N-MePhe(3),D-P ro(4)]-morphiceptin), and DAMGO, and the ORL1 receptor agonist nociceptin/O FQ produced dose-dependent decreases in hindquarters perfusion pressure. Va sodilator responses to endomorphin 1, PL017, and DAMGO, and the endothelium -dependent vasodilators acetylcholine and adrenomedullin were attenuated by the nitric oxide synthase inhibitor r-NAME (50 mg/kg IV) at a time when va sodilator responses to nociceptin/OFQ were not altered. Vasodilator respons es to isoproterenol and prostaglandin E-1, agents known to increase cAMP le vels, and the nitric oxide donor DEA/NO were not altered by the nitric oxid e synthase inhibitor. Responses to endomorphin 1, PL017, DAMGO, and nocicep tin/OFQ were not altered by sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administ ration of U-37883A at a time when vasodilator responses to levcromakalim we re reduced significantly. The results of these studies indicate that respon ses to endomorphin 1, PL017, and DAMGO are mediated in large part by the re lease of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that res ponses to these peptides are not mediated by the release of vasodilator pro staglandins or the opening of K+ATP channels the hindquarters vascular bed. (C) 1998 Elsevier Science Inc.