D-[ALA(2)]ENDOMORPHIN-2 AND ENDOMORPHIN-2 HAVE NITRIC OXIDE-DEPENDENTVASODILATOR ACTIVITY IN RATS

Endomorphin 1 and 2, newly discovered endogenous ligands for the mu-op ioid receptor, have vasodepressor activity in the rat. In the present study, the mechanism mediating hemodynamic responses to endomorphin 2 and the endomorphin analog [D-Ala(2)]endomorphin 2 (TAPP) was investig ated in the rat. Intravenous injections of TAPP and endomorphin 2 prod uced similar dose-dependent decreases in systemic arterial pressure an d were similar to 10-fold more potent than Met-enkephalin. TAPP and en domorphin 2 decreased heart rate, cardiac output, and total peripheral resistance, Under constant-flow conditions, injections of TAPP and en domorphin 2 into the perfusion circuit produced decreases in hindquart er perfusion pressure, and vasodilator responses were attenuated by th e opioid receptor antagonist naloxone. Hindquarter vasodilator respons es to TAPP and endomorphin 2 were attenuated by the nitric oxide synth ase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg iv), whereas responses to the endothelium-independent vasodilators cal citonin gene-related peptide, diethylamine/nitric oxide, and isoproter enol were not changed. Hindquarter vasodilator responses to TAPP and e ndomorphin 2 were not altered by the cyclooxygenase inhibitor sodium m eclofenamate, the ATP-dependent K+ channel antagonist U-3 7883A, or th e presence of a time-delay coil in the perfusion circuit. These result s indicate that vasodilator response to TAPP and endomorphin 2 are med iated by the activation of a naloxone-sensitive opioid receptor and th e release of nitric oxide from the endothelium within the hindquarter vascular bed of the rat.