D-[Ala2]endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats.
Endomorphin 1 and 2, newly discovered endogenous ligands for the mu-opioid receptor, have vasodepressor activity in the rat. In the present study, the mechanism mediating hemodynamic responses to endomorphin 2 and the endomorphin analog [D-Ala2]endomorphin 2 (TAPP) was investigated in the rat. Intravenous injections of TAPP and endomorphin 2 produced similar dose-dependent decreases in systemic arterial pressure and were approximately 10-fold more potent than Met-enkephalin. TAPP and endomorphin 2 decreased heart rate, cardiac output, and total peripheral resistance. Under constant-flow conditions, injections of TAPP and endomorphin 2 into the perfusion circuit produced decreases in hindquarter perfusion pressure, and vasodilator responses were attenuated by the opioid receptor antagonist naloxone. Hindquarter vasodilator responses to TAPP and endomorphin 2 were attenuated by the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg iv), whereas responses to the endothelium-independent vasodilators calcitonin gene-related peptide, diethylamine/nitric oxide, and isoproterenol were not changed. Hindquarter vasodilator responses to TAPP and endomorphin 2 were not altered by the cyclooxygenase inhibitor sodium meclofenamate, the ATP-dependent K+ channel antagonist U-37883A, or the presence of a time-delay coil in the perfusion circuit. These results indicate that vasodilator responses to TAPP and endomorphin 2 are mediated by the activation of a naloxone-sensitive opioid receptor and the release of nitric oxide from the endothelium within the hindquarter vascular bed of the rat.
Champion
H C
HC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Kadowitz
P J
PJ
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; C105294:endomorphin 2; D019331:NG-Nitroarginine Methyl Ester