BACKGROUND: Recent studies have shown that the newly discovered endogenous opioid-like peptide, nociceptin, has vasodilator activity in the peripheral vascular bed. However, little if anything is known about the effects of the peptide in the pulmonary vascular bed. Therefore, responses to nociceptin in the pulmonary vascular bed were investigated and compared with responses in the hindlimb and systemic vascular beds of the rat. METHODS AND RESULTS: Responses to nociceptin were investigated in the pulmonary and hindquarters vascular beds in the rat under constant flow conditions and were compared with decreases in systemic vascular resistance. Under conditions of constant flow, injections of nociceptin in doses of 3-30 nM induced dose-related decreases in pulmonary arterial perfusion pressure when baseline tone was increased to a high steady level with U46619. Pulmonary vasodilator responses to nociceptin were not modified by the opioid receptor antagonist naloxone, and the newly discovered ligand was 10-fold less potent than adrenomedullin in decreasing pulmonary vascular resistance when decreases in pulmonary hind quarters and systemic vascular resistances were compared, nociceptin was significantly more potent in decreasing hindquarters and systemic vascular resistance than in reducing pulmonary vascular resistance. CONCLUSIONS: The results of the present study indicate that nociceptin decreases pulmonary vascular resistance by a naloxone-insensitive mechanism, and that the peptide is less potent in decreasing pulmonary vascular resistance than in decreasing systemic vascular resistance in the rat.