Cardiovascular effects of nociceptin in unanesthetized mice

We evaluated the systemic hemodynamic effects induced by nociceptin (NC) an d NC-related peptides, including the NC receptor antagonist [Phe(1)psi(CH2- NH)Gly(2)]NC1-13)NH2 ([F/G]NC(1-13)NH2) in unanesthetized normotensive Swis s Morini mice. Bolus intravenous injection of NC decreased mean blood press ure and heart rate. The hypotensive response to 10 nmol/kg NC lasted <10 mi nutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114+/-3 to 97+/-2 mm Hg at 10 minutes, P<0.01). The latter dose reduced he art rate from 542+/-43 to 479+/-31 beats/min (P<0.05) and increased aortic blood flow by 41+/-5% (P<0.05). Hypotension and bradycardia were also evoke d by NC(1-17)NH2 and NC(1-13)NH2 fragments, whereas NC(1-13)OH and NC(1-9)N H2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11 , enhanced the hypotension induced by NC(1-13)NH2 and revealed the ability of NC(1-13)OH to decrease mean blood pressure. [F/G]NC(1-13)NH2, a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1-13)NH2 d id not alter the hypotension induced by bradykinin or endomorphin-1 (a mu-r eceptor agonist), and the bradycardia induced by leu-enkephalin (a delta-re ceptor agonist) or U504885 (a synthetic kappa-receptor agonist). In conclus ion, NC and some of its fragments cause hypotension and bradycardia and inc rease aortic blood flow in mice, with the NC(1-13) sequence being critical for these biological effects. Our results also demonstrate that the compoun d [F/G]NC(1-13)NH2 is a potent and selective antagonist of the NC receptor in vivo.