Cardiovascular Effects of Nociceptin in Unanesthetized Mice

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Abstract
Abstract —We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe 1 ψ(CH 2 -NH)Gly 2 ]NC(1–13)NH 2 ([F/G]NC(1–13)NH 2 ) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted P P P 2 and NC(1–13)NH 2 fragments, whereas NC(1–13)OH and NC(1–9)NH 2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1–13)NH 2 and revealed the ability of NC(1–13)OH to decrease mean blood pressure. [F/G]NC(1–13)NH 2 , 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)NH 2 did not alter the hypotension induced by bradykinin or endomorphin-1 (a μ-receptor agonist), and the bradycardia induced by leu-enkephalin (a δ-receptor agonist) or U504885 (a synthetic κ-receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice , with the NC(1–13) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1–13)NH 2 is a potent and selective antagonist of the NC receptor in vivo.