Abstract

We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe¹Ψ(CH₂-NH)Gly²]NC(1–13)NH₂ ([F/G]NC(1–13)NH₂) 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 ,10 minutes, 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 heart 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 evoked by NC(1–17)NH₂ and NC(1–13)NH₂ fragments, whereas NC(1–13)OH and NC(1–9)NH₂ 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 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)NH₂ is a potent and selective antagonist of the NC receptor in vivo.

I documenti depositati in UnissResearch sono protetti dalle leggi che regolano il diritto d'autore