We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1c(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 11463 to 9762 mm Hg at 10 minutes, P,0.01). The latter dose reduced heart rate from 542643 to 479631 beats/min (P,0.05) and increased aortic blood flow by 4165% (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 m-receptor agonist), and the bradycardia induced by leu-enkephalin (a d-receptor agonist) or U504885 (a synthetic k-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.
Cardiovascular effects of nociceptin in unanesthetized mice
GUERRINI, Remo;CALO', Girolamo
1999
Abstract
We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1c(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 11463 to 9762 mm Hg at 10 minutes, P,0.01). The latter dose reduced heart rate from 542643 to 479631 beats/min (P,0.05) and increased aortic blood flow by 4165% (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 m-receptor agonist), and the bradycardia induced by leu-enkephalin (a d-receptor agonist) or U504885 (a synthetic k-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 in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
