(Hypertension. 1999;33:914-919.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Cardiovascular Effects of Nociceptin in Unanesthetized Mice
From Clinica Medica (P.M.) and Farmacologia (P.M., M.B.S., A.F.M., C.E.), University of Sassari; National Laboratory of the National Institute of Biosystems and Biostructures (P.M., C.E.), Osilo; Department of Pharmaceutical Sciences (R.G.) and Department of Experimental and Clinical Medicine (D.R., G.C.), Section of Pharmacology, University of Ferrara; Laboratory of Vascular Pathology (P.M., M.B.S., C.E.), Istituto Dermopatico dell'Immacolata, Rome, Italy.
Correspondence to Paolo Madeddu, MD, Clinica Medica, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it
Abstract—We evaluated the
systemic hemodynamic effects induced by nociceptin (NC)
and NC-related peptides, including the NC receptor
antagonist
[Phe1
(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 
-receptor
agonist) or U504885 (a synthetic 
-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.
Key Words: hypotension • blood pressure • heart rate • nociceptin • [Phe1(CH2-NH)Gly2]NC(1–13)NH2 • mouse
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