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Br J Pharmacol. 2006 Nov;149(6):802-9. Epub 2006 Oct 3.

Effects of nitric oxide synthase inhibition with or without cyclooxygenase-2 inhibition on resting haemodynamics and responses to exendin-4.

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1
Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Nottinghamshire, UK. sheila.gardiner@nottingha.ac.uk

Abstract

BACKGROUND AND PURPOSE:

Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase-2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with NG-nitro-L-arginine methyl ester (L-NAME)), on resting cardiovascular variables and on responses to the glucagon-like peptide 1 agonist, exendin-4, which causes regionally-selective vasoconstriction and vasodilatation.

EXPERIMENTAL APPROACH:

Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L-NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin-4 was given 60 min after the onset of L-NAME infusion.

KEY RESULTS:

Parecoxib had no effect on resting cardiovascular variables or on responses to L-NAME. Exendin-4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin-4, but L-NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L-NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response.

CONCLUSIONS AND IMPLICATIONS:

Cyclooxygenase-2-derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L-NAME on the hindquarters vasodilator and tachycardic effects of exendin-4 are consistent with a previous study that showed those events to be beta-adrenoceptor mediated. The additional effect of parecoxib on responses to exendin-4 in the presence of L-NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced.

PMID:
17016494
PMCID:
PMC2014661
DOI:
10.1038/sj.bjp.0706931
[Indexed for MEDLINE]
Free PMC Article
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