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

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.