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CARDIOVASCULAR

NADPH-Induced Contractions of Mouse Aorta Do Not Involve NADPH Oxidase: A Role for P2X Receptors

Department of Pharmacology, Monash University, Clayton, Victoria, Australia (C.P.J., G.R.D.); Department of Pharmacology, University of Melbourne, Victoria, Australia (C.G.S., A.A.M.); Howard Florey Institute, University of Melbourne, Victoria, Australia (T.T.D.); and Bernard O'Brien Institute of Microsurgery, University of Melbourne, Fitzroy, Victoria, Australia (G.J.D.)

Reactive oxygen species elicit vascular effects ranging from acute dilatation because of hydrogen peroxide-mediated opening of K⁺ channels to contraction arising from superoxide-dependent inactivation of endothelium-derived nitric oxide. Given that NADPH oxidases are major sources of superoxide in the vascular wall, this study examined the effects of exogenous NADPH, a substrate of these enzymes, on superoxide generation and isometric tone in mouse isolated aortic rings. NADPH caused concentration-dependent increases in superoxide generation (measured by lucigenin-enhanced chemiluminescence) and vascular tone (isometric tension recordings). However, surprisingly, whereas oxidized NADP⁺ was unable to support superoxide production, it was equally as effective as reduced NADPH at stimulating vasocontraction. In addition, an NADPH oxidase inhibitor, diphenyleneiodonium, markedly attenuated NADPH-induced superoxide production, yet had no effect on vasocontractions to NADPH. In contrast, a broad specificity P2X receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, as well as the P2X1 selective antagonist, NF023, markedly attenuated both endothelium-dependent and -independent vasocontractions to NADPH, as did the P2X-desensitizing agent ,-methylene-ATP. Importantly, ,-methylene-ATP had no effect on superoxide production induced by NADPH. In conclusion, these findings suggest little role for NADPH oxidase-derived superoxide in the contractile effects of NADPH in the mouse aorta. Rather, NADPH seems to act as an agonist at two distinct P2X receptor populations; one located on the endothelium and the other on smooth muscle layer, both of which ultimately lead to contraction.

Address correspondence to: Dr. Grant Drummond, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia. E-mail: grant.drummond{at}med.monash.edu.au

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