PT  - JOURNAL ARTICLE
AU  - Courtney P. Judkins
AU  - Christopher G. Sobey
AU  - Thuy T. Dang
AU  - Alyson A. Miller
AU  - Gregory J. Dusting
AU  - Grant R. Drummond
TI  - NADPH-Induced Contractions of Mouse Aorta Do Not Involve NADPH Oxidase: A Role for P2X Receptors
AID  - 10.1124/jpet.105.096610
DP  - 2006 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 644--650
VI  - 317
IP  - 2
4099  - http://jpet.aspetjournals.org/content/317/2/644.short
4100  - http://jpet.aspetjournals.org/content/317/2/644.full
SO  - J Pharmacol Exp Ther2006 May 01; 317
AB  - 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 α,β-methylene-ATP. Importantly, α,β-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. The American Society for Pharmacology and Experimental Therapeutics