Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats.
We undertook these studies to determine whether a deficient nitric oxide production in genetically hypertensive rats could result from its being scavenged by an excess production of superoxide. In one study we used a porphyrinic microsensor to measure nitric oxide concentrations released by cultured endothelial cells from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). SHRSP cells released only about one third the concentration of nitric oxide as did WKY cells. Treatment of cells with superoxide dismutase increased nitric oxide release, demonstrating that normally nitric oxide is scavenged by endogenous superoxide. The increase in nitric oxide release in response to superoxide dismutase treatment was more than twice as great from SHRSP as from WKY cells, demonstrating the greater amount of superoxide in the hypertensive rats. A direct measure of superoxide with the use of lucigenin demonstrated the presence of 68.1 +/- 7.1 and 27.4 +/- 3.5 nmol/L of this anion in SHRSP and WKY endothelial cells, respectively. The presence of superoxide in the rat aorta was also estimated by quantification of its effect on carbachol relaxation. This relaxation was diminished when endogenous superoxide dismutase was blocked by diethyldithiocarbamic acid. This blockade reduced the relaxation by 51.2 +/- 5.2% in SHRSP aortas and by only 22.0 +/- 8.2% (P = .015) in WKY aortas. Data from these diverse systems are in agreement that superoxide production is excessive in SHRSP tissues. This excess superoxide, by scavenging endothelial nitric oxide, could contribute to the increased vascular smooth muscle contraction and hence to the elevated total peripheral resistance of these rats.
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003470:Culture Media; D003627:Data Interpretation, Statistical; D004050:Ditiocarb / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D016166:Free Radical Scavengers; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014655:Vascular Resistance
D003470:Culture Media; D016166:Free Radical Scavengers; D013481:Superoxides; D009569:Nitric Oxide; D004958:Estradiol; C073106:3,17-diacetoxyestra-1,3,5(10)-trien-2-carboxylic acid; D004050:Ditiocarb; D013482:Superoxide Dismutase