Superoxide Excess in Hypertension and Aging: A Common Cause of Endothelial Dysfunction

Abstract

There is evidence in humans that hypertension and aging similarly impair endothelial function, although the mechanism remains unclear. Superoxide anion (O 2 − ) is a major determinant of nitric oxide (NO) bioavailability and thus endothelial function. We sought to determine the relationship between endothelial function, O 2 − , and age in normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Aortic rings were removed from female WKY and SHRSP at 3 to 4 months (young) and 9 to 12 months (old). O 2 − generation by aortic rings was measured before and after removal of the endothelium or incubation with N G nitro- l -arginine methyl ester, diphenyleneiodonium, or apocynin. Levels of p22phox were studied with immunohistochemistry and used as a marker of NAD(P)H oxidase expression. NO bioavailability was significantly lower in old WKY compared with young WKY ( P =0.0009) and in old SHRSP compared with young SHRSP ( P =0.005). O 2 − generation was significantly greater in old WKY compared with young WKY ( P =0.0001). Removal of the endothelium and N G nitro- l -arginine methyl ester treatment resulted in a significant reduction in O 2 − generation in old SHRSP ( P =0.009 and 0.001, respectively). Diphenyleneiodonium significantly reduced O 2 − generation in 12-month WKY ( P =0.008) and 12-month SHRSP ( P =0.009). Apocynin attenuated O 2 − generation by older WKY ( P =0.038) and SHRSP ( P =0.028). p22phox was increased in older animals compared with young. We conclude that NO bioavailability decreases with age in female WKY and SHRSP. O 2 − generation increases with age in WKY and is higher in SHRSP and may contribute to the reduced NO by scavenging. NAD(P)H oxidase may contribute to the age-related increase in O 2 − .