Superoxide excess in hypertension and aging - A common cause of endothelial dysfunction

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(-).