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)(-).
Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK. cah1p@clinmed.gla.ac.uk
C A
CA
Hamilton
M J
MJ
Brosnan
M
M
McIntyre
D
D
Graham
A F
AF
Dominiczak
D000098:Acetophenones / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001011:Aorta; D001794:Blood Pressure; D002339:Carotid Arteries; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D026901:Membrane Transport Proteins; D009252:NADPH Dehydrogenase / Q000032:analysis; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D009861:Onium Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism*
D000098:Acetophenones; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D009861:Onium Compounds; D010750:Phosphoproteins; D013481:Superoxides; D009569:Nitric Oxide; C007517:diphenyleneiodonium; C056165:acetovanillone; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester