NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in older Fischer 344 rats

• Published in: American journal of physiology. Heart and circulatory physiology 2003-09, Vol.54 (3), p.H1015
• Main Authors: Adler, Alexandra, Messina, Eric, Sherman, Ben, Wang, Zipping
• Format: Article
• Language: English
• Subjects: Cardiovascular disease; Metabolism; Nitric oxide; Rodents
• ISSN: 0363-6135; 1522-1539

We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 plus or minus 2%at4moto66 plus or minus 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 plus or minus 0.04 to 1.00 plus or minus 0.10 ml (P < 0.01)] and heart weight (from 0.70 plus or minus 0.02 to 0.90 plus or minus 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 plus or minus 2 or 34 plus or minus 3%) and 14 mo (29 plus or minus 1 or 25 plus or minus 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 plus or minus 3 or 7 plus or minus 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 plus or minus 3%) or enalaprilat (28 plus or minus 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease. [PUBLICATION ABSTRACT]