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- Title
Increased Superoxide Production in Hypertensive Patients With Diabetes Mellitus: Role of Nitric Oxide Synthase
- Authors
Dixon, Lana J.; Hughes, Sinead M.; Rooney, Keith; Madden, Aine; Devine, Adrian; Leahey, William; Henry, Welby; Johnston, G. Dennis; McVeigh, Gary E.
- Abstract
Background: Hypertension and diabetes are important independent risk factors for increased oxidative stress and increased cardiovascular risk. The combination of hypertension and diabetes results in a dramatic increase in cardiovascular risk. Enhanced oxidative stress in hypertension and diabetes is linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2.−), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, NO synthase III (NOS III) can also produce O2.−. We studied platelet superoxide production in patients with hypertension alone and in patients with coexistent diabetes mellitus, investigating the contribution of NOS III uncoupling to platelet superoxide production. Methods and Results: Gel-filtered platelets were obtained and were stimulated with Phorbol 12-myristate 13-acetate, and O2.− production was detected using lucigenin-enhanced chemiluminescence. Superoxide production was significantly higher in patients with diabetes and hypertension (6.4 ± 1.6 pmol/min/108 platelets) than in patients with hypertension (1.6 ± 0.6 pmol/min/108 platelets) (P < .04). After incorporation of Nω -nitro-l-arginine methyl ester (L-NAME, 1 mmol/L), O2.− detection increased in 40% of patients with diabetes and hypertension and in 87% of patients with hypertension. This expected response results from L-NAME inhibition of NO production preventing NO scavenging of O2.−. A reduction in O2.− production in response to L-NAME occurred in the remaining patients and indicates O2.− production by the uncoupled NOS III enzyme. Conclusions: This study provides first published evidence that NOS III can reside in the uncoupled state in patients with hypertension and, to a greater extent, in patients with coexisting hypertension and diabetes, and that it contributes significantly to increased superoxide production in these disease states.
- Subjects
HYPERTENSION; OXIDATIVE stress; BLOOD platelets; PEOPLE with diabetes; DIABETES
- Publication
American Journal of Hypertension, 2005, Vol 18, Issue 6, p839
- ISSN
0895-7061
- Publication type
Article
- DOI
10.1016/j.amjhyper.2005.01.004