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 (O(2)(*-)), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, NO synthase III (NOS III) can also produce O(2)(*-). 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 O(2)(*-) production was detected using lucigenin-enhanced chemiluminescence. Superoxide production was significantly higher in patients with diabetes and hypertension (6.4 +/- 1.6 pmol/min/10(8) platelets) than in patients with hypertension (1.6 +/- 0.6 pmol/min/10(8) platelets) (P < .04). After incorporation of N(omega)-nitro-l-arginine methyl ester ( L-NAME, 1 mmol/L), O(2)(*-) 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 O(2)(*-). A reduction in O(2)(*-) production in response to L-NAME occurred in the remaining patients and indicates O(2)(*-) 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.
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Authors | Lana J Dixon, Sinead M Hughes, Keith Rooney, Aine Madden, Adrian Devine, William Leahey, Welby Henry, G Dennis Johnston, Gary E McVeigh |
Journal | American journal of hypertension
(Am J Hypertens)
Vol. 18
Issue 6
Pg. 839-43
(Jun 2005)
ISSN: 0895-7061 [Print] United States |
PMID | 15925745
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Biomarkers
- Biphenyl Compounds
- Enzyme Inhibitors
- Onium Compounds
- diphenyliodonium
- Superoxides
- NOS3 protein, human
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type III
- Quinacrine
- NG-Nitroarginine Methyl Ester
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Topics |
- Adult
- Aged
- Biomarkers
(blood)
- Biphenyl Compounds
(pharmacology)
- Blood Platelets
(metabolism)
- Diabetes Mellitus, Type 2
(blood, complications)
- Enzyme Inhibitors
(pharmacology)
- Female
- Follow-Up Studies
- Humans
- Hypertension
(blood, complications)
- In Vitro Techniques
- Luminescent Measurements
- Male
- Middle Aged
- NG-Nitroarginine Methyl Ester
(pharmacology)
- Nitric Oxide Synthase
(antagonists & inhibitors)
- Nitric Oxide Synthase Type III
- Onium Compounds
(pharmacology)
- Oxidative Stress
(physiology)
- Quinacrine
(pharmacology)
- Superoxides
(metabolism)
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