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Influence of polymorphism T-786C in the nitric oxide synthase gene in response to the acute inhibition of phosphodiesterase 5 in resistant hypertensives

Grant number: 09/13774-9
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2010
Effective date (End): January 31, 2011
Field of knowledge:Biological Sciences - Pharmacology - Clinical Pharmacology
Principal Investigator:Heitor Moreno Junior
Grantee:Caroline Demacq Souza Tarlá
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Endothelial dysfunction is one of the mechanisms involved in the maintenance of the high blood pressure levels in resistants hypertensives patients, which is directly related to the NO-GMPc pathway. The phosphodiesterase 5 inhibitor, sildenafil citrate, slightly reduces systolic and diastolic blood pressures in treated hypertensives patients. However, it is unknown if the simultaneous use of sildenafil plus, at least, 3 classes of antihypertensive agents in patients with resistant arterial hypertension may have a synergic effect on the patients blood pressure. Moreover, sildenafil improves the endogen nitric oxide effects produced by eNOS. Therefore, since the genetics polymorphisms of eNOS can affect the NO tissue levels, it seems reasonable to suppose that the acute effects of sildenafil may be modulated by them. Objective: To examine the influence of the T-786C polymorphism of eNOS gene in sildenafil acute effects on hemodynamic and cardiovascular function in resistant hypertensives patients. Casuistics and Methods: Around 120 patients with HAR will be genotyped for the T-786C eNOS polymorphism, from which we will enroll in this study 15 patients with TT genotype and 15 patients with CC genotype. The patients will be monitored with the Portapres system (non-invasive hemodynamic). After placebo administration and records of the studied variables, increasing doses of sildenafil will be administrated (0.25, 0.50, 2.5, 5.0, 25.0, 50.0 e 100.0 mg). One minute before each new dose, the studied variables will be recorded again. Hypothesis: We hypothesize that the sildenafil, besides the anti-ischemic effect, will improve the patients hemodynamic status and, moreover, that it will occur a modulation of this effect by the T-786C polymorphism. (AU)

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