Effects of Sildenafil in Resistant Hypertensives and Genetic Polymorphism
Sildenafil citrate slightly reduces blood pressure 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. The nitric oxide is an important signaling molecule in the body that contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth. Hypertension often impaired NO pathways. Nitric oxide is produced by an enzyme, called nitric oxide synthase (NOS3), that show some genetics variants, which means that this enzyme can be different from person to person. Therefore, the objective of the present study is to examine the influence of a genetic variant (known to affect NOS3 levels) in sildenafil acute effects on hemodynamic and cardiovascular function. The investigators hypothesis is that individuals with the genetic variant associated to higher levels of NOS3 will have more benefits from sildenafil treatment.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
|Official Title:||Influence of the Nitric Oxide Synthase T-786C Polymorphism on the Response to Acute Inhibition of Phosphodiesterase 5 in Resistant Hypertension|
- Cardiac Output, total peripheral resistance, mean arterial pressure [ Time Frame: Each 30 minutes ] [ Designated as safety issue: No ]Hemodynamic measures each 30 minutes
- Left ventricular diastolic function parameters, endothelial function [ Time Frame: Pre- and post-sildenafil accumulated doses ] [ Designated as safety issue: No ]Assessment of how hemodynamic changes determined by sildenafil would affect endothelial and left ventricular diastolic parameters.
|Study Start Date:||July 2010|
|Study Completion Date:||September 2012|
|Primary Completion Date:||July 2012 (Final data collection date for primary outcome measure)|
Placebo Comparator: sugar pill
Intervention: sugar pill
Other: sugar pill
Sugar pills: 37.5, 50.0, and 100.0 mg each 30 minutes.
Other Name: No brand name.
Active Comparator: sildenafil
Intervention: sildenafil citrate
Sildenafil pills: 37.5, 50.0, and 100.0 mg each 30 minutes.
Other Name: Viagra, Pfizzer Lab., USA
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 the investigators 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 basal records of the studied variables, increasing doses of sildenafil will be administrated (37.5, 50.0 e 100.0 mg). Five minutes before each new dose, the studied variables will be recorded again. Hypothesis: The investigators 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.
|Laboratory of Cardiovascular Pharmacology - FCM - Unicamp|
|Campinas, SP, Brazil|
|Principal Investigator:||Heitor Moreno, PhD||Faculty of Medical Sciences - Unicamp|