Effects of Sildenafil in Resistant Hypertensives and Genetic Polymorphism

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Influence of the Nitric Oxide Synthase T-786C Polymorphism on the Response to Acute Inhibition of Phosphodiesterase 5 in Resistant Hypertension

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Other: sugar pill
* Drug: sildenafil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: resistant hypertensive (according to Resistant Hypertension - AHA Statement - 2008); compliance with antihypertensive treatment; age >35 years; diastolic dysfunction Exclusion Criteria: valvulopathy decompensated heart failure important cardiac arrhythmias nephropathy hepatopathy autoimmune disease tabagism decompensated diabetes uncontrolled dislipidemia

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: sugar pill<br>Intervention: sugar pill | Other: sugar pill<br>* Sugar pills: 37.5, 50.0, and 100.0 mg each 30 minutes.<br>* Other names: No brand name.;|
| Active Comparator: sildenafil<br>Intervention: sildenafil citrate | Drug: sildenafil<br>* Sildenafil pills: 37.5, 50.0, and 100.0 mg each 30 minutes.<br>* Other names: Viagra, Pfizzer Lab., USA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Output, total peripheral resistance, mean arterial pressure | Hemodynamic measures each 30 minutes | Each 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular diastolic function parameters, endothelial function | Assessment of how hemodynamic changes determined by sildenafil would affect endothelial and left ventricular diastolic parameters. | Pre- and post-sildenafil accumulated doses | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sildenafil, Nitric oxide synthase, Polymorphism, Hemodynamics