Clinical trial NCT01392638: Effects of Sildenafil in Resistant Hypertensives and Genetic Polymorphism
Official title: Influence of the Nitric Oxide Synthase T-786C Polymorphism on the Response to Acute Inhibition of Phosphodiesterase 5 in Resistant Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypertension
Keywords: Sildenafil
Nitric oxide synthase
Polymorphism
Hemodynamics
Lead sponsor: University of Campinas, Brazil
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2011-07-12
Enrollment: 120
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Cardiac Output, total peripheral resistance, mean arterial pressure
timeFrame: Each 30 minutes
Secondary outcomes:
measure: Left ventricular diastolic function parameters, endothelial function
timeFrame: Pre- and post-sildenafil accumulated doses
Other outcomes:
Locations:
city: Campinas
country: Brazil
facility: Laboratory of Cardiovascular Pharmacology - FCM - Unicamp
state: SP
Study officials:
affiliation: Faculty of Medical Sciences - Unicamp
name: Heitor Moreno, PhD
role: PRINCIPAL_INVESTIGATOR
References: