Effects of Sildenafil in Resistant Hypertensives and Genetic Polymorphism

Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01392638
• Other study ID #: CAAE-0758.0.146.000-09
• Secondary ID: FAPESP
• Status: Completed
• Phase: N/A
• First received: January 25, 2011
• Last updated: October 29, 2012
• Start date: July 2010
• Est. completion date: September 2012

Study information

• Verified date: October 2012
• Source: University of Campinas, Brazil
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: September 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 75 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension

Intervention

Other:
• sugar pill
Sugar pills: 37.5, 50.0, and 100.0 mg each 30 minutes.

Drug:
• sildenafil
Sildenafil pills: 37.5, 50.0, and 100.0 mg each 30 minutes.

Locations

Country	Name	City	State
Brazil	Laboratory of Cardiovascular Pharmacology - FCM - Unicamp	Campinas	SP

Sponsors (2)

Lead Sponsor	Collaborator
University of Campinas, Brazil	Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiac Output, total peripheral resistance, mean arterial pressure	Hemodynamic measures each 30 minutes	Each 30 minutes	No
Secondary	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	No