Effects of Sildenafil in Resistant Hypertensives and Genetic Polymorphism

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

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 Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Other: sugar pill; Drug: sildenafil

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Campinas, SP, Brazil
      • Laboratory of Cardiovascular Pharmacology - FCM - Unicamp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: sugar pill; Intervention: sugar pill	Other: sugar pill; Sugar pills: 37.5, 50.0, and 100.0 mg each 30 minutes.; Other Names: No brand name.
Active Comparator: sildenafil; Intervention: sildenafil citrate	Drug: sildenafil; Sildenafil pills: 37.5, 50.0, and 100.0 mg each 30 minutes.; 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

Collaborators and Investigators

• Sponsor: University of Campinas, Brazil
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Heitor Moreno, PhD, Faculty of Medical Sciences - Unicamp

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: January 25, 2011
• First Submitted That Met QC Criteria: July 10, 2011
• First Posted (Estimate): July 12, 2011

Study Record Updates

• Last Update Posted (Estimate): October 30, 2012
• Last Update Submitted That Met QC Criteria: October 29, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Polymorphism; Hemodynamics; Sildenafil; Nitric oxide synthase
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: CAAE-0758.0.146.000-09; FAPESP (Other Grant/Funding Number: 2010/50120-4)