Effect of Gene Variants on Dopamine Receptor Natriuretic Responses - Full Text View

Sponsors and Collaborators:	University of Virginia National Institutes of Health (NIH)
Information provided by:	University of Virginia
ClinicalTrials.gov Identifier:	NCT00592150

Purpose

Hypothesis to be tested: Dopamine D1-like receptor-induced natriuresis is impaired in humans with G protein-related kinase 4 gene variants.

Our research group has discovered a D1 receptor/adenylyl cyclase coupling defect in renal PTCs from subjects with essential hypertension. We have found increased GRK-4 activity in renal PTCs in human essential hypertension due to activating variants of GRK-4, an effect that was reproduced in a transfected cell model. Preventing the translation of GRK-4 normalized the coupling of the D1 receptor to adenylyl cyclase in hypertension. Gene variants of GRK-4 cause a ligand-independent serine-phosphorylation of the D1 receptor, resulting in its uncoupling from the G-protein/effector complex.

The desensitization of the D1 receptor in the renal PTC is hypothesized to be the cause of the compromised natriuretic effect of DA that eventually leads to Na+ retention and hypertension. The primary objective of this protocol is to demonstrate that natriuresis engendered by D1-like receptor activation with fenoldopam is blunted in subjects with 3 or more SNPs of GRK-4 compared with responses in subjects with 0-2 SNPs.

Condition	Intervention	Phase
Hypertension	Drug: fenoldopam Drug: Placebo	Phase I

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Dopamine Dopamine hydrochloride Fenoldopam Fenoldopam mesylate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Crossover Assignment, Safety/Efficacy Study
Official Title:	Effect of Gene Variants on Dopamine Receptor Natriuretic Responses (RMC033)

Further study details as provided by University of Virginia:

Primary Outcome Measures:

Urine sodium excretion [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

gene dose effect of GPK-4 on fenoldopam induced natriuresis [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	44
Study Start Date:	June 2007
Estimated Study Completion Date:	June 2010
Estimated Primary Completion Date:	June 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Fenoldopam infusion	Drug: fenoldopam The fenoldopam infusion rate will be 0.05 μg/kg/min for 3 hours
2: Placebo Comparator Placebo infusion	Drug: Placebo Placebo infusion for 3 hours

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Normotensive (NT) Subjects

Men and women between ages of 18 and 70 years (inclusive)
BMI of 18-29 (inclusive).
Healthy as determined by updated full medical history, physical exam and:
Standard 12-lead EKG
Complete blood count and differential
Fasting blood chemistry (metabolic screen and liver enzymes), lipid panel (cholesterol, triglycerides, HDL and LDL cholesterol)
Urinalysis with microscopy.

Hypertensive (HT) Subjects

Men and women between ages of 18 and 70 years (inclusive)
BMI of 18-29 (inclusive).
Mild to moderate hypertension
Established by prior diagnosis
Or established with screening (sitting) diastolic blood pressure in the range of 90 to 114 mm
Healthy as determined by updated full medical history and physical exam and:
Standard 12-lead EKG
Complete blood count and differential
Fasting blood chemistry (metabolic screen and liver enzymes), lipid panel (cholesterol, triglycerides, HDL and LDL cholesterol)
Urinalysis with microscopy.

Exclusion Criteria:

Younger than 18; 71 and older
History of malignant or accelerated hypertension
Contraindication to discontinuing anti-hypertensive medications
Currently taking clonidine
Impaired renal function (serum creatinine > 1.5 mg/dl) or urinary protein excretion > 200 mg/day or continuing active urinary sediment
Myocardial infarction, cerebrovascular accident or transient ischemic attack
Congestive heart failure by history and physical examination, severe peripheral vascular disease
Glaucoma as determined by the referring physician
Pregnancy or nursing
Failure to give informed consent or comply with the protocol
Systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 114 mm Hg (based on the mean of three consecutive measurements) following a three-week withdrawal of antihypertensive medications
Protocol violations such as: failure to discontinue anti-hypertensive medications, failure to be admitted to the GCRC and complete failure to adhere to the prescribed diet.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00592150

Locations

United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22903

Sponsors and Collaborators

University of Virginia

National Institutes of Health (NIH)

Investigators

Principal Investigator:

Robert M Carey, MD

University of Virginia

More Information

No publications provided

Responsible Party:	University of Virginia ( Robert Carey, MD )
Study ID Numbers:	13072
Study First Received:	December 27, 2007
Last Updated:	August 6, 2008
ClinicalTrials.gov Identifier:	NCT00592150 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Virginia:

Essential Hypertension

Study placed in the following topic categories:

Neurotransmitter Agents
Vasodilator Agents
Essential Hypertension
Dopamine
Fenoldopam
Vascular Diseases

Dopamine Agents
Cardiovascular Agents
Dopamine Agonists
Antihypertensive Agents
Hypertension

Additional relevant MeSH terms:

Vasodilator Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Vascular Diseases
Cardiovascular Agents
Antihypertensive Agents

Dopamine Agonists
Pharmacologic Actions
Therapeutic Uses
Fenoldopam
Cardiovascular Diseases
Dopamine Agents
Hypertension

ClinicalTrials.gov processed this record on May 07, 2009