Effect of Gene Variants on Dopamine Receptor Natriuretic Responses

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Robert M. Carey, MD, University of Virginia
ClinicalTrials.gov Identifier:
NCT00592150
First received: December 27, 2007
Last updated: January 22, 2013
Last verified: January 2013
  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 1

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

Resource links provided by NLM:


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 2013
Primary Completion Date: March 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Fenoldopam infusion
Drug: fenoldopam
The fenoldopam infusion rate will be 0.05 μg/kg/min for 3 hours
Placebo Comparator: 2
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
Investigators
Principal Investigator: Robert M Carey, MD University of Virginia
  More Information

No publications provided

Responsible Party: Robert M. Carey, MD, Distinguished Professor of Medicine, University of Virginia
ClinicalTrials.gov Identifier: NCT00592150     History of Changes
Other Study ID Numbers: 13072
Study First Received: December 27, 2007
Last Updated: January 22, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Virginia:
Essential Hypertension

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Dopamine
Fenoldopam
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antihypertensive Agents
Vasodilator Agents
Dopamine Agonists

ClinicalTrials.gov processed this record on April 17, 2014