Effect of Gene Variants on Dopamine Receptor Natriuretic Responses
This study is ongoing, but not recruiting participants.
Sponsor:
University of Virginia
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
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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 June 18, 2013