Effect of Gene Variants on Dopamine Receptor Natriuretic Responses

NCT00592150 | Unknown Phase 1

• 1 other identifier: 13072
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertension

Keywords

Essential Hypertension

Outcome Measures

Primary Outcomes (1)

• Urine sodium excretion

  7 days

Secondary Outcomes (1)

• gene dose effect of GPK-4 on fenoldopam induced natriuresis

  7 days

Study Arms (2)

1

EXPERIMENTAL

Fenoldopam infusion

Drug: fenoldopam

2

PLACEBO COMPARATOR

Placebo infusion

Drug: Placebo

Interventions

fenoldopam DRUG

The fenoldopam infusion rate will be 0.05 μg/kg/min for 3 hours

1

Placebo DRUG

Placebo infusion for 3 hours

2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Virginia: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

MeSH Terms

Conditions

Hypertension; Essential Hypertension

Interventions

Fenoldopam

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Robert M Carey, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Distinguished Professor of Medicine

Study Record Dates

• First Submitted: December 27, 2007
• First Posted: January 11, 2008
• Study Start: June 1, 2007
• Primary Completion: March 1, 2008
• Study Completion: June 1, 2013
• Last Updated: January 23, 2013

Record last verified: 2013-01

Locations

US (1)