Effect of Gene Variants on Dopamine Receptor Natriuretic Responses

Status unconfirmed · Phase 1 · Has a placebo group

Conditions studied: Hypertension

In brief

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.

Key facts

Study ID

NCT00592150

Run by

University of Virginia

People needed

44

Starts

2007-06-01

Expected to finish

2013-06-01

Last updated by the study team

2013-01-23

Who can join

Age: 18 and older, up to 70. Sex: any. Healthy volunteers: accepted.

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:
• 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.

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.

Where it is running

• University of Virginia — Charlottesville, Virginia, United States

Full record on ClinicalTrials.gov

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