Effect of Gene Variants on Dopamine Receptor Natriuretic Responses

• Status: Unknown status
• Trial end date: 2013-06-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Virginia
• Collaborator: National Institutes of Health (NIH)
• Treatments: Dopamine; Fenoldopam

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.