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D5 dopamine receptor knockout mice and hypertension
Zhiwei Yang1, David R Sibley, Pedro A Jose
1Georgetown University Medical Center, Washington, District of Columbia, USA. zy4@georgetown.edu
Journal of Receptor and Signal Transduction Research
|November 4, 2004
Summary
Dopamine receptor dysfunction contributes to hypertension by impairing sodium transport inhibition. This uncoupling is genetic, leading to elevated blood pressure in both humans and animal models.
Area of Science:
- Cardiovascular Research
- Neuroendocrinology
- Molecular Genetics
Background:
- Dopamine receptor abnormalities are linked to human essential hypertension and rodent genetic hypertension models.
- Genes for dopamine receptors (D1-D5) and regulators are located in hypertension-associated genetic loci.
- D1-like receptors (D1, D5) normally inhibit kidney and intestinal sodium transport.
Purpose of the Study:
- Investigate the role of dopamine receptor dysfunction in hypertension.
- Elucidate the mechanisms underlying impaired D1-like receptor signaling in hypertension.
- Examine the contribution of D1 and D5 receptors to blood pressure regulation and associated pathologies.
Main Methods:
- Analysis of dopamine receptor gene loci in human and rodent hypertension models.
- Assessment of D1-like receptor-mediated sodium transport inhibition in hypertensive rats and humans.
- Genetic disruption of D1 and D5 receptors in mice to evaluate their role in blood pressure regulation.
Main Results:
- D1-like receptor-mediated inhibition of sodium transport is impaired in Dahl salt-sensitive rats, spontaneously hypertensive rats, and humans with essential hypertension.
- This impairment results from a genetic, receptor-, organ-, and nephron segment-specific uncoupling of D1-like receptors from their G protein/effector complex.
- In human essential hypertension, D1 receptor uncoupling is mediated by G protein-coupled receptor kinase type 4.
- D1 and D5 receptor gene disruption in mice increases blood pressure.
- Hypertension in D5 receptor null mice is associated with increased sympathetic nervous system activity via central nervous system receptor activation.
Conclusions:
- Genetic uncoupling of D1-like dopamine receptors is a key mechanism contributing to hypertension.
- Dopamine receptor signaling pathways are critical targets for understanding and potentially treating hypertension.
- Further research is needed to determine the cause of central nervous system receptor activation in D5 receptor null mice.