Dopamine produced by the kidney counteracts the prohypertensive and sodium retaining actions of the renin-angiotensin system (RAS). In hypertension, the ability of dopamine to counteract the actions of the RAS is impaired by an increased constitutive activity of genetic variants of G protein-coupled receptor kinase type 4 (GRK4) that act to desensitize dopamine receptors, especially D1 and D3 dopamine receptors. In spontaneously hypertensive rats silencing the GRK4 gene in the kidney improves D1R function, ameliorating the hypertension. More recently, we have reported that GRK4 and the angiotensin II type 1 receptor (AT1R) expressed in the kidney interact to regulate blood pressure in both the normotensive Wistar-Kyoto and spontaneously hypertensive rats. The current study was designed to test the association between GRK4 gene variants R65L, A142V, and A486V and angiotensin II type 1 receptor blocker (ARBs) response in 161 Japanese with essential hypertension. We found that the response (≤140/90 mm Hg) to monotherapy with ARBs (losartan, candesartan, valsartan, or telmisartan) was highly associated with the GRK4 gene variant A142V. The absolute decrease in blood pressure in response to the ARB was also associated with GRK4 A142V only. GRK4 genotype was not associated with plasma aldosterone concentration, plasma renin activity or their ratio. We conclude that the GRK4 gene variant 142V may be both strongly predisposing to essential hypertension and predictive of the initial response to ARB monotherapy.
Hironobu Sanada Junichi Yatabe Midori Sasaki Yatabe Tsuyoshi Watanebe Hirohide Yokokawa Scott M.Williams Jacquelaine Bartlett Robin A Felder Pedro A.Jose
Division of Health Science Research, Fukushima Welfare Federation of Agricultural cooperatives, Fuku Department of Internal Medicine III, Fukushima Medical University School of Medicine,Fukushima, Japa Department of Public Health, Fukushima Medical University School of Medicine, Fukushima,Japan Division of Cardiovascular Medicine, Vanderbilt University Medical Center,Nashville, TN 37232, USA Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Pathology, The University of Virginia Health System, Charlottesville, VA 22908 USA Center for Molecular Physiology Research, Childrens National Medical Center, and Department of Pedi