Background: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension. Methods: In Japanese patients with newly diagnosed, untreated hypertension (n ‫؍‬ 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D 1 receptor (D 1 R)-inhibited renal sodium transport. We used the multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (>10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D 1 R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n ‫؍‬ 18). Results: A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predic-

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

Abstract-Abnormalities in D 1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D 1 receptor function in hypertension. We measured renal GRK4 and D 1 and serine-phosphorylated D 1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious-uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D 1 receptors were Ϸ90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D 1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D 1 receptor control of sodium excretion and blood pressure in genetic hypertension. The uncoupling of the D 1 -like receptor from its effector proteins in the kidney in hypertension is associated with increased phosphorylation of the D 1 receptor. 4,5 In human essential hypertension, single nucleotide polymorphisms of the G protein-coupled receptor (GPCR) kinase 4 (GRK4) are associated with constitutive phosphorylation and desensitization of the D 1 receptor in renal proximal tubules. 4 -6 These lead to sodium retention and hypertension. Indeed, transgenic mice expressing the GRK4 variant, GRK4␥A142V, develop hypertension that is associated with an impaired D 1 receptormediated natriuresis. 5 To determine whether aberrant GRK4 function contributes to the impaired renal D 1 receptor function in SHRs, we studied the renal expression of GRK4 and the effects of decreasing its expression in the kidney by a chronic renal cortical interstitial infusion of GRK4 antisense (As) oligodeoxynucleotides (Odns) in conscious SHRs and their normotensive controls, Wistar-Kyoto (WKY) rats. If an increased GRK4 activity in the kidney is responsible for the increased blood pressure in SHRs, this maneuver should improve D 1 receptor-mediated renal tubular handling of sodium and ameliorate the high blood pressure in SHRs without affecting these variables in WKY rats.