Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients

The relationship between blood pressure and sodium (Na) excretion is less steep in hypertension caused by increased renal tubular reabsorption. We recently demonstrated that one mutation in rat α-adducin gene: (1) is responsible for approximately 50% of the hypertension of MHS rats, and (2) stimulates tubular Na-K pump activity when transfected in renal epithelial cell, suggesting that its pressor effect may occur because an increased tubular reabsorption. Linkage and association studies demonstrated that the α-adducin locus is relevant for human hypertension. A point mutation (G460W) was found in human α-adducin gene, the 460W variant (G/W) is more frequent in hypertensives than in normotensives. The aim of this study was to test whether acute changes in body Na may differently affect blood pressure in humans as a function of α-adducin genotype. The pressure-natriuresis relationship was analyzed in 108 hypertensives using two different acute maneuvers: Na removal (furosemide 25 mg p.o.) and, two days later, Na load (310 mmoles i.v. in 2 hr). We found that 80 patients were wild-type homozygous (G/G), 26 were G/W heterozygous, and 2 were W/W homozygous with similar blood pressure, age, body mass index, gender, plasma and urinary sodium and potassium. In basal condition G/W-W/W patients showed a lower plasma renin activity and fractional excretion of Na. In either case the pressure-natriuresis relationship was less steep in G/W-W/W than in G/G patients, obviously negative for Na depletion with furosemide (-0.011 ± 0.004 vs. -0.002 ± 0.002 mm Hg/μmol/min, P < 0.03), and positive for Na load (0.086 ± 0.02 vs. 0.027 ± 0.007 mm Hg/μmol/min, P < 0.001). The finding of reduced slope after Na depletion or Na load supports the hypothesis that, as MHS rats, humans bearing one W α-adducin variant display an increased of renal tubular sodium reabsorption.