Mutations in the Na-Cl cotransporter reduce blood pressure in humans

The relationship between salt homeostasis and blood pressure has remained d ifficult to establish from epidemiological studies of the general populatio n. Recently, mendelian forms of hypertension have demonstrated that mutatio ns that increase renal salt balance lead to higher blood pressure, suggesti ng that mutations that decrease the net salt balance might have the convers e effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inheri ted hypokalemic alkalosis with so-called "normal" blood pressure. We hypoth esized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addresse d this question through the study of 199 members of a large Amish kindred w ith Gitelman's syndrome. Through genetic testing, family members were ident ified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, per mitting an unbiased assessment of the clinical consequences of inheriting t hese mutations by comparison of the phenotypes of relatives with contrastin g genotypes. The results demonstrate high penetrance of hypokalemic alkalos is, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of bloo d pressure, with homozygous mutant family members having significantly lowe r age- and gender-adjusted systolic and diastolic blood pressures than thos e of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na+ than did wild-type su bjects, reflecting a self-selected higher salt intake. Finally, heterozygou s children, but not adults, had significantly lower blood pressures than th ose of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood press ure in humans.