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Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

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Abstract-The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (nϭ60), 1 (nϭ113), or 2 (nϭ26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age-and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na ϩ than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.

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A B S T R A C T The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136±18 (SE) and 37.4±5.3 Ag/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195±20 Ag/day (P < 0.01) whereas urinary norepinephrine decreased to 21.1±3.0 Ag/day (P < 0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18±0.22 to 2.72 ±0.19 jg/20 min, P < 0.01), but decreased plasma dopamine-fl-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and paminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

Patients with adrenal cortical insufficiency exhibit an increased taste sensitivity for sodium chloride (NaCl) (1). Treatment with carbohydrate-active steroids returns the abnormal threshold to normal levels (1). In a variety of acute and chronic debilitating diseases, a number of them exhibiting major abnormalities of water and electrolyte metabolism, taste threshold for NaCi is comparable to that observed in healthy subjects (1). Taste thresholds for all modalities are decreased in cystic fibrosis, but they do not change after treatment with steroids (2).The present study was designed to examine in detail taste thresholds in adrenal insufficiency and to explore the effect of adrenal cortical hormones on taste. METHODSThe subjects of this study were 13 normal volunteers, aged 6 to 35, two patients with anterior pituitary insufficiency, aged 21 and 36, and seven patients with Addison's disease, aged 25 to 65. All patients with Addison's disease had clinical features of this disease, urinary 17-hydroxycorticosteroids that were below 2 mg per 24 hours and did not increase with adrenocorticotropin (ACTH), 40 U given intravenously over 8 hours, each day for 5 days. Both patients with anterior pituitary insufficiency had hypothyroidism, hypogonadism, and adrenal insufficiency, with urinary 1 7-hydroxycorticosteroids in J.M. and S.P. of 1.1 and 2.2 mg per day, respectively, rising to 27 and 10.9 mg per day, respectively, with ACTH. All patients remained on an air-conditioned metabolic ward and ate a normal diet, which was well tolerated even when they were not receiving treatment. Sodium intake was 100 to 200 mEq per day. Body weight, determined with metabolic scales daily on arising, was used to provide a gross estimate of changes in the volume of body fluids. The patients were studied under each of three conditions: a) untreated for 4 or more days, b) treated with desoxycorticosterone acetate (DOCA), 20 mg per day for 1 to 7 days, and c) treated with prednisolone (A1F), 20 mg per day for 2 to 5 days.In addition, detection thresholds for the taste of NaCl were measured between 7 and 8 a.m. in three normal Caucasian males, aged 18 to 20, before and during treatment with Pitressin. The two levels of sodium intake during Pitressin were 9 mEq and 150 mEq per day. Taste was evaluated by measuring the detection threshold. A detection threshold is defined as the lowest concentration of test solution that can be consistently distinguished from distilled water. Thresholds were measured by one observer in the early morning hours in the normal subjects and in the morning or evening hours, or both, in the patients with adrenal insufficiency. Occasional retesting of the patient by another observer gave comparable results on each occasion. At the time of testing, the patients had not smoked or eaten for at least 1 hour. After the mouth was rinsed with distilled water, the solutions of test substance or glass-distilled water were administered as single drops and placed on alternate sides of the anterior one-third of the tongue.Each...