We recently implicated two recurrent somatic mutations in an adrenal potassium channel, KCNJ5, as a cause of aldosterone-producing adrenal adenomas (APAs) and one inherited KCNJ5 mutation in a Mendelian form of early severe hypertension with massive adrenal hyperplasia. The mutations identified all altered the channel selectivity filter, producing increased Na + conductance and membrane depolarization, the signal for aldosterone production and proliferation of adrenal glomerulosa cells. We report herein members of four kindreds with early onset primary aldosteronism of unknown cause. Sequencing of KCNJ5 revealed that affected members of two kindreds had KCNJ5 G151R mutations, identical to one of the prevalent recurrent mutations in APAs. These individuals had severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control. Affected members of the other two kindreds had KCNJ5 G151E mutations, which are not seen in APAs. These subjects had easily controlled hypertension and no evidence of hyperplasia. Surprisingly, electrophysiology of channels expressed in 293T cells demonstrated that KCNJ5 G151E was the more extreme mutation, producing a much larger Na + conductance than KCNJ5 G151R, resulting in rapid Na + -dependent cell lethality. We infer that this increased lethality limits adrenocortical cell mass and the severity of aldosteronism in vivo, accounting for the milder phenotype among these patients. These findings demonstrate striking variations in phenotypes and clinical outcome resulting from different mutations of the same amino acid in KCNJ5 and have implications for the diagnosis and pathogenesis of primary aldosteronism with and without adrenal hyperplasia.adrenal gland | inwardly rectifying potassium channel | Kir3.4 H ypertension affects >1 billion people worldwide (1, 2) and contributes to >7 million deaths each year (3). In the United States, approximately half of adults with hypertension fail to achieve control of blood pressure (4), and successful treatment commonly requires three or more drugs. The study of rare Mendelian forms of hypertension has demonstrated the key role of renal salt reabsorption in blood pressure regulation. Mutations in genes resulting in increased net salt reabsorption markedly raise blood pressure, whereas those that reduce salt reabsorption can cause life-threatening low blood pressure (5, 6).Although in the large majority of hypertensive subjects, the underlying causes are unknown ("essential hypertension"), some cases can be attributed to specific disorders of the kidney and endocrine system (7). Among these, primary aldosteronism is found in ∼10% of patients referred for evaluation of hypertension (8). These patients typically present with hypertension owing to excessive aldosterone secretion that is independent of activity of the renin-angiotensin system and plasma K + levels. High aldosterone levels increase renal salt reabsorption, leading to hypertension.Hypokalemia and metabolic alkalosis are variable feat...
MethodsAtrial natriuretic factor (ANF), a recently sequenced cardiac peptide, has been shown to have potent natriuretic, diuretic, and vasodilating effects in several species. We have developed a radioimmunoassay to measure the levels of immunoreactive ANF in human plasma. Plasma levels of ANF in healthy volunteers on a low sodium diet were 9.8±1.4 pmol/liter and increased to 21.9±3.0 on a high sodium diet. The levels of atrial natriuretic factor correlated directly with urinary sodium and inversely with plasma renin activity and plasma aldosterone levels. Patients with marked edema due to congestive heart failure had plasma levels of atrial natriuretic factor five times higher than normal (P < 0.05), whereas patients with cirrhosis and edema had levels that were not different from normal. These results suggest that atrial natriuretic factor plays an important role in the adaptation to increased sodium intake.
Remodeling of the cerebral vasculature contributes to the pathogenesis of cerebral ischemia. Remodeling is caused by increased smooth muscle proliferation and may be due to an increase in the responsiveness of vascular cells to epidermal growth factor (EGF). Aldosterone is a risk factor for stroke, and the literature suggests it may play a role in increasing the expression of the receptor for EGF (EGFR). We hypothesized that mRNA for the EGF-stimulated pathway would be elevated in the vasculature of stroke-prone spontaneously hypertensive rats (SHRSP) and that this and experimental ischemic cerebral infract size would be reduced by aldosterone inhibition with spironolactone. We found that spironolactone treatment reduced the size of cerebral infarcts after middle cerebral artery occlusion in SHRSP (51.69 +/- 3.60 vs. 22.00 +/- 6.69% of hemisphere-infarcted SHRSP vs. SHRSP + spironolactone P < 0.05). Expression of EGF and EGFR mRNA was higher in cerebral vessels and aorta from adult SHRSP compared with Wistar-Kyoto rats. Only the expression of EGFR mRNA was elevated in the young SHRSP. Spironolactone reduced the EGFR mRNA expression in the aorta (1.09 +/- 0.25 vs. 0.56 +/- 0.11 phosphorimage units SHRSP vs. SHRSP + spironolactone P < 0.05) but had no effect on EGF mRNA. In vitro incubation of aorta with aldosterone +/- spironolactone produced similar results, suggesting a direct effect of aldosterone. Thus spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.
To evaluate the relationship between plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH) and different hemodynamic parameters in man, we studied 34 patients undergoing right heart catheterization. Plasma levels of IR-ANH in blood samples withdrawn from the femoral vein (n = 28), right ventricle (n = 27), and left ventricle (n = 17) were determined by radioimmunoassay. Right atrial pressure, pulmonary arterial wedge pressure, heart rate, and mean arterial pressure were found to be independent and significant predictors of IR-ANH plasma levels. The closest correlations were between right atrial pressure and either right ventricular IR-ANH levels ( evidence of congestive heart failure.14 The purpose of this investigation was to establish the relationship between different hemodynamic parameters and plasma IR-ANH levels in man. MethodsStudy population. Thirty-four patients (33 men and one woman) undergoing right heart catheterization for clinically indicated purposes were studied after informed consent was obtained. Left heart catheterization was also performed in 21 of these patients. Ages ranged from 39 to 74 years (59 + 2). Longterm medications included diuretics in 19, nitrates in 18, X3-blockers in 14, calcium-channel blockers in 10, digitalis in 10, and vasodilators in five patients. Eighteen had left ventricular ejection fractions calculated from contrast ventriculograms, whereas ejection fractions were obtained in 13 from radionuclide ventriculograms. Heart rate, arterial blood pressure, and cardiac output by the thermodilution method were measured, as were pressures in the right atrial, pulmonary arterial, and pulmonary arterial wedge positions. Cardiac index, mean pulmonary arterial pressure, mean systemic arterial pressure, pulmonary vascular resistance, and systemic vascular resistance were calculated from standard fornulas. Before administration of contrast medium and after each patient had been supine for at least 15 min, 7 ml blood samples were withdrawn from the femoral vein (28 patients), right ventricle (27 patients
To determine the role of aldosterone in the regulation of blood pressure (BP) in obese adolescents, supine and 2-hour upright plasma renin activity (PRA), and aldosterone and cortisol were measured in 10 nonobese and 30 obese adolescents before and after a 20-week weight loss program. The obese adolescents had significantly higher supine and 2-hour upright plasma aldosterone concentrations (17 +/- 8 vs 6 +/- 2 ng/dl [p less than 0.01 supine obese vs nonobese] and 30 +/- 11 vs 14 +/- 8 ng/dl [p less than 0.01 2-hour upright]). Although PRA was not significantly different between the 2 groups of children, a given increment in PRA produced a greater increment in aldosterone in the obese adolescents. In addition, obese subjects had a significantly increased mean BP (93 +/- 12 vs 74 +/- 8, p less than 0.005) and a weak correlation between BP and plasma aldosterone concentration. Compared with an obese control group, weight loss resulted in a significant decrease in plasma aldosterone (p less than 0.01) without an associated decrease in PRA. After weight loss there was also a significant decrease in the slope of the posture-induced relation between PRA and aldosterone. In addition to weight loss being associated with a significant decrease in BP (p less than 0.01), there was a significant correlation between the change in plasma aldosterone and the change in mean BP (r = 0.538; p less than 0.002 change in upright aldosterone vs change in mean BP). Obese adolescents have an increased plasma aldosterone concentration that may be important in the regulation of their BP.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.