Cellular Pathophysiology of Mutant Voltage-Dependent Ca2+ Channel CACNA1H in Primary Aldosteronism.

The physiological stimulation of aldosterone production in adrenocortical glomerulosa cells by angiotensin II and high plasma K+ depends on the depolarization of the cell membrane potential and the subsequent Ca2+ influx via voltage-activated Ca2+ channels. Germline mutations of the low-voltage activated T-type Ca2+ channel CACNA1H (Cav3.2) have been found in patients with primary aldosteronism. Here, we investigated the electrophysiology and Ca2+ signaling of adrenal NCI-H295R cells overexpressing CACNA1H wildtype and mutant M1549V in order to understand how mutant CACNA1H alters adrenal cell function. Whole-cell patch-clamp measurements revealed a strong activation of mutant CACNA1H at the resting membrane potential of adrenal cells. Both the expression of wildtype and mutant CACNA1H led to a depolarized membrane potential. In addition, cells expressing mutant CACNA1H developed pronounced action potential-like membrane voltage oscillations. Ca2+ measurements showed an increased basal Ca2+ activity, an altered K+ sensitivity, and abnormal oscillating Ca2+ changes in cells with mutant CACNA1H. In addition, removal of extracellular Na+ reduced CACNA1H current, voltage oscillations, and Ca2+ levels in mutant cells, suggesting a role of the partial Na+ conductance of CACNA1H in cellular pathology. In conclusion, the pathogenesis of stimulus-independent aldosterone production in patients with CACNA1H mutations involves several factors: i) a loss of normal control of the membrane potential, ii) an increased Ca2+ influx at basal conditions, and iii) alterations in sensitivity to extracellular K+ and Na+. Finally, our findings underline the importance of CACNA1H in the control of aldosterone production and support the concept of the glomerulosa cell as an electrical oscillator.

Insufficiency of the zona glomerulosa of the adrenal cortex and progressive kidney insufficiency following unilateral adrenalectomy - case report and discussion.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension and bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) seem to be the most common causes of PA. Unilateral adrenalectomy (UA) is the preferred treatment for APA, although the benefits are still difficult to assess. CASE REPORT: We present a case report of a 69-year old man with a 30 year history of hypertension and probably long-standing PA due to APA, with typical organ complications. Since repeated abdominal CT scans were equivocal, not showing radiological changes characteristic for PA, the diagnosis of APA was delayed and was only finally confirmed by adrenal venous sampling which demonstrated unilateral aldosteronism. The patient underwent UA, complicated by mineralocorticoid deficiency syndrome and increased creatinine and potassium levels. At 12 months follow-up the patient still had hyperkalemia and was fludrocortisone dependent. CONCLUSIONS: Older patients and patients with long-lasting PA who are treated with UA may demonstrate deterioration of renal function and develop transient or persistent insufficiency of the zona glomerulosa of the remaining adrenal gland necessitating fludrocortisone supplementation. Transient hyperkalemia may be observed following UA as a result of the prolonged effects of aldosterone antagonists and/or transient mineralocorticoid/glucocorticoid insufficiency. Additionally, the level of progression of chronic kidney disease after UA is difficult to predict. There likely exists a group of patients who might paradoxically have higher cardiovascular risk due to significant deterioration in kidney function not only resulting from the removal of the aldosterone induced glomerular hyperfiltration phenomenon. Identification of such a group requires further detailed investigation.

Combined Salt and Caloric Restrictions: Potential Adverse Outcomes.

BACKGROUND: We hypothesized that caloric restriction (CR) and salt restriction (ResS) would have similar effects on reducing cardiovascular risk markers and that combining CR and ResS would be synergistic in modulating these markers. METHODS AND RESULTS: To test our hypothesis, rats were randomized into 2 groups: ad libitum liberal salt diet (ad libitum/high-sodium, 1.6% sodium) or ResS diet (ad libitum/ResS, 0.03% sodium). CR was initiated in half of the rats in each group by reducing caloric intake to 60% while maintaining sodium intake constant (CR/high-sodium, 2.7% sodium or CR/ResS, 0.05% sodium) for 4 weeks. CR in rats on a high-sodium diet improved metabolic parameters, renal transforming growth factor-ß and collagen-1α1 and increased plasma adiponectin and renal visfatin and NAD+ protein levels. Although CR produced some beneficial cardiovascular effects (increased sodium excretion and reduced blood pressure), it also was associated with potentially adverse cardiovascular effects. Adrenal zona glomerulosa cell responsiveness and aldosterone levels and activation were inappropriately increased for the volume state of the rodent. Like CR on HS, CR on a ResS diet also produced relative increased zona glomerulosa responsiveness and an increased blood pressure with no improvement in metabolic parameters. CONCLUSIONS: These results suggest that combining CR and ResS may decrease the beneficial effects of each alone. Furthermore, CR, regardless of dietary salt intake, inappropriately activates aldosterone production. Thus, caution should be used in combining ResS and CR because the combination may lead to increased cardiovascular risk.

Effect of exposure to hypoxia from birth on aldosterone in rabbits: role of unesterified fatty acids.

Hypoxia and fluid and electrolyte disturbances are serious risks to normal postnatal development. Because a decrease in inspired O2 (hypoxic hypoxia) inhibits aldosterone synthesis in the adult and aldosterone controls water and electrolyte balance, we studied adrenocortical function in rabbits exposed to normobaric normoxia or hypoxic hypoxia (fraction of inspired O2 0.09) from birth. At 21 days of age, rabbits were anesthetized, the adrenals were rapidly removed, and the adrenal capsules containing mostly zona glomerulosa cells were separated. Cells were dispersed with collagenase and studied in vitro. Hypoxia in vivo resulted in a 73% decrease in basal aldosterone release and a 86% decrease in adenosine 3',5'-cyclic monophosphate-stimulated aldosterone release in vitro. We hypothesized that increased unesterified fatty acids could be partly responsible for inhibition of aldosterone synthesis. Total serum unesterified fatty acids in hypoxic kits were significantly increased (298 +/- 14 micromol/l) compared with normoxic kits (184 +/- 31 micromol/l). When cells from hypoxic rabbits were washed with fatty acid-free albumin and studied under conditions devoid of fatty acids, aldosterone production was partially restored. Corticosterone production was not affected by washing. Washing had no effect on aldosterone synthesis by cells from normoxic rats. Finally, exposing washed zona glomerulosa cells to oleic acid (10-50 microM) inhibited aldosteronogenesis. We conclude that exposure to hypoxia from birth attenuates aldosterone production in part due to an increase in levels of unesterified fatty acid levels.

[The morphofunctional characteristics of the zona glomerulosa of the adrenal cortex in rats with hereditary stress-induced arterial hypertension]. / Morfofunktsional'nye osobennosti klubochkovoi zony kory nadpochechnika krys s nasledstvennoi stress-indutsirovannoi arterial'noi gipertenziei.

Morphometrical analysis of adrenal cortex glomerular zone performed in rats with hereditary stress-induced arterial hypertension assisted in establishing important peculiarities of the zone structure. Adrenocorticocytes of adrenal cortex glomerular zone in hypertension rats are subjected to hyperplastic intercellular changes, suggesting the increase of the zone functional activity, which is substantiated by data on significantly high aldosterone concentration in plasma of these animals.

Gingival hyperplasia induced by calcium channel blockers: mode of action.

Gingival hyperplasia is a known side effect in patients treated with diphenylhydantoin, cyclosporin and the calcium channel antagonists. The present study proposes a mechanism by which calcium channel antagonists may induce gingival hyperplasia. The calcium antagonist induces blockage of the aldosterone synthesis in zona glomerulosa of the adrenal cortex since this pathway is calcium-dependent, cyclic nucleotide-independent. This may produce a feedback stimulation of an increase in pituitary secretion of ACTH which affects zona glomerulosa hyperplasia. This hyperplasia is merely related by accumulation of steroid intermediate products (androgens) that are transformed to testosterone because of an increase in 17-alpha-hydroxylase enzyme activity. Elevated levels of testosterone may act on the gingival cells and matrix to produce gingival hyperplasia.