Apparent activities of 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase are impaired in adrenal incidentalomas.
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OBJECTIVE: An increased response of 17-hydroxyprogesterone to ACTH stimulation has been observed in adrenal incidentaloma and linked to an impairment of either 21-hydroxylase or of 11beta-hydroxylase activity. To analyse this question further, we investigated the steroidogenic pathways in a series of 17 adrenal incidentalomas. DESIGN AND PATIENTS: 17 patients (7 women, 10 men; mean age, 62 +/- 12 years) with non-histologically analyzed adrenal incidentalomas were prospectively evaluated. METHODS: The following variables were investigated: 24-h urinary methanephrines and free cortisol excretion; plasma levels of ACTH and dehydroepiandrosterone; overnight dexamethasone suppression test; 1-24 ACTH stimulation test with measurement of: cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, 11-deoxycorticosterone, progesterone, 17-hydroxypregnenolone, Delta4-androstenedione, dehydroepiandrosterone and 21-deoxycortisol. RESULTS: Discordant features of subclinical hypercorticism were noted in one case. No patient had dehydroepiandrosterone sulfate levels in the normal range for his or her age. Peak 17-hydroxyprogesterone and peak 21-deoxycortisol disclosed impairment of 21-hydroxylase in 11 and 10 cases respectively. An increased 11-deoxycortisol/cortisol ratio identified reduced activity of 11beta-hydroxylase in 11 patients. Eight patients displayed features of mild 17,20-lyase impairment, which was related to 21-hydroxylase dysfunction. Whereas only 2 patients showed no enzyme modification, 9 displayed alterations of at least two pathways. CONCLUSION: In our hands, a combination of enzyme dysfunction was frequently observed. Shared biochemical mechanisms could explain combined 17,20-lyase and 21-hydroxylase alterations, whereas coexistence of 21-hydroxylase (particularly when based on peak 21-deoxycortisol) and 11beta-hydroxylase is more puzzling. (+info)
Aldosterone-producing adenoma without hypertension: a report of two cases.
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Normotensive primary hyperaldosteronism is exceedingly rare. We report two new cases of this syndrome in two middle-aged women, one of Asian origin. The presenting signs were tetany in one case and an adrenal mass in the other. Neither patient had hypertension, despite repeated measurements with a manual armlet. A typical biological profile of primary hyperaldosteronism was demonstrated in both patients, including hypokalemia with inappropriate kaliuresis, elevated resting plasma aldosterone, and undetectable plasma renin activity. The circadian rhythm of blood pressure was studied by ambulatory monitoring pre- and post-operatively. It confirmed the lack of hypertension, but the circadian rhythm of blood pressure was lost before surgery in one patient. Surgical removal of the histologically typical aldosterone-producing adenomas normalized the kalemia. The main finding in these two patients was spontaneously low blood pressure in the post-operative period. This suggests that excess aldosterone induced relative hypertension in these patients whose blood pressure was spontaneously very low. Genetic screening for dexamethasone-sensitive hyperaldosteronism was negative in both patients. (+info)
Vascular remodeling in hypertensive transgenic mice.
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We physiologically and histopathologically analyzed vascular damage due to hypertension and vascular remodeling in hypertensive transgenic mice (Tsukuba hypertensive mice; THM). Pubertal (6-week-old) THM already had hypertension similar to blood pressure in adult THM due to an enhanced renin angiotensin system (RAS). They progressively developed remarkable vascular hypertrophy composed of dedifferentiation of vascular smooth muscle cells (VSMCs) and extracellular matrix accumulation in the thoracic aorta, and VSMC hyperplasia was predominant in the abdominal aorta. THM are therefore a useful animal model for studying vascular remodeling mediated by enhanced RAS. (+info)
The Xenopus laevis distal tubule epithelial cell line A6 was used as a model epithelia to study the role of isoprenylcysteine-O-carboxyl methyltransferase (pcMTase) in aldosterone-mediated stimulation of Na(+) transport. Polyclonal antibodies raised against X. laevis pcMTase were immunoreactive with a 33-kDa protein in whole cell lysate. These antibodies were also reactive with a 33-kDa product from in vitro translation of the pcMTase cDNA. Aldosterone application increased pcMTase activity resulting in elevation of total protein methyl esterification in vivo, but pcMTase protein levels were not affected by steroid, suggesting that aldosterone increased activity independent of enzyme number. Inhibition of pcMTase resulted in a reduction of aldosterone-induced Na(+) transport demonstrating the necessity of pcMTase-mediated transmethylation for steroid induced Na(+) reabsorption. Transfection with an eukaryotic expression construct containing pcMTase cDNA increased pcMTase protein level and activity. This resulted in potentiation of the natriferic actions of aldosterone. However, overexpression did not change Na(+) reabsorption in the absence of steroid, suggesting that pcMTase activity is not limiting Na(+) transport in the absence of steroid, but that subsequent to aldosterone addition, pcMTase activity becomes limiting. These results suggest that a critical transmethylation is necessary for aldosterone-induction of Na(+) transport. It is likely that the protein catalyzing this methylation is isoprenylcysteine-O-carboxyl methyltransferase and that aldosterone activates pcMTase without affecting transferase expression. (+info)
Phosphoinositide 3-kinase is required for aldosterone-regulated sodium reabsorption.
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Aldosterone, a steroid hormone, regulates renal Na+ reabsorption and, therefore, plays an important role in the maintenance of salt and water balance. In a model renal epithelial cell line (A6) we have found that phosphoinositide 3-kinase (PI 3-kinase) activity is required for aldosterone-stimulated Na+ reabsorption. Inhibition of PI 3-kinase by the specific inhibitor LY-294002 markedly reduces both basal and aldosterone-stimulated Na+ transport. Further, one of the products of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate, is increased in response to aldosterone in intact A6 monolayers. This increase occurs just before the manifestation of the functional effect of the hormone and is also inhibited by LY-294002. With the use of blocker-induced noise analysis, it has been demonstrated that inhibition of phosphoinositide formation causes an inhibition of Na+ entry in both control and aldosterone-pretreated cultures by reducing the number of open functional epithelial Na+ channels (ENaCs) in the apical membrane of the A6 cells. These novel observations indicate that phosphoinositides are required for ENaC expression and suggest a mechanism for aldosterone regulation of channel function. (+info)
Early aldosterone action: toward filling the gap between transcription and transport.
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The mineralocorticoid hormone aldosterone stimulates transcellular Na+ reabsorption across target epithelia after a lag period of 20 to 60 min by first activating preexisting channels (epithelial sodium channels, ENaC) and pumps (Na-K-ATPase) and, subsequently, increasing the overall transport capacity of the cells. Both these early regulatory and late anabolic-type actions depend on the transcriptional regulation exerted by hormone-activated mineralocorticoid and/or glucocorticoid receptors (MR and/or GR). Starting at the transcriptional side of the aldosterone action, recent studies have identified the small G protein K-Ras2 and the kinase sgk as the first early aldosterone-induced gene products potentially regulating Na+ transport. At the level of the Na+ transport effectors, much knowledge about ENaC and Na-K-ATPase structure-function relationship and regulation has accumulated. However, the regulatory pathway(s) that link the transcriptional action of aldosterone to these Na+ transport proteins is still to a large extent unknown. The available data suggest that the early regulatory action of aldosterone is pleiotropic, similarly to the late anabolic-type action. The early Na+ transport stimulation would be mediated by the rapid induction of gene products belonging to the regulatory network that integrates the inputs of diverse pathways and finally controls the function of the Na+ transport machinery. (+info)
Nifedipine and arotinolol in combination for accelerated-malignant hypertension: results of one year follow-up.
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The effects of a combined therapy with a calcium channel antagonist and alphabeta-blocker in patients with accelerated-malignant hypertension on blood pressure and renal function were examined. Thirteen patients presented with the clinical features of malignant hypertension (diastolic blood pressure >130 mmHg, retinal damage and progressive renal failure) at our hospital, over the 3 yr period from 1995 to 1997. These patients were treated with both a calcium antagonist, 60-80 mg/d dose of long acting nifedipine, and an alphabeta-blocker, 20 mg/d dose of arotinolol, for over 12 mo. At admission, the average blood pressure of the patients was 233+/-8/144+/-3 mmHg. The level of serum creatinine in these patients was 6.2+/-1.0 mg/dl. Intermittent hemodialysis therapy was introduced in 7 patients. Three days after treatment, blood pressure decreased to 162+/-4/102+/-4 mmHg. A month later, blood pressure decreased to 148+/-3/89+/-2 mmHg and serum creatinine levels were 3.6+/-0.4 mg/dl. Renal function in these patients improved, and they completely recovered from renal dysfunction, allowing withdrawal of haemodialysis therapy. One year later, the blood pressure in all of these patients was well controlled and no further renal deterioration was observed, except in one patient. Despite the reduction in blood pressure, one patient was on hemodialysis three times a week after 8 mo of treatment. From these finding, it is concluded that combination therapy with a calcium antagonist and alphabeta-blocker is effective in both the reduction of highly elevated blood pressure and protection of the kidneys, resulting in amelioration of accelerated-malignant hypertension. (+info)
Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension.
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Low-renin essential hypertension (LREH) describes a widely recognized classification validated by clinical features, including salt-sensitive blood pressure and diuretic responsiveness. Classic physiological teaching has cited normal plasma aldosterone concentration despite suppressed renin as evidence for adrenal supersensitivity to angiotensin II (Ang II). We studied 94 patients with LREH, 242 normal-renin hypertensives, and 135 normal subjects as controls. Low-renin hypertensives did not differ significantly from the other groups in either basal or Ang II-stimulated aldosterone concentrations on a high-sodium diet. Stimulated with a low-sodium diet, LREH patients demonstrated the smallest rise in basal aldosterone secretion. Ang II responsiveness was also subnormal: the rise in aldosterone after Ang II infusion in LREH (613+/-39 pmol/L), although greater than in nonmodulators (180+/-17 pmol/L; P=0.001), was less than either the patients with intact modulation (940+/-53 pmol/L; P=0.001) or normotensives (804+/-50 pmol/L; P<0.05). Blacks with LREH demonstrated an even lower response than low-renin whites ((388+/-50 versus 610+/-47 pmol/L; P=0.0001). In contrast, the rise in systolic blood pressure with Ang II infusion on a low-salt diet was greatest among LREH patients (P=0. 001). Patients with LREH and nonmodulators were equally salt-sensitive. These results indicate that the adrenal response in LREH is normal on a high-salt diet but becomes progressively more abnormal as sodium control mechanisms are stressed. The factors that mediate enhanced adrenal response to Ang II with sodium restriction may be defective, suggesting the existence of alternative physiological mechanisms for sodium homeostasis in the low-renin state. (+info)