Role of the renin-angiotensin system in the biosynthesis of aldosterone

Acute infusions of angiotensin II or dog renin into hypophysectomized nephrectomized dogs has no effect on the conversion of corticosterone to aldosterone. This conversion was measured in an isolated mitochondrial fraction obtained from glands excised immediately after the infusion was over.In dogs injected for 4 days with homologous renin, the conversion of corticosterone to aldosterone was significantly increased. This increase resembles that seen in dogs fed with a low sodium diet, which also increases renin secretion. In dogs hypophysectomized the day before starting the renin injections, there was also a significant increase on the conversion of corticosterone to aldosterone.These data suggest that the increased conversion of corticosterone to aldosterone in the sodium deficient animals, is regulated by the renin-angiotensin system. The data also suggests that there is a double effect of angiotensin in the aldosterone biosynthetic pathway: one in “acute” conditions, increasing th

Further studies on the relationship between potassium and sodium levels and adrenocortical activity

Steroid production in vitro by dog adrenal cortical slices was measured in the presence of varying concentrations of sodium and potassium ions. Increasing concentrations of potassium produced a signincant increase in the intracellular potassium content and in the rate of synthesis of aldosterone. However, the potassium effect on aldosterone secretion may also occur without changes in tissue potassium content. Ouabain significantly diminished intracellular potassium content, but inhibited aldosterone production only at the high dose of 2.5 × 10-3 M in the presence of an elevated external potassium level. Physiological changes in sodium concentration can modify aldosterone production. The effect was observed with changes as small as 10 mEq/liter sodium. Changes in external potassium and sodium levels modulate aldosterone as well as corticosterone, but not cortisol production. No changes in the intracellular content of potassium were detectable in angiotensin-stimulated tissue. Neverthel

Hyperreninemic hypoaldosteronism after chronic stress in the rat

The effects of chronic stress on the renin-angiotensin-aldosterone system were studied by analysis of plasma hormone levels, kidney renin mRNA levels, adrenal angiotensin II receptors, and steroidogenesis in rats subjected to repeated immobilization (2 h daily) or intraperitoneal injections of 1.5 M NaCl for 14 d. 24 h after the last stress in both stress models, plasma aldosterone levels were reduced in spite of significant increases in plasma renin activity. Repeatedly intraperitoneal hypertonic saline-injected rats showed plasma renin activity responses to acute immobilization similar to controls, but markedly reduced plasma aldosterone responses. Concomitant with the increases in plasma renin activity, renin mRNA levels in the kidney were significantly increased in intraperitoneal hypertonic saline-injected rats, and these increases were prevented by,B-adrenergic receptor blockade with propranolol. In isolated adrenal glomerulosa cells from chronically stressed rats, maximum aldosterone responses to angiotensin II, ACTH, and 8-Br-cAMP were significantly decreased, whereas pregnenolone responses were increased. P450-aldosterone synthetase mRNA levels and binding of '"I- [Sar',Ile8] angiotensin II were significantly reduced in the adrenal zona glomerulosa of stressed rats. These studies show that chronic repeated stress leads to renin stimulation due to sympathetic activation, and inhibition of aldosterone secretion due to inhibition of the late steroidogenic pathway. The data provide evidence for a role of chronic stress in the development of hyperreninemi

Angiotensin II AT\u3csub\u3e1\u3c/sub\u3e receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress

Sustained pretreatment with angiotensin II AT1 receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT1 receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT1 receptor antagonist, 0.5 mg/kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT1 receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. In rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT1 receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT1 receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT1 receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT1 receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT1 receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions. © 2007 Elsevier B.V. All rights reserved

Acute endotoxemia in rats induces down−regulation of V2 vasopressin receptors and aquaporin−2 content in the kidney medulla

Acute endotoxemia in rats induces down−regulation of V2 vasopressin receptors and aquaporin−2 content in the kidney medulla. Endotoxemia can lead to fluid metabolism alterations despite unchanged or elevated plasma vasopressin (VP) levels, suggesting a refractoriness of the kidney to the effect of the peptide. To test this hypothesis, we examined the effect of lipopolysaccharide (LPS) injection on the expression of V2 receptors and aquaporin−2 in the kidney. Plasma VP and urine osmolality, and binding of [3H]VP to kidney membranes, Western blot, and immunohistochemical analysis of aquaporin−2, in situ hybridization for V2 VP receptors and cytokines mRNAs were measured in the kidney 3 to 24 hours after LPS injection, 250 mug/100 g, intraperitoneally. LPS injection caused prolonged decreases in urine osmolality (up to 24 hours) without significant changes in plasma levels of sodium or VP. This was associated with marked decreases in V2 VP receptor mRNA and VP receptor number in the kidney, which were evident for up to 12 hours after LPS injection. Aquaporin−2 in kidney inner medulla was also reduced by about 50%. LPS induced interleukin (IL)−1beta in the kidney medulla by 3 hours, reached maximum at 6 hours, and started to decline by 12 hours, while it increased IL−6 mRNA significantly only at 3 hours. Interleukin mRNA expression was absent in kidneys of control rats. In vitro incubation of kidney medulla slices with IL−1beta reduced VP binding. The inflammatory response to acute endotoxemia down regulates V2 VP receptors and aquaporin−2 of the kidney inner medulla resulting in prolonged impairment of the renal capacity to concentrate urin