ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension

Gómez-Sánchez, Elise P.; Venkataraman, Mythili T.; Thwaites, D.; Fort, C.

doi:10.1152/ajpendo.1990.258.4.e649

Cited by 105 publications

(96 citation statements)

References 30 publications

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“…It has also been shown that intracerebroventricularly administered aldosterone increases blood pressure in the unilaterally nephrectomized rat, and this effect is not mimicked by corticosterone. In fact, corticosterone antagonizes the action of aldosterone (35).…”

Section: Figmentioning

confidence: 98%

Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Rogerson¹,

Dimopoulos²,

Sluka³

et al. 1999

Journal of Biological Chemistry

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The structural determinants of aldosterone binding specificity in the mineralocorticoid receptor (MR) have not been determined. The MR has greatest sequence identity with the better characterized glucocorticoid receptor (GR), which is reflected in their overlapping ligand binding specificities. There must be subtle sequence differences that can account for the MR-specific binding of aldosterone and the shared binding of cortisol. To characterize ligand binding specificity, chimeras were made between the human MR and GR ligand-binding domains (LBDs). Three points were chosen as break points to generate a total of 16 different constructs. These chimeric LBDs were placed in a human GR expression vector containing the GR DNA-binding and N-

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Section: Figmentioning

confidence: 98%

Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Rogerson¹,

Dimopoulos²,

Sluka³

et al. 1999

Journal of Biological Chemistry

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“…Other investigators have administered glucocorticoid agonists and antagonists into the brain to investigate the central nervous system actions of glucocorticoids on blood pressure regulation, but the results have been varied due in part to differences in dose, stress level of the animals, and route of administration (26,27,59,60,62,69). Most of the previous studies have utilized intracerebroventricular administration of these drugs, confounding interpretation of the results since glucocorticoids might have opposing effects on blood pressure at different locations within the central nervous system.…”

Section: Chronic Delivery Of Mif To the Dhbmentioning

confidence: 99%

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

Bechtold

Patel²,

Hochhaus³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Exogenous glucocorticoids act within the hindbrain to enhance the arterial pressure response to acute novel stress. Here we tested the hypothesis that endogenous glucocorticoids act at hindbrain glucocorticoid receptors (GR) to augment cardiovascular responses to restraint stress in a model of stress hyperreactivity, the borderline hypertensive rat (BHR). A 3-to 4-mg pellet of the GR antagonist mifepristone (Mif) was implanted over the dorsal hindbrain (DHB) in WistarKyoto (WKY) and BHRs. Control pellets consisted of either sham DHB or subcutaneous Mif pellets. Rats were either subjected to repeated restraint stress (chronic stress) or only handled (acute stress) for 3-4 wk, then all rats were stressed on the final day of the experiment. BHR showed limited adaptation of the arterial pressure response to restraint, and DHB Mif significantly (P Յ 0.05) attenuated the arterial pressure response to restraint in both acutely and chronically stressed BHR. In contrast, WKY exhibited a substantial adaptation of the pressure response to repeated restraint that was significantly reversed by DHB Mif. DHB Mif and chronic stress each significantly increased baseline plasma corticosterone concentration and adrenal weight and reduced the corticosterone response to stress in all rats. We conclude that endogenous corticosterone acts via hindbrain GR to enhance the arterial pressure response to stress in BHR, but to promote the adaptation of the arterial pressure response to stress in normotensive rats. Endogenous corticosterone also acts in the hindbrain to restrain corticosterone at rest but to maintain the corticosterone response to stress in both BHR and WKY rats. corticosterone; brain; nucleus of the solitary tract; hypothalamicpituitary-adrenal axis; chronic stress EXAGGERATED CARDIOVASCULAR responses to acute stress and chronic stress increase the risk for hypertension and cardiovascular disease (1,3,13,15,31,38,42,58,68). Acute stress rapidly increases blood pressure, heart rate, plasma glucocorticoid concentration, and blood glucose levels (8), while chronic or repeated stress is associated with increases in baseline blood pressure and glucocorticoids (17). Chronically elevated glucocorticoids increase morbidity and mortality from cardiovascular disease and alterations in the glucocorticoid receptor (GR), and in glucocorticoid metabolizing enzymes are associated with hypertension and cardiovascular disease in humans (28,30,35,36,39,48,49,61, 65,67,70,71). Thus, chronic stress-induced elevations in glucocorticoids likely contribute to the adverse effects of stress on cardiovascular health.The mechanisms by which glucocorticoids modulate cardiovascular stress responses are not fully understood. A review by Sapolsky et al. (52) concluded that glucocorticoids act permissively to enhance the arterial pressure response to many physical stressors, in part by supporting the peripheral effects of catecholamines. Other studies indicate that chronic, systemic elevations in glucocorticoids enhance cardiovascular and catecholamine re...

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“…For example, in cardiomyocytes and the hippocampus, which both express MR but not 11␤HSD2, the receptor is effectively occupied by endogenous glucocorticoids, which have opposing effects to aldosterone. 64,65 In contrast, VSMCs express the MR and show 11␤HSD2 activity; 54 enzyme blockade by carbenoxolone in these cells allows physiological levels of cortisol to activate MR and produce similar responses to aldosterone or deoxycorticosterone.…”

Section: Nonepithelial Mechanisms Of Aldosterone Actionmentioning

confidence: 99%

Mechanisms of Mineralocorticoid Action

Fuller¹,

Young²

2005

Hypertension

280

169

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Abstract-Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum-and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4 -2, a ubiquitin protein ligase; serum-and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4 -2, thereby rendering it unable to bind the sodium channels. Key Words: aldosterone Ⅲ sodium channels Ⅲ fibrosis T he isolation of aldosterone just over 50 years ago established it as the primary physiological mineralocorticoid. 1 Sodium transport, and hence salt balance, is regulated by a number of mechanisms; however, aldosterone has a critical role. Aldosterone exerts its effects on the distal nephron (and colon) as the last point of sodium reabsorption; it is thus the final arbiter. 2,3 The importance of aldosterone in the maintenance of sodium homeostasis is seen in a series of monogenetic causes of hypertension, 2 in Conn's syndrome, and in disorders in which mineralocorticoid action is compromised with consequent, life-threatening salt losses. 3 Although other pathophysiological consequences of aldosterone excess were identified by Selye 4 over 60 years ago, their significance has only recently been appreciated. Evidence from the Randomized ALdactone Evaluation Study (RALES) and EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS) trials of beneficial effects of mineralocorticoid antagonist therapy on morbidity and mortality in cardiac failure has focused attention beyond the kidney to effects of mineralocorticoids more broadly in the cardiovascular system. 5 Although an understanding of the molecular basis of aldosterone action has tended to lag behind advances in the biology of other steroid hormones, the last decade has seen significant advances toward an understanding of the mechanisms of mineralocorticoid action. The primary mediator of the response to aldosterone is the mineralocorticoid receptor (MR), the ligand-binding domain (LBD) of which has been recently crystallized. 6 -8 Although the MR primarily acts as a transcription factor, recent evidence suggests that it may also mediate nongenomic (or nonnuclear) activation of second messenger pathways. In addition, there is a growing body of evidence that some actions of aldosterone may involve a receptor other than the MR. The cellular and molecular mediators, including proteins induced by aldosterone, have been characterized in sodium transporting epithelia; however, the critical molecular events in the vasculature remain to be determined. In this brief r...

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ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension

Cited by 105 publications

References 30 publications

Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

Mechanisms of Mineralocorticoid Action

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