Cortisol metabolism in hypertension.
Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension.
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CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
steroids carbenoxolone Cortisol HSD11B2 11beta-hydroxysteroid dehydrogenases 11beta-HSDs 11Beta-HSD1 glucocorticoid receptor GR 11beta-HSD2 Corticosteroids mineralocorticoid receptor MR 11beta-HSD2 MR 11beta-HSD2 11beta-hydroxysteroid cortisone cortisol aldosterone cortisol cortisone cortisol cortisol