Hypertension mineralocorticoid receptor

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slighdy favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the llp-hydroxysteroid dehydrogenase enzyme system and requires NAD(P)+ /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineralocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000 289(5476) 119-123. 

Spiro compounds 202 and 203 are antagonists of the mineralocorticoid receptor. This limits the production of excess aldosterone, which, in turn, leads to increased sodium uptake and potassium loss. This condition, known as Conn s syndrome, is associated with hypertension <2005W02005110992>. Amine 204 is a seratonergic 5-HY5-HT2 agonist for the treatment of glaucoma <2003W003051352>. 

Funder JW, Krozowski Z, Myles K, Sato A, Sheppard KE, Young M. Mineralocorticoid receptors, salt, and hypertension. Recent Prog Horm Res 1997 52 247-62. 

Benign tumors in the pituitary or adrenal glands can lead to excess release of ACTH or cortisol into the blood, causing the symptoms of Cushing syndrome. Typically, excess levels of endogenous cortisol— not synthetic forms of cortisol—can cause hypertension, most likely because of its weak binding capacity with mineralocorticoid receptors (i.e., aldosterone receptors). 

Licorice has a well-documented mineralocorticoid-like effect. This effect occurs not because licorice mimics mineralocorticoid action, but rather is due to the inhibition of 11-P-hydroxysteroid dehydrogenase (1 lP-OHSD), the enzyme that catalyzes the conversion ofcortisol to cortisone (Stewart et al., 1987). Deficiency or inhibition of this enzyme leads to an increase in renal cortisol, which can bind to mineralocorticoid receptors (Stewart et al., 1987). The inhibiting substance in licorice appears to be 3-monoglucuronylglycyrrhetinic acid, a metabolite of glycyrrhetinic acid (Kato et al., 1995). This resultant mineralocorticoid effect may cause sodium retention, hypertension, hypokalemia, and suppression of plasma renin activity (Epstein et al. 977). 

Kolkhof, P., Flamme, I., Figueroa Perez, L., Baerfacker, L., Hartmann, E., Rinke, M. and Schafer, S. (2006) Cardiac and renal protection by a new mineralocorticoid receptor antagonist in salt-sensitive arterial hypertension. European Heart Journal, 27 (Suppl 1), 110. 

Kolkhof, P., Jilg, V. and Schafer, S. (2007) Pharmacological characterization of a mutant mineralocorticoid receptor responsible for severe, early-onset hypertension. Clinical Research in Cardiology, 96 (Suppl 1). P525. 

Mineralocorticoid receptor antagonists for the treatment of hypertension and diabetic nephropathy 12JMC7957. 

Glucocorticoid resistance is characterized by high levels of cortisol (without stigmata of Cushing syndrome), resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone, and an affinity defect of the glucocorticoid receptor. Some of the affected patients presented with hypertension and hypokalemia due to illegal activation of the mineralocorticoid receptor by cortisol [16]. 

The mineralocorticoid aldosterone is also produced by the adrenal cortex and promotes retention of H20 and Na+ and loss of K+ by the kidney. Cortisol is also an agonist of the aldosterone receptor but the level of cortisol is kept low by type 2 11 (Thydroxysteroid dehydrogenase, which converts cortisol to the inactive cortisone (11-dehydrocortisol). Accordingly inhibition of this enzyme by 18(i>-glycyrrhetinic acid (from liquorice) elevates cortisol with consequent effects of H20 and Na+ retention, oedema and hypertension. Further potential sites of interference by plant substances with steroid hormone metabolism include enzymes involved in steroid hormone synthesis such as the cytochrome P450-linked 11 -hydroxylase that catalyses the last step of corticosterone synthesis. 

The mineralocorticoid properties of carbenoxolone are probably exerted by displacement of aldosterone from non-specific receptor sites in cells, thus making it more available to affect mineral metabolism. What this means in practice is that in normal doses carbenoxolone can cause salt and water retention, with occasional hypokalemia. These effects are common but usually mUd they are detected more often during treatment if patients are weighed, their blood pressure measured, and serum potassium concentrations checked. Those who take prolonged courses, elderly patients, and those with hepatic, cardiac, or renal impairment are at special risk severe effects, with serious hypertension, heart failure, and hypokalemia of sufficient degree to induce myopathy and tubular necrosis, can usually be ascribed to ill-advised treatment of people in whom carbenoxolone is contraindicated, to its use in elderly patients, or to prolonged intake without supervision. 

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