Aldosterone binding

Two distinct classes of mineralocorticoid-binding sites were first described in the rat kidney. High-affinity cytosolic aldosterone-binding sites are termed mineralocorticoid receptors [4]. Lower-affinity aldosterone-binding sites... 

Spironolactone - Spironolactone, a competitive inhibitor of aldosterone, binds to aldosterone receptors of the distal tubule and prevents the formation of a... 

Tubular Unresponsiveness to Aldosterone Certain medical conditions, such as sickle cell anemia, systemic lupus erythematosus, and amyloidosis, can produce a defect in tubular potassium secretion, possibly as the result of an alteration in the aldosterone-binding site. The exact mechanism of the tubular unresponsiveness is unknown. 

Spironolactone is a competitive antagonist to the mineralocorticoids, such as aldosterone. The mineraiocorticoid receptor is an intracellular protein that can bind aldosterone. Spironolactone binds to the receptor and competitively inhibits aldosterone binding to the receptor. The inability of aldosterone to bind to its receptor prevents reabsorption of sodium and chloride ions and the associated water. The most important site of these receptors is in the late distal convoluted tubule and collecting system (collecting duct). 

Other investigators have also shown that actinomy-cin interferes with the action of aldosterone in vivo, and that aldosterone binds to a nuclear receptor believed to be a protein. Binding between receptor and aldosterone requires the presence of SH groups on the protein. The role played by the complex of aldosterone and protein in gene expression is still not clear, but the complex of hormone and protein is believed to induce the biosynthesis of a new protein. The most popular hypothesis proposes that the new protein is in some way involved in NADH electron transport and coupled to phosphorylation of ADP. 

The first demonstration of intracellular steroid-hormone receptors was by Jensen and Jacobson (1962) for estradiol. Levinson et al. (1972) showed that hormone binding to the glucocorticoid receptor in cultured rat hepatoma cells takes place inside the cell membrane rather than at the cell surface, but did not exclude the existence of other biological actions of steroids mediated by surface membrane receptors. Indeed, Ozegovic et al. (1977) have shown that aldosterone binds to isolated kidney plasma membranes and have proposed that this steroid-membrane interaction may reflect an early event in the transmembrance movement of aldosterone. 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

ACE inhibitors are approved for the treatment of hypertension and cardiac failure [5]. For cardiac failure, many studies have demonstrated increased survival rates independently of the initial degree of failure. They effectively decrease work load of the heart as well as cardiac hypertrophy and relieve the patients symptoms. In contrast to previous assumptions, ACE inhibitors do not inhibit aldosterone production on a long-term scale sufficiently. Correspondingly, additional inhibition of aldosterone effects significantly reduces cardiac failure and increases survival even further in patients already receiving diuretics and ACE inhibitors. This can be achieved by coadministration of spironolactone, which inhibits binding of aldosterone to its receptor. 

Although MR also binds glucocorticoids, its main ligand in classical mineralocorticoid target tissues such as kidney and colon is aldosterone ( d 1.3 nM). This can be granted to the ability of 11 (3-hydioxysteroid dehydrogenase type II (11 (3-HSD II) to convert active cortisol into its inactive metabolite cortisone in these tissues. Since aldosterone is no substrate for this enzyme it can readily bind to MR, leading to exclusive occupation of the receptor by aldosterone. In contrast, no such mechanism exists in brain and presumably... 

MR has a high affinity for mineralocorticoids such as aldosterone and DOC. In addition, MR also binds glucocorticoids although in mineralocorticoid target tissues this is prevented by the enzyme 11 (3-HSDII (see above). Since mineralocorticoids are no substrate for 11 (3-HSD II due to their cyclic 11,18-hemiacetyl-group, they are able to bind to MR despite the 1,000-fold lower concentration in plasma as compared with cortisol. 

The main endogenous mineralocorticoid is aldosterone, which is mainly produced by the outer layer of the adrenal medulla, the zonaglomerulosa. Aldostorone, like other steroids, binds to a specific intracellular (nuclear) receptor, the mineralocorticoid receptor (MR). Its main action is to increase sodium reabsotption by an action on the distal tubules in the kidney, which is accompanied by an increased excretion of potassium and hydrogen ions. 

Angiotensin II binds to specific adrenal cortex glomerulosa cell receptors. The hormone-receptor interaction does not activate adenylyl cyclase, and cAMP does not appear to mediate the action of this hormone. The actions of angiotensin II, which are to stimulate the conversion of cholesterol to pregnenolone and of corticosterone to 18-hydroxycorticosterone and aldosterone, may involve changes in the concentration of intracellular calcium and of phospholipid metabolites by mechanisms similar to those described in Chapter 43. 

Cyclic GMP is made from GTP by the enzyme gua-nylyl cyclase, which exists in soluble and membrane-bound forms. Each of these isozymes has unique physiologic properties. The atriopeptins, a family of peptides produced in cardiac atrial tissues, cause natriuresis, diuresis, vasodilation, and inhibition of aldosterone secretion. These peptides (eg, atrial natriuretic factor) bind to and activate the membrane-bound form of guanylyl cyclase. This results in an increase of cGMP by as much as 50-fold in some cases, and this is thought to mediate the effects mentioned above. Other evidence links cGMP to vasodilation. A series of compounds, including nitroprusside, nitroglycerin, nitric oxide, sodium nitrite, and sodium azide, all cause smooth muscle re-... 

Like all steroids, aldosterone enters the target cell and combines with cytosolic mineralocorticoid receptor. Such receptors are not entirely specific for aldosterone and will also bind cortisol, the principal glucocorticoid hormone. The receptors are protected from cortisol activation by 11 3 hydroxysteroid dehydrogenase which... 

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

The same basic biochemical control mechanism causes contraction of the smooth muscle as well as secretion of aldosterone. The binding of angiotensin to its receptor activates a membrane phospholipase-C. It catalyses the hydrolysis of phosphoinositide phosphatidylinositol bis-phosphate to produce the two intracellular messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). 

Angiotensin-II-receptor antagonists These block the binding of this messenger to its receptors on the two target tissues, i.e. smooth muscle in the arterioles and the aldosterone-secreting cells in the adrenal cortex. 

The adrenal glands secrete over 50 different steroids, the most important of which are aldosterone and hydrocortisone. Aldosterone causes salt retention in the body. It is not commercially available. Hydrocortisone is useful for its anti-inflammatory and antiallergic activity. Cortisone and its derivatives have similar activity and it is reduced in vivo to hydrocortisone. The two substances are used to treat rheumatoid arthritis. The 11-P-hydroxyl of hydrocortisone is believed to be of major importance in binding to the receptors of enzymes. Anti-inflammatory activity is significantly Increased by various substituents 6a-fluoro, 9a-fluoro, 21-hydroxy, 2a-methyl, 9a-chloro, and a double bond at C-1. 

Triamterene is a pyrazine derivative that inhibits reabsorption of sodium ions without increasing excretion of potassium ions. It exhibits the same approximate effect as spironolactone however, it does not competitively bind with aldosterone receptors. Its action does not have an effect on secretion of aldosterone or its antagonists, which are a result of direct action on renal tubules. 

Angiotensin II receptor antagonists (AIIRAs) block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT- receptor found in many tissues. 

Pharmacology Epierenone blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone system (RAAS). 

Spironolactone competitively inhibits the binding of aldosterone to cytosolic mineralocorticoid receptors in the epithelial cells in the late distal tubule and collect-... 

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