Mineralocorticoid Aldosterone

Mineralocorticoids. Aldosterone [6251-69-0] (32), the most potent natural rnineralocorticoid, also possesses a A -3-one group, an oxygen substituent at Clip, and a C17P-2-hydroxyethan-l-one side chain. In addition, the C18 of aldosterone is oxidized to an aldehyde. Mineralocorticoids, particularly aldosterone, act to retain sodium and to prevent the retention of excess potassium. Antimineral ocorticoids have been used therapeutically as diuretics and as agents that regulate blood pressure (63—65). 

An endocrine disorder first described by the British Physician Thomas Addison in the mid 1800 s. The adrenal glands fail to produce sufficient amounts of glucocorticoid hormones (cortisol) and sometime mineralocorticoid (aldosterone). If left untreated it is life-threatening, the patient will show muscle weakness, hyperpigmentation and even depression. Typical treatment is hydrocortisone replacement therapy. 

The renin-angiotensin-aldosterone system (RAAS) generates the peptide hormone angiotensin II and subsequently the mineralocorticoid aldosterone, which both exert considerable impact on blood pressure ( blood pressure control) and fluid homeostasis, and... 

The major mineralocorticoid, aldosterone, is secreted by cells of the zona glomerulosa. Primary hyperaldosteronism (Conn s syndrome) is associated with potassium depletion which is, in mm, responsible for the observed neuromuscular abnormalities seen in the disorder. These are similar to those seen in hypokalemic periodic paralysis (PP), with episodic and severe exacerbations of fixed muscle weakness. Muscle biopsy shows occasional muscle necrosis and vacuoles often these feamres are accompanied by mbular aggregates as in hypokalemic PP. All these changes can be attributed to the hypokalemia and not to excess aldosterone production per se. 

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

Finally, we have the mineralocorticoids. Aldosterone is a good example ... 

Cortical hormones include glucocorticoids (cortisol/corticosterone) and mineralocorticoids (aldosterone) medullar hormones are adrenaline and noradrenaline Pancreas Regulates glucose in blood via production of the hormones glucagon and insulin... 

Another major function of the adrenal cortex is the regulation of water and electrolyte metabolism. The principal mineralocorticoid, aldosterone, can increase the rate of sodium reabsorption and potassium excretion severalfold. This will occur physiologically in response to sodium or volume depletion or both. The primary site of... 

The remaining steroid lipids constitute two main classes of steroid hormones sex hormones and adrenocortical hormones. The sex hormones include androgens (testosterone, androsterone), estrogens (estrone, estradiol), and progestins (progesterone). The adrenocortical hormones include mineralocorticoids (aldosterone) and glucocorticoids (hydrocortisone). 

The adrenocorticotrophic hormone ACTH (corticotropin) stimulates the adrenal cortex to secrete the glucocorticoids hydrocortisone (cortisol) and corticosterone, the mineralocorticoid aldosterone, and a number of weakly androgenic substances, as well as a small amount of testosterone. Aldosterone synthesis is also regulated by renin and angiotensin. 

FIGURE 29-1 Pathways of adrenal steroid biosynthesis. Cholesterol is the precursor for the three steroid hormone pathways. Note the similarity between the structures of the primary mineralocorticoid (aldosterone), the primary glucocorticoid (cortisol), and the sex hormones (testosterone, estradiol). See text for further discussion. 

In the adrenal cortex, the outermost zona glomerulosa secretes the mineralocorticoid aldosterone, and corticosterone. The middle zona fasciculata and the inner zona reticularis secrete predominately the glucocorticoids cortisol and corticosterone. In the human, the inner zona reticularis secretes large amounts of the adrenal androgens, DHEA and DHEAS, as well as cortisol [12]. Whereas steroidogenesis in the... 

The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) in the zona fasciculata and the mineralocorticoid aldosterone in the zona glomerulosa. Both steroid hormones are vitally important in adaptation responses to stress situations, such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal ACTH aldosterone secretion by angiotensin II in particular (p. 128). In AC failure (primary adrenocortical insuf ciency, Addison disease), both cortisol and aldosterone must be replaced when ACTH production is deficient (secondary adrenocortical insuf ciency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/day, 2/3 a.m 1 /3 p.m.). In stress situations, the dose is raised 5- to 10-fold. Aldosterone is poorly effective via the oral route instead, the mineralocorticoid fludrocortisone (0.1 mg/day) is given. 

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

Adrenocorticotropic hormone derives from the anterior pituitary in response to the leptin-or stress-induced anorexigenic, hypothalamic CRH. Corticotropin (like enkephalins and MSHs) derives from a precursor polypeptide pro-opiomelanocortin. Corticotropin induces the catabolic adrenal cortex corticosteroid cortisol and the mineralocorticoid aldosterone (Chapter 11) and is an important regulator of immune responses including chemotaxis and phagocytosis. Corticotropin acts via GPCRs to activate Gas and increase cAMP in anterior pituitary cells. 

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. 

Q1 Each adrenal gland is composed of an outer cortex and an inner medulla. The cortex consists of three layers where several steroid hormones, synthesized from cholesterol, are produced and secreted. The outer layer of the cortex, the zona glomerulosa, produces the mineralocorticoid aldosterone. The zona fasciculata lies under this layer and, together with the inner layer, the zona reticularis, secretes glucocorticoids, mainly cortisol, corticosterone and androgens. 

If progesterone is directly acted on by 2l-hydroxylu.se (Cyp21). 11 -deoxycorticosterone is produced, a precursor lo the mineralocorticoid aldosterone. In tissues where aldosterone is synthesized, the multifunctional enzyme aldosterone synthase (Cypl IB2) mediates the hydroxylalion at Cl i as well as the two-step oxidation ofCIS lo an aldehyde, providing aldo.sicronc. which exists predominantly in the cyciic hcmiacclal form. 

The release of the primaiy mineralocorticoid aldosterone depends only slightly on ACTH. Aldosterone is an active part of the angiotensin-ienin-blood pressure cycle that controls blood volume. A decrease in blood volume. stimulates the kidneys to. secrete the enzyme renin. Renin, in turn, con-terts angiotensinogen to angiotensin, which stimulates the adrenal cortex to release aldosterone. Aldosterone then causes the kidneys to retain sodium, and blood volume increases. When the blood volume has increased sufTicicntly. renin production decreases, until blocxl volume drops again. 

Mineralocorticoids (aldosterone) Mineralocorticoids cause the kidneys to retain sodium and water, increasing fluid volume and increasing blood pressure. Blocking mineralocorticoid receptors by medication such as spironolactone decreases blood pressure. 

The answer is c. (Murray, pp 505—626. Scriver, pp 4029—4240. Sack, pp 121-138. Wilson, pp 287-320.) Vasopressin, which is also called antidiuretic hormone, increases the permeability of the collecting ducts and distal convoluted tubules of the kidney and thus allows passage of water. Like the mineralocorticoid aldosterone, vasopressin results in an expansion of blood volume. However, the mode of action of aldosterone is different it causes sodium reabsorption, not water reabsorption. Sodium reabsorption indirectly leads to increased plasma osmolality and thus water retention in the blood. Cortisol is a glucocorticoid that potentiates catabolic metabolism chronically. Epinephrine stimulates catabolic metabolism acutely. Insulin acutely favors anabolic metabolism, in large part by allowing glucose and amino acid transport into cells. 

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