Mineralocorticoid

Mineralocorticoids foUow a mechanistic route similar to that of glucocorticoids, though differing in the proteins expressed. The activated MR-DNA complex promotes the expression of aldosterone-induced proteins (AIPs), which then act to increase conductance of the luminal membrane and concurrently increase pump activity of the basolateral membrane. These actions result from a number of AlP-influenced cellular characteristics,... 

Methylated Glucocorticoids. The preparation of 2a-methyl-9a- uorocortisol has been reported (76). This compound shows enhanced glucocorticoid activity and greatiy enhanced mineralocorticoid activity, so much that it surpasses aldosterone (19) ia sodium-retaining and potassium-excreting potency. Attention was then turned to the preparation of 6-methylated corticoids... 

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

Steroid Hormones and Neurosteroids. Steroids (qv) can affect neuroendocrine function, stress responses, and behavioral sexual dimorphism (78,79) (see Steroids). Mineralocorticoid, glucocorticoid, androgen, estrogen, and progesterone receptors are localized in the brain and spinal cord. In addition to genomic actions, the neurosteroid can act more acutely to modulate the actions of other receptors or ion channels (80). Pregnenolone [145-13-17, ( ) dehydroepiandosterone [53-43-0] C H2 02 (319) are excitatory neurosteroids found in rat brain, independent of adrenal... 

Steroid hormones can be subdivided into sex hormones (androgens, estrogens, and progestins) and corticosteroids (glucocorticoids and mineralocorticoids). 

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). 

FIGURE 25.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to /3-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. 

Aldosterone, the most potent of the mineralocorticoids (Figure 25.43), is involved in the regulation of sodium and potassium balances in tissues. Aldosterone increases the kidney s capacity to absorb Na, Cl, and HgO from the glomerular filtrate in the kidney tubules. 

It was known for some time that even after the corticoids had been separated from crude extracts of the adrenal cortex, the remaining material, the so-called "amorphous fraction" still possessed considerable mineralocorticoid activity. Aldosterone (250), one of the last steroids to be isolated from this fraction, proved to be the active principle. This compound proved to be an extremely potent agent for the retention of salt, and thus water, in body fluids. An antagonist would be expected to act as a diuretic in those edematous states caused by excess sodium retention. Although aldosterone has been prepared by both total and partial synthesis, the complexity of the molecule discouraged attempts to prepare antagonists based directly on the parent compound. 

Adrenocortical hormone (Section 27.6) A steroid hormone secreted by the adrenal glands. There are two types of adrenocortical hormones mineralocorticoids and glucocorticoids. 

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. 

Adrenocorticotrope Hormone (ACTH) Gluco-mineralocorticoid Receptors... 

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