Aldosterone structure

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

Spironolactone (Aldactone) is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of protein synthesis necessary for Na+ reabsorption and K+ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na excretion associated with a decrease in elimination. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

Aldosterone is synthesized mainly in the zona glomerulosa of the adrenal cortex. Its structure and synthesis are illustrated in Figure 39-1. 

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 1957, Celia and Kagawa [5] reported about the preparation of two steroidal 17-spirolactones, which were capable of blocking the urinary sodium/potassium action of aldosterone and desoxycorticosterone-acetate in adrenalectomized rats. These compounds were closely related in structure to aldosterone and were assigned the code names SC 5233 and SC 8109, respectively. Structures of these three compounds are shown in Figure 1. 

The mineralocorticoid receptor (MR) mediates the sodium-retaining effects of aldosterone in the kidney, salivary glands, sweat glands, and colon. The human MR gene was cloned in 1987 and bears structural and functional kinships to the glucocorticoid receptor (11). It consists of 984 amino acids, spans 60 90 kb on chromosome 4q31.2 (50,51) and contains 10 exons including two exons (la and 1 p) that encode different 5 untranslated sequences whose expression is controlled by two different promoters (52). 

The last important steroidal hormone of the adrenal cortex to be characterized was aldosterone la. This substance was only available in minute amounts from natural sources and the determination of structure by Reichstein and his colleagues1-2 was a masterpiece of collaboration between University (Basel) and Industry (Ciba-Geigy). The masked aldehyde group at C18 is an unusual feature for a steroidal molecule and at once posed interesting problems of synthesis. There are very few natural steroids which are substituted at C18, so a partial synthesis did not, at first, seem very practical. 

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. 

Fig. 11.4 (a) Structure of vitamin D3. Vitamin D3 is derived from cholesterol by UV irradiation, (b) Structures of cortisol and aldosterone. Cortisol is a major glucocorticoid, and aldosterone is a major mineralocorticoid. Both are derived by a series of hydroxylation reactions from progesterone, from which androgens and oestrogens are also synthesized. 

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