Aldosterone production

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. 

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. 

As previously discussed, increased portal pressure triggers the release of nitric oxide to directly vasodilate the splanchnic arterial bed and decrease portal pressure. Unfortunately, nitric oxide also dilates the systemic arterial system, causing a decrease in blood pressure and a decrease in renal perfusion by lowering the effective intravascular volume. The kidney reacts by activating the renin-angiotensin-aldosterone system, which increases plasma renin activity, aldosterone production, and sodium retention. This increase in intravascular volume furthers the imbalance of intravascular oncotic pressure, allowing even more fluid to escape to the extravascular spaces. 

Diuretics are often required in addition to the sodium restriction described previously. Spironolactone and jurosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the renin-angiotensin-aldosterone system. In hepatic disease not only is aldosterone production increased, but its half-life is prolonged because it is hepatically metabolized. Spironolactone acts to conserve the potassium that would be otherwise excreted because of elevated aldosterone levels. 

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. 

Secondary adrenal insufficiency occurs as a result of a pituitary gland dysfunction whereby decreased production and secretion of ACTH leads to a decrease in cortisol synthesis. Tertiary adrenal insufficiency is a disorder of the hypothalamus that results in decreased production and release of CRH, which, in turn, decreases pituitary ACTH production and release. In contrast to Addison s disease (i.e., primary adrenal insufficiency), aldosterone production is unaffected in the secondary and tertiary forms of the disease. Chronic adrenal insufficiency often has a good prognosis if diagnosed early and treated appropriately. 

Congenital enzymatic defects in the adrenal biosynthetic pathways lead to diminished cortisol and aldosterone production and release. In these conditions, corticotrophin secretion is increased, and adrenal hyperplasia occurs, accompanied by enhanced secretion of steroid intermediates, especially adrenal androgens. More than 90% of cases of congenital adrenal hyperplasia are due to 21-hydroxylase deficiency, which is cre-afed by mufafions in fhe CYP21 gene encoding fhe en-... 

A. 17,20 lyase is required for androgen synthesis, cyclooxygenase for prostaglandin production, 11- 3-hydroxysteroid dehydrogenase-2 acts as a reductase-converting cortisol to its inactive 11-keto derivative cortisone, whereas 18-hydroxylase is required for aldosterone production. 

Mineralocorticoid disorders can have high or low aldosterone production. Even in hyperaldosteronism disorders, circulating aldosterone and aldosterone metabolite excretion can be in the upper normal range. For this reason it is important to determine the aldosteroneirenin ratio. 

These conditions are associated with high renin and high aldosterone production. The hybrid corticosteroids 18-OHF, 18-oxo-F and 18-oxo-THF were isolated from the urine of a patient with adrenal adenoma by Ulick and coworkers [11]. These steroids were subsequently also shown to be dominant in GRA. Their formation in the latter condition was explained by Lifton and co-workers [51] with the discovery of a chimeric gene formed crossover of the 1 1//-hydroxylase (CYPllfil) and aldosterone synthase (CYP11B2) genes. 

It has also been suggested that certain diuretics such as spironolactone (Aldactone) might be especially helpful in heart failure.14,42 Spironolactone blocks aldosterone receptors in the kidneys and other tissues, thereby producing a diuretic effect as well as preventing adverse cardiovascular changes associated with excess aldosterone production. Future studies will help clarify whether spironolactone should be used preferentially in heart failure because of its ability to reduce fluid volume and protect against aldosterone-induced damage.53... 

In addition to its normal role in controlling fluid and electrolyte balance, aldosterone can have detrimental effects on the heart and vasculature. Excess or prolonged aldosterone production can cause hypertrophy and fibrosis of cardiac and vascular tissues and lead to detrimental changes in these tissues.30,78 Moreover, it is now apparent that aldosterone can be produced locally within certain tissues including the heart and vascular endothelium.78,83 That is, these tissues may produce their own supply of aldosterone as well as receive circulating levels of aldosterone from the... 

Aldosterone production is initiated by 21-hydroxylation of pregnenolone in the adrenal glomerulosa, where there is no 17-hydroxylase activity. The product of hydroxylation of pregnenolone by P450c21 is 21-hydroxy-progesterone, also known as deoxycorticosterone (DOC). The quantity of aldosterone produced by the adrenal is only 1% of that of cortisol for this reason, not all patients with classic P450c21 deficiency manifest with salt wasting. 

ANP is a 28-amino-acid peptide first discovered by de Bold et al. (2). It is released from heart atrial myocytes in response to a local arterial wall stretch. ANP acts on outer adrenal cells to decrease aldosterone production and blood pressure, increase salt and water excretion, and transudate plasma water to the interstitium (3). 

NOTE Aldosterone production requires the renin-angiotension system Renin is an enzyme secreted by the juxtaglomerular ceils of the kidney in response to decreased arterial blood pressure and blood flow. Renin stimulates conversion of the protein angiotensinogen to angiotensin I which then becomes angiotensin II. Angiotensin II stimulates the synthesis and release of aldosterone by the adrenal cortex. 

Hypertension. The antihypertensive effect of ACE inhibitors and AT receptor blockers results primarily from vasodilatation (reduction of peripheral resistance) with little change in cardiac output or rate renal blood flow may increase (desirable). A fall in aldosterone production may also contribute to the blood pressure lowering action of ACE inhibitors. Both classes slow progression of glomerulopathy. Whether the long-term benefit of these drugs in hypertension exceeds that to be expected from blood pressure reduction alone remains controversial. 

The earliest endocrine abnormality in almost all types of cardiac disease is increased release of the heart s own hormones, the natriuretic peptides ANP and BNP (A for atrial, B for brain, where it was first discovered), and their concentration in plasma may become a guide to therapy. These peptides normally suppress renin and aldosterone production. 

This occurs in hypopituitarism. In theory the best treatment is corticotropin, but the disadvantages of frequent injection are such that hydrocortisone is preferred. Usually less hydrocortisone is needed than in primary insufficiency. Special sodium-retaining hormone is seldom required, for the pituitary has little control over aldosterone production which responds principally to plasma potassium concentration and to the renin-angiotensin system. Thyroxine and sex hormones are given when appropriate. The general conduct of therapy does not differ significantly from that in primary adrenal insufficiency. 

Corticotropin stimulates the synthesis of corticosteroids (of which the most important is hydrocortisone) and to a lesser extent of androgens, by the cells of the adrenal cortex. It has only a minor (transient) effect on aldosterone production, which can proceed independently in the absence of corticotropin the cells of the inner cortex atrophy. 

Alkalosis and hypokalaemia (possibly caused by secondary hyperaldosteronism or use of diuretics) shift the dissociation constant towards free, toxic NH3. By contrast, ammonia is considered - in a process resembling a vicious circle - to be a secondary stimulus for aldosterone production. Thiazide diuretics in particular put an overload on the detoxification capacity of the scavenger cells. This is because of an insufficient supply of bicarbonate for carbamoyl phosphate synthetase reaction due to diuretic-induced inhibition of the mitochondrial carboanhydrase. 

Deficient aldosterone production occurs in conditions other than Addison s disease (Table 51-6). Isolated aldosterone deficiency accompanied by normal cortisol production is seen in patients with (1) inadequate production of renin by the kidney, which leads to secondary aldosterone deficiency... 

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