Sodium-retaining Effect Of Aldosterone Research Articles

Use of Diuretics in Heart Failure and Cirrhosis

Sodium and water retention in cardiac failure and cirrhosis is pivotal in the morbidity and mortality of patients with these disorders. Moreover, the pathophysiology of these edematous disorders is quite similar. Both disorders have activation of the renin-angiotensin-aldosterone system, increased sympathetic activity, and nonosmotic stimulation of arginine vasopressin, which is initiated by unloading of the arterial baroreceptors; this occurs secondary to diminished cardiac output with heart failure and primary systemic arterial vasodilation with cirrhosis. With this common pathophysiology causing pulmonary congestion, ascites, and peripheral edema, diuretics are pivotal in the therapy of patients with heart failure and cirrhosis. Advanced cardiac failure and cirrhosis both show secondary hyperaldosteronism and impaired renal escape from the sodium-retaining effect of aldosterone. However, currently there are contradictory uses of mineralocorticoid-receptor antagonists in cardiac failure (non-natriuretic doses) versus cirrhosis (natriuretic doses). This disparity relates to the greater potential of hyperkalemia in cardiac failure patients receiving inhibitors of the renin-angiotensin-aldosterone system. This review discusses the beneficial and potentially deleterious effects of diuretic use in patients with cardiac failure and cirrhosis.

Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease

The pathogenesis of renal sodium and water retention in cirrhosis involves extrarenal mechanisms because when kidneys from cirrhotic patients are transplanted into persons with normal livers, renal sodium and water retention no longer occurs. Cirrhosis is accompanied by portal hypertension, which leads to a hyperdynamic circulatory state. The Peripheral Arterial Vasodilation Hypothesis incriminates a relative underfilling of the arterial vascular compartment, which leads to the same neurohumoral responses that occurs in low cardiac output. Activation of the renain-angiotensin-aldosterone axis and the sympathetic system as well as non-osmotic release of vasopressin are well documented in cirrhosis. This sequence of events results in renal water and sodium retention, failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. Dilutional hyponatremia is the strongest predictor of the occurrence of hepatorenal syndrome. The pathogenesis of the peripheral arterial vasodilation is not completely elucidated, but there is evidence for a major role of nitric oxide (NO). Increased vascular NO production has been demonstrated in cirrhosis. In the rat model of cirrhosis, normalization of vascular NO production with a NOS inhibitor corrects the hyperdynamic circulation, improves sodium and water excretion, and decreases neurohumoral activation. This insight into the mechanism(s) of the peripheral arterial vasodilation in cirrhosis should provide new tools in the treatment of edema and ascites, a major cause of morbidity and mortality in cirrhosis.

Edematous disorders

The pathogenesis of renal sodium and water retention in cardiac failure, cirrhosis, and the nephrotic syndrome may be explained by the unifying hypothesis of body fluid volume regulation. According to this hypothesis, underfilling of the arterial vascular compartment initiates a sequence of events, including activation of various neurohormonal vasoconstrictor systems, which results in enhanced renal sodium and water reabsorption, the failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. In patients with low-output cardiac failure, a decrease in cardiac output results in arterial underfilling. Peripheral arterial vasodilation diminishes the fullness of the arterial vascular compartment in patients with high-output cardiac failure and cirrhosis. In the nephrotic syndrome, the decrease in plasma oncotic pressure due to hypoalbuminemia initiates arterial underfilling. The factors that are responsible for the peripheral arterial vasodilation in patients with cirrhosis remain obscure. Diuretics are initially effective in reducing the excess of total-body sodium and water in edematous patients. Loop diuretics, with or without metolazone or a thiazide diuretic, are quite useful in patients with heart failure. In cirrhosis and the nephrotic syndrome, the specific aldosterone antagonist spironolactone, alone or in combination with other diuretics, has proven to be highly efficacious. However, in all instances, the emergence of diuretic resistance represents a major limitation of diuretic therapy for the edematous patient. This diuretic resistance may be mediated by further activation of vasoconstrictor, antinatriuretic neurohormones.

Body Fluid Volume Regulation in Health and Disease: A Unifying Hypothesis

In studies in experimental animals and in edematous patients, the nonosmotic release of vasopressin has been found to be consistently associated with activation of the sympathetic nervous and renin-angiotensin-aldosterone systems. Moreover, the sympathetic nervous system is known to modulate the nonosmotic release of vasopressin and activation of the renin-angiotensin-aldosterone system. These findings led to our proposal that body fluid volume regulation involves dynamic interaction between cardiac output and peripheral arterial resistance. In this context, neither total extracellular fluid volume nor total blood volume are determinants of renal sodium and water excretion. With a decrease in effective arterial blood volume (EABV) initiated by either decreased cardiac output or peripheral arterial vasodilation, the acute response involves vasoconstriction mediated by angiotensin, sympathetic mediators, and vasopressin. The renal vasoconstriction, which accompanies either decreased cardiac output or peripheral arterial vasodilation, causes a decreased distal tubular delivery of sodium and water, thus maximizing the water-retaining effect of vasopressin and impairing normal escape from the sodium-retaining effect of aldosterone. The elevated glomerular filtration rate and filtered sodium load seen in pregnant women allow increased distal sodium and water delivery despite a decrease in EABV, thus limiting edema formation during gestation.

ROLE OF NATRIURETIC FACTORS IN MINERALOCORTICOID ESCAPE PHENOMENON IN PATIENTS WITH PRIMARY ALDOSTERONISM

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) and digitalis-like substance (DLS) in 5 patients with primary aldosteronism due to adrenal adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight and urinary excretion of DLS and sodium were measured daily. Venous sample were obtained twice a week for measurements of plasma renin activity (PRA) and plasma levels of aldosterone, ANP and DLS. Plasma volume was determined by radioisotope dilution using 125I-human serum albumin during the control period and on the 13th day after stopping spironolactone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA decreased markedly (p <0.05) from 2.1 ± 0.6 ng/ml/hr on the control days to 0.2 ± 0.1 ng/ml/hr on the 8 th day after stopping spironolactone. Plasma levels of aldosterone was 387± 150 pg/ml on the control days and did not change significantly after the withdrawal (278 ± 94 pg/ml on the 17th day). Plasma ANP levels increased significantly (p<0.05) from 26 ± 4 pg/ml on the control days to 195 ± 47 pg/ml on the 13th day ; however, plasma and urine levels of DLS decreased significantly (p <0.05). The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP but not by the changes in DLS.

Role of atrial natriuretic peptide in mineralocorticoid escape phenomenon in patients with primary aldosteronism.

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.

NATURE OF RENAL ESCAPE FROM THE SODIUM-RETAINING EFFECT OF ALDOSTERONE IN PRIMARY ALDOSTERONISM AND IN NORMAL SUBJECTS.

Six patients with primary aldosteronism have been subjected to a series of standardized saline infusion tests and various indices have been studied in an attempt to clarify the mechanism of renal escape. Similar studies have been made in 5 normal control subjects who have been tested under 4 experimental situations: a) while consuming 10 mEq of dietary sodium per day, b) while consuming 180 mEq of sodium per day, c) 24 hr after the onset of administration of d-aldosterone while on the high intake of sodium, and d) 5–7 days after the onset of administration of aldosterone, while on the high intake of sodium, when escape had fully developed. The maximum mean rate of sodium excretion in response to the intravenous saline load (UNsV) in the control subjects was decreased below base line at the end of the first day of administration of aldosterone. It was significantly increased above base-line values after escape had developed and while aldosterone was still being given. UNaV was even higher in patients with ...

Effects of 16α-OH-Δ4- and Δ5-Pregnene Compounds with Respect to Electrolyte Excretion of Aldosterone

The effect of 16α-hydroxylated Δ4- and Δ5 pregnene compounds on electrolyte excretion was studied in adrenalectomized rats. Hydrocortisone diminished the sodium-retaining action of aldosterone and enhanced the potassium-excreting effect of aldosterone. When this steroid was hydroxylated at C-16 these effects were decreased. Progesterone diminished the sodium-retaining effect of aldosterone without significantly affecting the potassium excretion. 16α-Hydroxyprogesterone and 17α-hydroxyprogesterone were less effective in inhibiting the sodium-retaining effect of aldosterone than progesterone. Δ5-Pregnene compounds such as dehydroisoandrosterone, 16α-hydroxydehydroisoandrosterone, pregnenolone, 16α-hydroxypregnenolone and 17α-hydroxypregnenolone did not exert a significant effect on the excretion of water and electrolytes, nor did they modify the electrolyte effect of aldosterone.