Renal and systemic acid-base effects of chronic spironolactone administration.

Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.

Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs.

Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH3 production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6-8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (sigma delta NAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH4+ excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH4+ was accompanied by an increase in urine pH (delta UpH, +0.18 +/- 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH4+ + Na+ + K+] - [Cl- + HCO3- + HPO4(2-) + H2PO4-]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.

Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.

Clinical states of hyperglucocorticoidism are associated with renal metabolic alkalosis, yet the systemic and renal acid-base response to chronic administration of glucocorticoid steroids (dexamethasone, triamcinolone) possessing little or no mineralocorticoid activity has not been investigated. In balance studies studies in dogs administration of triamcinolone (Tcn), 1.0 mg . kg-1 . day-1 for 6-9 days (group I, n = 5), resulted in a persistent reduction in urine pH and increase in net acid excretion (NAE), and in the excretion of urinary unmeasured anions (C+NH4,Na;K minus A-Cl,HCO3,Pi), which were identified as organic anions and sulfate. A significant degree of metabolic acidosis occurred initially (delta [HCO3-]p, -3.4 meq/liter, P less than 0.05, day 1). As Tcn administration was continued, the cumulative increment in net acid excreted exceeded the cumulative increment in urinary unmeasured anion excreted and [HCO-3]p returned to pre-Tcn control values and remained stable thereafter. In the steady state of Tcn administration plasma potassium concentration and renal potassium clearance were not significantly different from pre-Tcn control, in contrast to the findings of hypokalemia and increased renal potassium clearance during chronic administration of deoxycorticosterone (DOC). Triamcinolone did not result in antinatriuresis or antichloruresis. Chronic administration of a 10-fold smaller dose of Tcn (0.1 mg . kg-1 . day-1) in an additional group (group III) also resulted in a persisting reduction in urine pH and an increase in net acid excretion that exceeded unmeasured anion excretion and resulted in a small increase in steady-state plasma bicarbonate concentration. These results suggest that chronic administration of potent glucocorticoid steroids results in 1) a persisting increase in endogenous acid production, and 2) stimulation of renal hydrogen ion secretion that was of greater degree than accounted for by the increment in endogenous acid production and that was not accompanied by renal mineralocorticoid effects on sodium and potassium transport.

Pathophysiology of chronic renal tubular acidosis induced by administration of amiloride.

Amiloride is a "potassium-sparing" diuretic agent of moderate natriuretic potency with site of action in postmacula densa segments of the distal nephron. In isolated segments of mammalian cortical distal nephron, amiloride diminishes sodium reabsorption and transtubular electrical PD and inhibits potassium secretion. We investigated the effects of long-term administration of a demonstrably maximal dose of amiloride (1.0 mg/kg b.i.d.) on plasma and urine acid-base and electrolyte composition in fixed steroid-replaced ADX dogs. Amiloride administration resulted in potassium retention and hyperkalemia and reduced net acid excretion and caused chronic hyperchloremic metabolic acidosis. The cumulative reduction in net acid excretion and severity of systemic acidosis were not significantly different in additional groups in which potassium retention was prevented by restriction of dietary potassium during amiloride administration or in which amiloride was administered to animals with pre-existing dietary potassium depletion. The response of urine pH and ammonium excretion, however, differed among groups. In the steady state of chronic acidosis, urine pH and ammonium concentration were lowest in the hyperkalemic group and highest in the hypokalemic group, and among the three groups pH and ammonium were positively correlated (r = 0.67, p less than 0.001). Ammonium concentration varied inversely with plasma potassium concentration. Net acid excretion rates returned to control levels during the steady state of chronic amiloride-induced acidosis in the three groups. During continued amiloride administration, sustained correction of acidosis by long-term oral administration of sodium bicarbonate did not result in negative values of net acid excretion; that is, amiloride did not cause net wasting of base at normal plasma bicarbonate concentration. The results of these studies suggest that chronic amiloride administration results in a sustained impairment of renal hydrogen ion secretion restricted to the distal nephron and not dependent on alterations in potassium balance. Differences in potassium balance (positive or negative) appeared to influence only the availability of ammonia for diffusion into urine and steady-state urine pH, but not the steady-state net rate of renal hydrogen ion secretion during amiloride. These studies identify an experimental model of chronic distal renal tubular acidosis in which external hydrogen ion balance is re-established during chronic acidosis even when the availability of ammonia for excretion is decreased.

Pathogenesis of renal hyperchloremic acidosis resulting from dietary potassium restriction in the dog: role of aldosterone.

In dogs dietary K+ restriction (16 days) results in diminished urinary net acid excretion (NAE) and systemic hyperchloremic metabolic acidosis (sigma delta NAE, -200 meq; delta[HCO3-]p, -2.9 +/- 0.3 meq/liter, P less than 0.05). Urinary aldosterone (aldo) excretion decreased by 34 +/- 3% (P less than 0.001) and metabolic clearance rate of aldo increased by 80 +/- 17% (P less than 0.02) during K+ restriction. Daily subcutaneous injection of a small amount of exogenous aldo (20 micrograms) during K+ restriction significantly attenuated the reduction in NAE (sigma delta NAE -51 vs. -200 meq, P less than 0.05) without raising plasma aldo concentrations to levels greater than control. These findings suggest that hypoaldosteronism induced by potassium depletion is at least in part the cause of the observed renal tubular acidosis. In adrenalectomized (ADX) dogs maintained on fixed mineralocorticoid and glucocorticoid replacement (aldo dose 60 micrograms/day), K+ restriction resulted in a significant degree of renal metabolic acidosis (delta[HCO3-]p, -1.4 +/- 0.3 meq/liter, P less than 0.01). In these ADX dogs, the exogenous supply of aldo was fixed but hypoaldosteronism may have developed owing to increased metabolic clearance rate of aldo caused by dietary K+ depletion. When mineralocorticoid replacement was withheld in ADX dogs, the steady-state degree of renal metabolic acidosis was no more severe in animals with preexisting dietary K+ depletion (16 days) than in the same animals when mineralocorticoid was withheld without preexisting K+ depletion. Thus, when neither endogenous nor exogenous aldo is present, K+ depletion does not result in a renal acidosis-producing effect that exacerbates that of aldo deficiency. The results of these studies suggest that the reduction in NAE and consequent metabolic acidosis induced by dietary K+ depletion is at least in part a consequence of aldo deficiency, and provide no evidence of an additional defect in acidification not caused by aldo deficiency.

Maximal concanavalin A-specific agglutinability without loss of density-dependent growth control.

Density-inhibited 3T3 mouse fibroblasts were treated for 10 min with nine concentrations of Pronase ranging from 0.25 to 40 mug/ml. Concanavalin A-specific agglutinability increased from control values of about 25% to plateau values of about 80%. None of these Pronase concentrations brought about an increase in cell number within 84 hr. Pronase-treated cells remained responsive to growth stimulation by serum and cortisol. Therefore, the protease-mediated surface change measured by increased concanavalin A-specific agglutinability is not an event sufficient by itself to bring about cell division.