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Sprague-Dawley rats given gentamicin from 10 to 70 mg/kg/day for 9 days showed a linear decrease in glomerular filtration rate with increasing dose, paralleled by histologic changes of acute tubular necrosis and cast formation only at the higher doses. Nephrotoxicity was correlated with the peak, rather than trough, serum gentamicin levels in this study, suggesting that it is the mean level of gentamicin over time that determines renal injury. The polyuria caused by gentamicin resulted mainly from a tubular concentrating defect rather than enhanced sodium or osmolal excretion and may be explained by the finding of a predominance of casts in the medullary thin limbs of the loops of Henle. No effect of gentamicin on the activity of cortical or medullary sodium-potassium adenosine triphosphatase was found to account for the modest sodium wasting. Concurrent administration of sodium cephalothin decreased the renal toxicity of gentamicin at high doses, an effect not explained by the added sodium or nonreabsorbable anion.

The role of aldosterone in extrarenal potassium tolerance: Studies in anephric man. Since the role of aldosterone in mediating extrarenal potassium transport remains uncertain, the effect of mineralocorticoid on potassium metabolism was assessed in anephric patients. Seven anephric patients underwent three identical 72-hour periods between hemodialyses during which treatment with either 10 mg/day deoxycorticosterone acetate (DOCA) intramuscularly or 300 mg/day spironolactone orally was compared to a baseline control period. The serum potassium rise, plasma aldosterone, salivary and stool electrolytes were measured in response to potassium loading over 48 hours with a metabolic diet containing 38 mEq/day followed by an “acute” oral potassium load of 0.5 mEq/kg. Acute potassium loading with DOCA resulted in a lower increment in serum potassium than with spironolactone (P < 0.01). The volume of distribution of the acute potassium load at three hours was 55% of body weight with DOCA, which was significantly greater (P < 0.05) than with either spironolactone (35%) or control (34%). However, with the dietary load of potassium, the increments in serum potassium measured at 24 and 48 hours (13 hours post-prandial) were similar in all three periods. The volume of distribution of the dietary potassium was not altered by DOCA or spironolactone but had risen to an average of 172% at 24 hours and 243% at 48 hours in the three periods. Plasma aldosterone levels were low, positively correlated to the serum potassium and similar in all three periods without evidence of feedback inhibition by DOCA or stimulated by spironolactone. The salivary potassium was high despite low aldosterone levels. Salivary and stool sodium and potassium concentrations were unaltered by DOCA or spironolactone. Stool potassium excretion was approximately 10% of daily intake and consequently failed to serve as a major route for potassium disposal. In conclusion, the rate of removal of an acute oral potassium load from the extracellular fluid is enhanced by a mineralocorticoid, suggesting that aldosterone may be important in mediating acute elevations in serum potassium in anephric man. The administration of a dietary potassium load of comparable size results in a much greater sequestration of potassium outside of the extracellular fluid. This enhanced transfer does not appear to be affected by DOCA or spironolactone as reflected by serum potassium levels measured at 24 and 48 hours. This would suggest that the activity of aldosterone in improving extrarenal potassium tolerance is greatest within the first few hours of potassium administration.

To the Editor. —Recent letters to JAMA have discussed the issue of hyperkalemia in association with the use of calcium channel antagonists. 1,2 The link between calcium and potassium transport at the cellular level has been well recognized. Membrane permeability to potassium in many cell types has been shown to be related to the concentration of intracellular calcium. 3 Studies have revealed that maneuvers designed to increase effective intracellular calcium concentration enhance net potassium efflux from cells, 4 whereas those directed at reducing effective intracellular calcium concentration impair net potassium efflux from cells. 5 Our studies have shown that verapamil and nifedipine enhance the extrarenal disposal of an acute intravenous potassium load administered to acutely nephrectomized rats. 6 This enhanced extrarenal potassium tolerance could not be accounted for by the intervention of insulin, aldosterone, or β 2 -catecholamines. We postulated that the impaired calcium entry into cells mediated by the