H-K-ATPASE IN DISTAL RENAL TUBULAR-ACIDOSIS - URINARY-TRACT OBSTRUCTION, LITHIUM, AND AMILORIDE

In previous studies we suggested that urinary tract obstruction and chronic administration of lithium or amiloride were models of ''voltage-dependent'' distal renal tubular acidosis (DRTA). Subsequently, differences among these three models suggested that the pathogenesis was far more complex than we originally proposed. A recent study showed that H-adenosinetriphosphatase (H-ATPase) activity was decreased in all three experimental models. In the current experiments we examined the effect of 24-h unilateral ureteral obstruction (UUO) and chronic administration of amiloride and lithium on collecting tubule H-K-ATPase, the other renal H-ATPase enzyme. In the obstructed kidney, cortical collecting tubule (CCT) H-K-ATPase activity was enhanced by 73 +/- 10.0%, whereas the enzyme activity in medullary collecting tubule (MCT) was decreased by 67 +/- 5.4%. In the normal contralateral kidney, activities of H-ATPase, H-K-ATPase, and Na-K-ATPase were increased by approximately 30% in both CCT and MCT. Following amiloride (3 mg . kg-1 . day-1 x 3 days ip), rats had normal acid-base status, slight hyperkalemia, and markedly elevated plasma aldosterone levels. Both CCT and MCT H-K-ATPase activities in amiloride-treated rats were unchanged. After LiCl (4 meq . kg-1 . day-1 x 3 days ip), rats developed mild metabolic acidosis and had normokalemia and normal aldosterone status. CCT H-K-ATPase activity in lithium-treated rats was decreased by 64 +/- 8.8%, whereas the enzyme activity in MCT remained unchanged. Lithium in vitro (30 meq/l) inhibited CCT, but not MCT, H-K-ATPase activity, whereas amiloride had no effect on the enzyme activity. These data suggest that the acidification defect seen after 24-h UUO is mediated by impaired proton transport in MCT. Our data further suggest that, in rats, lithium administration consistently results in a more severe metabolic acidosis than amiloride because lithium inhibits both proton pumps in the CCT. Moreover, the differences in potassium transport seen in these three models of DRTA could be the result of differing effects on both CCT Na-K-ATPase and H-K-ATPase activities.