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

In previous studies we suggested that urinary tract obstruction and ch ronic administration of lithium or amiloride were models of ''voltage- dependent'' distal renal tubular acidosis (DRTA). Subsequently, differ ences 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 thr ee experimental models. In the current experiments we examined the eff ect of 24-h unilateral ureteral obstruction (UUO) and chronic administ ration of amiloride and lithium on collecting tubule H-K-ATPase, the o ther renal H-ATPase enzyme. In the obstructed kidney, cortical collect ing tubule (CCT) H-K-ATPase activity was enhanced by 73 +/- 10.0%, whe reas the enzyme activity in medullary collecting tubule (MCT) was decr eased by 67 +/- 5.4%. In the normal contralateral kidney, activities o f H-ATPase, H-K-ATPase, and Na-K-ATPase were increased by approximatel y 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-ATP ase activities in amiloride-treated rats were unchanged. After LiCl (4 meq . kg-1 . day-1 x 3 days ip), rats developed mild metabolic acidos is 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 m eq/l) inhibited CCT, but not MCT, H-K-ATPase activity, whereas amilori de had no effect on the enzyme activity. These data suggest that the a cidification defect seen after 24-h UUO is mediated by impaired proton transport in MCT. Our data further suggest that, in rats, lithium adm inistration consistently results in a more severe metabolic acidosis t han amiloride because lithium inhibits both proton pumps in the CCT. M oreover, the differences in potassium transport seen in these three mo dels of DRTA could be the result of differing effects on both CCT Na-K -ATPase and H-K-ATPase activities.