Hulter H N, Licht J H, Glynn R D, Sebastian A, Ilnicki L P
J Lab Clin Med. 1980 May;95(5):637-53.
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.
氨氯吡咪是一种“保钾”利尿剂，利钠作用中等，作用部位在远端肾单位的致密斑后段。在哺乳动物皮质远端肾单位的分离节段中，氨氯吡咪可减少钠重吸收和跨管电PD，并抑制钾分泌。我们研究了给固定剂量类固醇替代的去肾上腺（ADX）犬长期给予明显最大剂量的氨氯吡咪（1.0mg/kg，每日两次）对血浆和尿液酸碱及电解质组成的影响。给予氨氯吡咪导致钾潴留和高钾血症，净酸排泄减少，并引起慢性高氯性代谢性酸中毒。在氨氯吡咪给药期间通过限制饮食钾来预防钾潴留的其他组，或给已有饮食钾缺乏的动物给予氨氯吡咪的组中，净酸排泄的累积减少和全身酸中毒的严重程度没有显著差异。然而，各组尿液pH和铵排泄的反应有所不同。在慢性酸中毒的稳态下，高钾血症组的尿液pH和铵浓度最低，低钾血症组最高，三组中pH和铵呈正相关（r=0.67，p<0.001）。铵浓度与血浆钾浓度呈反比。在三组中，氨氯吡咪诱导的慢性酸中毒稳态期间，净酸排泄率恢复到对照水平。在持续给予氨氯吡咪期间，长期口服碳酸氢钠持续纠正酸中毒并未导致净酸排泄出现负值；也就是说，在正常血浆碳酸氢盐浓度下，氨氯吡咪不会导致碱的净消耗。这些研究结果表明，长期给予氨氯吡咪会导致肾脏氢离子分泌持续受损，仅限于远端肾单位，且不依赖于钾平衡的改变。钾平衡（正或负）的差异似乎仅影响氨扩散到尿液中的可用性和稳态尿液pH，但不影响氨氯吡咪期间肾脏氢离子分泌的稳态净速率。这些研究确定了一种慢性远端肾小管酸中毒的实验模型，其中即使氨排泄的可用性降低，在慢性酸中毒期间外部氢离子平衡仍可重新建立。
