Henger A, Tutt P, Riesen W F, Hulter H N, Krapf R
Medizinische Universitätsklinik, Kantonsspital Bruderholz, Basel, Switzerland.
J Lab Clin Med. 2000 Nov;136(5):379-89. doi: 10.1067/mlc.2000.110371.
Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (i.e., angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ((HCO3)p decreased from 19.8+/-0.4 mmol/L to 17.7+/-0.6 mmol/L, P<.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P<.005), urinary anion gap (+31 mEq/day, P<.05), and sulfate excretion (+32 mEq/day, P<.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P<.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P<.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ((HCO3)p decreased to 15.7+/-0.4 mmol/L, P<.05) and hyperkalemia (5.0 mmol/L, P<.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P<.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism.
人类慢性代谢性酸中毒（CMA）的特征是肾素 - 血管紧张素 - 醛固酮（RAA）活性增加、皮质醇分泌增加以及氮消耗。本研究的目的是检验RAA活性增加（即血管紧张素II或醛固酮）是否以及在何种程度上调节CMA中的酸碱平衡，从而可能共同决定酸中毒的严重程度。通过口服氯化铵（每天2.1 mmol/kg体重）7天，在8名正常受试者中诱导出CMA，随后给予螺内酯（100 mg，每天口服4次）7天，接着给予螺内酯和氯沙坦（100 mg，每天口服）4天。在所有研究期间均持续给予氯化铵。螺内酯导致酸中毒加重（（HCO3）p从19.8±0.4 mmol/L降至17.7±0.6 mmol/L，P<0.005），这是由于内源性酸产生大幅增加，净酸排泄显著增加（从116增至185 mmol/天，P<0.005）、尿阴离子间隙增加（+31 mEq/天，P<0.05）以及硫酸盐排泄增加（+32 mEq/天，P<0.05）证明了这一点。由于尿钾排泄减少（从108降至92 mmol/天，P<0.05），血浆钾从4.2 mmol/L增至4.6 mmol/L（P<0.05）。血浆血管紧张素II,皮质醇,醛固酮,尿醛固酮,尿四氢皮质醇,游离皮质醇和氮排泄显著增加。随后在螺内酯给药基础上加用氯沙坦导致酸中毒进一步加重（（HCO3）p降至15.7±0.4 mmol/L，P<0.05）和高钾血症（5.0 mmol/L，P<0.05），而血浆阴离子间隙无变化。第1天肾钾排泄从92降至73 mmol/天（P<0.05）。酸中毒加重是由肾脏机制引起的，净酸排泄显著减少以及尿中未测定阴离子和氮排泄未变证明了这一点。我们得出以下结论：（1）氯沙坦对AT-1的阻断通过诱导远端肾小管酸化缺陷而加重酸中毒。血管紧张素II是人类肾脏对CMA酸排泄反应的重要调节因子。（2）在CMA中螺内酯对醛固酮作用的抑制导致内源性酸产生增加，并通过一种非肾脏机制加重酸中毒，这种机制至少部分由糖皮质激素过多介导。
