Tsuruoka Shuichi, Schwartz George J, Ioka Takashi, Yamamoto Hisashi, Ando Hitoshi, Fujimura Akio
Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Mimamikawachi, Tochigi, Japan.
Am J Nephrol. 2005 May-Jun;25(3):233-9. doi: 10.1159/000085969. Epub 2005 May 24.
Cyclosporine A (CsA) causes distal renal tubular acidosis (RTA) and osteoporosis. We have recently reported that the reduction of nitric oxide (NO) exacerbates this condition. Distal RTA may deplete bone mineral due to the chronic buffering of acid in the blood. The interaction of CsA and NO in causing metabolic acidosis and bone demineralization has not been studied previously. Nor has the salubrious effect of citrate therapy.
To examine the effect of systemic pH correction by citrate on renal electrolyte (Na, K, Cl, NH3, HCO3) excretion following acute water loading in CsA-treated and NO-reduced rats. We further evaluated femoral bone density and bone demineralization activity after the same treatments.
Rats received CsA, L-arginine (L-Arg), or nitro-L-arginine-methyl ester (L-NAME), or a combination of CsA+L-NAME plus or minus citrate. Urine and blood electrolytes were examined, as well as the urine excretion of deoxypyridinoline and the bone density of both femurs.
CsA and L-NAME reduced urine pH and the serum HCO3- concentration, and increased serum K+ and Cl- concentrations. The combination of CsA with L-NAME caused more severe deficits in the serum HCO3- concentration and elevations in serum K+ and Cl- concentrations than either drug alone. Both CsA and L-NAME reduced urinary nitrate excretion, which was reversed by co-administration of L-Arg. Co-administration of citrate or L-Arg improved the CsA- and L-NAME-induced acidosis and hyperkalemia. Bone resorption and density of the femurs were decreased by CsA and L-NAME and were additive for both drugs. Co-administration of citrate or L-Arg restored both bone resorption and density to normal levels.
CsA induces a hyperchloremic metabolic acidosis with hyperkalemia and a reduction in NO. The ensuing systemic acidosis causes bone resorption and demineralization. These effects were corrected by co-treatment with citrate. Citrate, at least in part, directly reduces the protonation of bone in animals treated with CsA and is recommended as a potential adjunct drug to prevent bone demineralization in patients chronically receiving CsA.
环孢素A（CsA）可导致远端肾小管性酸中毒（RTA）和骨质疏松症。我们最近报道，一氧化氮（NO）减少会加剧这种情况。远端RTA可能由于血液中酸的慢性缓冲作用而导致骨矿物质流失。此前尚未研究CsA与NO在引起代谢性酸中毒和骨质脱矿方面的相互作用。柠檬酸盐疗法的有益效果也未被研究过。
研究柠檬酸盐纠正全身pH值对经CsA处理和NO减少的大鼠急性水负荷后肾脏电解质（钠、钾、氯、氨、碳酸氢根）排泄的影响。我们还评估了相同处理后股骨的骨密度和骨质脱矿活性。
大鼠接受CsA、L-精氨酸（L-Arg）、硝基-L-精氨酸甲酯（L-NAME），或CsA+L-NAME加或减柠檬酸盐的组合。检测尿液和血液中的电解质，以及脱氧吡啶啉的尿排泄量和双侧股骨的骨密度。
CsA和L-NAME降低了尿液pH值和血清碳酸氢根浓度，并提高了血清钾离子和氯离子浓度。CsA与L-NAME联合使用导致血清碳酸氢根浓度的下降和血清钾离子及氯离子浓度的升高比单独使用任何一种药物都更严重。CsA和L-NAME均降低了尿硝酸盐排泄，L-Arg共同给药可使其逆转。柠檬酸盐或L-Arg共同给药改善了CsA和L-NAME诱导的酸中毒和高钾血症。CsA和L-NAME降低了股骨的骨吸收和骨密度，两种药物的作用是相加的。柠檬酸盐或L-Arg共同给药使骨吸收和骨密度恢复到正常水平。
CsA可诱发高氯性代谢性酸中毒伴高钾血症及NO减少。随之而来的全身酸中毒导致骨吸收和骨质脱矿。这些影响通过与柠檬酸盐共同治疗得到纠正。柠檬酸盐至少部分地直接减少了CsA处理动物骨骼的质子化，建议作为一种潜在的辅助药物，用于预防长期接受CsA治疗患者的骨质脱矿。
