Assael B M, Chiabrando C, Gagliardi L, Noseda A, Bamonte F, Salmona M
Toxicol Appl Pharmacol. 1985 May;78(3):386-94. doi: 10.1016/0041-008x(85)90244-3.
The role of prostaglandins in the development of aminoglycoside-induced acute renal failure was studied in CD-COBS rats (200 to 250 g). The animals were treated with gentamicin (80 mg/kg), acetylsalicylic acid (ASA, 100 or 200 mg/kg), or both drugs or saline for 5 or 10 days. Renal function was studied measuring creatinine clearance, blood urea nitrogen (BUN), and serum electrolytes, urine osmolality, and maximal urinary concentrating capacity after water deprivation and vasopressin administration. Gentamicin toxicity on the proximal tubule was evaluated by measuring urinary excretion of the lysosomal enzyme N-acetylglucosaminidase (NAG). Renal prostaglandin (PG) production was evaluated measuring the concentration of PGE2, PGD2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) in whole renal homogenate after a 15-min incubation at 37 degrees C using gas chromatography-mass spectrometry. Gentamicin alone reduced the glomerular filtration rate (GFR) 20 to 30% after 5 and 10 days of treatment. Combination with ASA potentiated the toxic effect of the aminoglycoside after 10 but not after 5 days of treatment. Similarly, gentamicin reduced the urinary concentrating capacity and addition of ASA worsened the effects. Gentamicin markedly increased NAG excretion but this effect was reduced by ASA, probably as a result of lysosomal stabilization. ASA alone inhibited the production of prostaglandins in renal tissue by 70 to 90% after single or multiple doses. The animals treated with gentamicin alone presented a significant, specific increase in PGE2 production after 10 days of treatment but this increase did not occur when the two compounds were given together. Since PGE2 has a vasodilatory effect in the kidney these results suggest that it may play a specific role in maintaining normal renal blood flow and GFR during the development of aminoglycoside nephrotoxicity. The inhibition of prostaglandin production by nonsteroid anti-inflammatory drugs prevents this compensatory mechanism and worsens the renal damage.
在CD-COBS大鼠（200至250克）中研究了前列腺素在氨基糖苷类药物诱导的急性肾衰竭发展过程中的作用。动物分别接受庆大霉素（80毫克/千克）、乙酰水杨酸（ASA，100或200毫克/千克）、两种药物联合或生理盐水治疗5或10天。通过测量肌酐清除率、血尿素氮（BUN）、血清电解质、尿渗透压以及禁水和注射血管加压素后的最大尿浓缩能力来研究肾功能。通过测量溶酶体酶N-乙酰氨基葡萄糖苷酶（NAG）的尿排泄量来评估庆大霉素对近端小管的毒性。在37℃孵育15分钟后，使用气相色谱-质谱法测量全肾匀浆中前列腺素（PG）E2、PGD2、PGF2α、6-酮-PGF1α和血栓素B2（TXB2）的浓度，以此评估肾脏前列腺素的产生。单独使用庆大霉素治疗5天和10天后，肾小球滤过率（GFR）降低20%至30%。治疗10天后，与ASA联合使用会增强氨基糖苷类药物的毒性作用，但治疗5天后则不会。同样，庆大霉素降低了尿浓缩能力，添加ASA会使这种影响恶化。庆大霉素显著增加了NAG的排泄，但ASA可能通过稳定溶酶体而降低了这种作用。单独使用ASA单次或多次给药后，可使肾组织中前列腺素的产生减少70%至90%。单独使用庆大霉素治疗的动物在治疗10天后，PGE2的产生显著且特异性增加，但两种化合物一起给药时，这种增加并未出现。由于PGE2在肾脏中具有血管舒张作用，这些结果表明，在氨基糖苷类药物肾毒性发展过程中，它可能在维持正常肾血流量和GFR方面发挥特定作用。非甾体类抗炎药对前列腺素产生的抑制作用会阻止这种代偿机制，并加重肾脏损伤。
