Laboratory Investigation

Kidney International (1985) 28, 118–127; doi:10.1038/ki.1985.130

Captopril enhances aminoglycoside nephrotoxicity in potassium-depleted rats

Paul E Klotman1, James E Boatman1, Bryan D Volpp1, James D Baker1 and William E Yarger1

1Department of Medicine, Duke University, and the Veterans Administration Medical Center, Durham, North Carolina, USA

Correspondence: Dr P E Klotman, Nephrology Section, VA Medical Center, 508 Fulton Street, Durham, North Carolina 27705 USA

Received 18 October 1984; Revised 4 January 1985.

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Abstract

Captopril enhances aminoglycoside nephrotoxicity in potassium-depleted rats. We demonstrated that potassium depletion significantly increased gentamicin nephrotoxicity in Sprague-Dawley rats (100 mgdotkg-1dotday-1). To determine whether this enhanced toxicity was mediated by renin secretion, we evaluated the effect of a converting enzyme inhibitor in this model. When we administered the combination of captopril (100 mgdotkg-1dotday-1) and gentamicin in potassium-depleted rats, we observed a surprising and significant adverse effect of this combination on the clearances of inulin (CIn) and PAH (CPAH) and renal blood flow (RBF). Pretreatment with indomethacin significantly improved CIn and CPAH, and potassium repletion abolished this effect entirely. In potassium-depleted animals that received both gentamicin and captopril, the intra-arterial administration of imidazole, a thromboxane synthétase inhibitor, significantly reduced urinary TXB2 excretion and significantly improved RBF and CIn in vivo. In the same group of animals, administration of the kallikrein antagonist aprotinin also significantly increased both RBF and CIn. To measure total renal thromboxane B2 production (TXB2), we perfused kidneys ex vivo with cell-free perfusate. Three groups of animals were studied: potassium-repleted control animals, potassium-depleted control animals, and potassium-depleted animals treated with gentamicin alone, captopril alone, or the combination of gentamicin and captopril. We measured TXB2 in renal venous effluent by radioimmunoassay. Ex vivo perfused kidneys from potassium-depleted control animals produced significantly more TXB2 than potassium-repleted controls. Kidneys from potassium-depleted animals that received both gentamicin and captopril produced significantly greater amounts of TXB2 than did kidneys from potassium-depleted animals treated with captopril alone, gentamicin alone, or control potassium-depleted kidneys. The administration of imidazole ex vivo at a rate equivalent to in vivo administration (10 microM/min) reduced TXB2 production by potassium-depleted kidneys that received the combination of gentamicin and captopril to that of potassium-repleted control kidneys. These results suggest that the deleterious effect of captopril in potassium-depleted rats that received gentamicin is due at least in part to kinin-stimulated renal TXB2 production.

Le captopril accroît la néphrotoxicité des amino-glycosides chez des rats déplétés en potassium. Nous avons démontré que la déplétion potassique augmentait significativement la néphrotoxicité de la gentamicine chez des rats Sprague-Dawley (100 mg/kg-1/jour-1). Afin de déterminer si cette toxicité accrue était médiée par une sécrétion de rénine, nous avons évalué l'effet d'un inhibiteur de l'enzyme de conversion dans ce modèle. Quand nous avons administré une association de captopril (100 mg/kg-1/jour-1) et de gentamicine chez des rats déplétés en potassium, nous avons observé un effet adverse surprenant et significatif de cette association sur les clearances de l'inuline (CIn) et du PAH (CPAH) et sur le débit sanguin rénal (RBF). Le prétraitement avec de l'indométacine a significativement amélioré CIn et CPAH, et la réplétion potassique a aboli cet effet entièrement. Chez des animaux déplétés en potassium qui ont reçu à la fois de la gentamicine et du captopril, l'administration intra-artérielle d'imidazole, un inhibiteur de la thromboxane synthetase, a réduit significativement l'excrétion urinaire de TXB2 et a amélioré significativement RBF et CIn in vivo. Dans le même groupe d'animaux, l'administration d'apronitine, un antagoniste de kallikréine, a aussi significativement accru RBF et CIn. Afin de mesurer la production rénale totale de thromboxane B2 (TXB2), nous avons perfusé des reins ex vivo avec un perfusat acellulaire. Trois groupes d'animaux ont été étudiés: des animaux contrôles répiétés en potassium, des animaux contrôles déplétés en potassium, et des animaux déplétés en potassium traités avec de la gentamicine seule, du captopril seul, ou l'association de gentamicine et de captopril. Nous avons mesuré TXB2 dans l'effluent veineux rénal par radioimmunoessai. Les reins perfuses ex vivo des animaux contrôles déplétés en potassium ont produit significativement plus de TXB2 que les contrôles répiétés en potassium. Les reins des animaux déplétés en potassium qui ont reçu à la fois la gentamicine et le captopril ont produit significativement plus de TXB2 que les reins d'animaux déplétés en potassium traités avec le captopril seul, la gentamicine seule, ou que les reins de contrôles déplétés en potassium. L'administration d'imidazole ex vivo à une vitesse équivalente à une administration in vivo (10 microM/min) a réduit la production de TXB2 par les reins déplétés en potassium ayant reçu l'association de gentamicine et de captopril à celle des reins contrôles répiétés en potassium. Ces résultats suggèrent que l'effet délétère du captopril chez les rats déplétés en potassium ayant reçu de la gentamicine est dû, au moins en partie, à une production de TXB2 stimulée par les kinines.

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