Captopril enhances aminoglycoside nephrotoxicity in potassium-depleted rats.
We demonstrated that potassium depletion significantly increased gentamicin nephrotoxicity in Sprague-Dawley rats (100 mg X kg-1 X day-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 mg X kg-1 X day-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 synthetase 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.
P E
PE
Klotman
J E
JE
Boatman
B D
BD
Volpp
J D
JD
Baker
W E
WE
Yarger
D000617:Aminoglycosides / Q000633:toxicity; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology*; D005839:Gentamicins / Q000633:toxicity*; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007444:Inulin; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D011191:Potassium Deficiency / Q000150:complications*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation; D012083:Renin / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D010130:p-Aminohippuric Acid
D000617:Aminoglycosides; D000806:Angiotensin-Converting Enzyme Inhibitors; D005839:Gentamicins; D007093:Imidazoles; D013929:Thromboxane B2; C029899:imidazole; D007444:Inulin; D007611:Aprotinin; D002216:Captopril; D012083:Renin; D007213:Indomethacin; D010130:p-Aminohippuric Acid