Mechanisms of amphotericin B-induced decrease in glomerular filtration rate in rats.
Mechanisms responsible for the reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) in response to acute infusions of amphotericin B were investigated in vivo in rats. The influence of salt status and the roles of adenosine, cyclic AMP, and calcium influx were examined. Amphotericin B was infused into the renal artery in seven groups of rats at 0.025 mg/kg of body weight per min for 15 min. RBF and GFR were measured over 15 min before, during, and after the infusion. Control rats were maintained on a normal salt diet; a second group of rats received a salt-depleted diet, and a third group received a high-salt intake. Four other groups were kept on a normal diet and received theophylline (0.5 mumol/kg/min into the renal artery, intra-arterially [i.a.]), dibutyryl cyclic AMP (85 micrograms/min, i.a.), the 5'-nucleotidase inhibitor adenosine alpha,beta-methylene diphosphate (4 mg/kg, intramuscularly), or diltiazem (20 micrograms/kg/min, i.a.). Control rats had a prompt 50% decrease in RBF in response to amphotericin B. This was sustained over the 15-min infusion period and was accompanied by a decrease in creatinine clearance (CLCR) (from 0.83 +/- 0.08 to 0.40 +/- 0.09 ml/min; P less than 0.05). On stopping the infusion, RBF returned quickly to baseline but CLCR continued to decrease further (to 0.35 +/- 0.07 ml/min; P less than 0.05). Salt loading, theophylline, and diltiazem administration prevented the decreases in both RBF and CLCR. Both RBF and CLCR responses in the remaining groups were not significantly different from those in controls. The results of this study reveal a protective effect of salt loading and theophylline against amphotericin B nephrotoxicity in the rat but deny a role for adenosine in mediating these effects. They further suggest that theophylline inhibits the acute responses by a mechanism unrelated to either adenosine receptor blockade or phosphodiesterase inhibition and that calcium influx into the cells is probably responsible for the acute changes in RBF and GFR in response to amphotericin B.
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Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
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D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007261:Infusions, Intra-Arterial; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D013806:Theophylline / Q000494:pharmacology
D012965:Sodium Chloride; D003994:Bucladesine; D000666:Amphotericin B; D003404:Creatinine; D013806:Theophylline; D004110:Diltiazem