Effect of an adenosine receptor antagonist on acute amphotericin B nephrotoxicity.
The clinical usage of amphotericin B in treating systemic fungal infections is limited by its nephrotoxicity, which is caused by reductions in renal blood flow and alterations in renal tubular function. Aminophylline, an adenosine receptor antagonist, attenuates amphotericin B-induced reductions in renal blood flow in both dogs and rats, which suggests that endogenous adenosine may participate in this response. However, aminophylline per se is a vasodilator and also changes intracellular levels of cyclic nucleotides and calcium. In this study, we re-examined the hypothesis that adenosine participates in amphotericin B-induced renal vasoconstriction by employing a novel adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX). This antagonist because of its negative charge at physiological pH, has limited access to the intracellular space. In a group of male Sprague-Dawley rats, an extracorporeal shunt was established between the carotid artery and left renal artery, via an aortic pouch, such that flow through the shunt was equivalent to renal blood flow. Also, a catheter was inserted into the left ureter for collection of urine and measurement of creatinine and electrolyte excretion. Amphotericin B-induced changes in renal blood flow and renal excretory function were measured in both control rats and rats pretreated with DPSPX at a dosage that abolishes the renovascular effects of exogenous adenosine in this model. In both control rats and rats pretreated with DPSPX, amphotericin B caused a marked decrease in renal blood flow, creatinine excretion, and potassium excretion; however, these effects of amphotericin B were similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Kuan
C J
CJ
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Branch
R A
RA
Jackson
E K
EK
D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D003404:Creatinine / Q000097:blood; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D011188:Potassium / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014970:Xanthines
D011983:Receptors, Purinergic; D014970:Xanthines; D000666:Amphotericin B; C053896:1,3-dipropyl-8-(4-sulfophenyl)xanthine; D012964:Sodium; D003404:Creatinine; D011188:Potassium