In vivo effect of a selective endothelin receptor antagonist, BQ-123, on renal function in cyclosporin A-treated rats.
To investigate the possible involvement of endogenous endothelin (ET) in cyclosporin A (CsA) nephrotoxicity, we examined the renal effects of the selective [125I]ET-1 binding to porcine aortic membrane (ETA) receptor antagonist, BQ-123 (BQ), on CsA-treated rats. An osmotic minipump filled with BQ or its vehicle (saline), was subcutaneously implanted and animals were treated with CsA (50 mg/kg/d, i.p.) for 4 d. In both BQ- and its vehicle-treated rats, the 24-hour urine volume, urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion, urinary Ca/creatinine (Cr) and urinary NAG/Cr ratios were significantly increased compared with those before administration of CsA. In contrast, after administration of CsA, urinary Cr excretion was significantly decreased in both rat groups. Although urinary NAG excretion and the NAG/Cr ratio in the rats treated with BQ were significantly increased compared with those treated with saline, the serum Cr levels in BQ-treated rats were significantly lower than those in saline-treated rats. Urinary immunoreactive ET-1 (irET-1) excretion in all animals was significantly increased after administration of CsA. There were no significant differences in urinary irET-1 excretion in both BQ-treated and saline-treated rats with and without CsA. Expression of irET-1 was seen in the cytoplasm of renal tubules, but the degree of expression was similar in the BQ-treated and saline-treated rats on CsA. In the BQ-treated rats, small round areas with high grain densities over the glomeruli in the cortex and vesa recta bundles in the outer medulla were masked by the antagonist action of BQ.(ABSTRACT TRUNCATED AT 250 WORDS)
Tanda
K
K
Department of Urology, Hokkaido University School of Medicine, Sapporo, Japan.
Seki
T
T
Kobayashi
S
S
Kanagawa
K
K
Chikaraishi
T
T
Togashi
M
M
Nonomura
K
K
Koyanagi
T
T
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000276:immunology / Q000502:physiology / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D016572:Cyclosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)