Protective effect of a selective endothelin receptor antagonist, BQ-123, in ischemic acute renal failure in rats.
To elucidate the pathophysiological role of endogenous endothelin (ET), we examined the effects of the newly synthesized ETA receptor-selective antagonist, BQ-123, on ischemic acute renal failure induced by bilateral clamping of renal artery and vein followed by reperfusion in rats. BQ-123, when given by i.v. infusion of 0.5 mg/kg per min for 2.5 h during the pre- and post-ischemic period, was found to prevent the decrease in creatinine clearance and increases in blood urea nitrogen, plasma creatinine and the fractional excretion of sodium. Morphological observation also showed an effect of BQ-123, i.e. prevention of proximal tubular (S3 segment) necrosis. At 2 h after the start of reperfusion, the ET-1 content in the kidney increased to its maximal level. At this time, the Ca2+ content in the mitochondrial fraction of the renal cortex increased, with a concomitant increase in blood urea nitrogen. However, these increases were limited by treatment with BQ-123. Thus, BQ-123 was effective to both prevent mitochondrial Ca2+ accumulation in the early phase of ischemic acute renal failure and protect proximal tubular cells from post-ischemic degeneration. We conclude that ET may be at least partially involved in the pathogenesis of tubular cell injury in this acute renal failure model.
Mino
N
N
New Drug Discovery Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan.
Kobayashi
M
M
Nakajima
A
A
Amano
H
H
Shimamoto
K
K
Ishikawa
K
K
Watanabe
K
K
Nishikibe
M
M
Yano
M
M
Ikemoto
F
F
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium