Diltiazem facilitates endothelin clearance from the blood stream to reduce toxic elevation of plasma endothelin level in rodents.
Pretreatment with diltiazem at a dose of 2 mg kg-1 intravenously protected against sudden death induced by intravenous administration of endothelin-1 (ET-1, 5 nmol kg-1), with an apparent decrease in the plasma immunoreactive-ET-1 (IR-ET-1) in mice. These effects, which were also observed in anaesthetized rats, disappeared in rats with bilateral ligation of the renal arteries. In the latter, the exogenous ET-1-induced elevation of plasma IR-ET-1 tended to be higher than that in the sham-operated controls. Furthermore, in anaesthetized rats, diltiazem inhibited ET-1-induced decreases in renal blood flow and increased renal accumulation of IR-ET-1. These results indicate that part of the clearance of ET-1 from the bloodstream occurs in the kidney, and that diltiazem enhances the elimination of the peptide, presumably by improvement in the renal circulation, this action leading to alleviation of the toxic effects of ET-1.
Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
N
N
Ashizawa
H
H
Okumura
A
A
Matsuura
F
F
Kobayashi
D000758:Anesthesia; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003645:Death, Sudden; D004110:Diltiazem / Q000494:pharmacology*; D016232:Endothelins / Q000097:blood* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects
D016232:Endothelins; D004110:Diltiazem