Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat.
The effect of cyclosporine on renal function was first investigated in the isolated perfused rat kidney. Kidneys from normal male Sprague-Dawley rats were perfused at constant pressure. After control clearance periods, cyclosporine (0.6, 1.2, or 3 mg/min) or vehicle was infused over 5 min period in the renal artery and then four 10-min experimental periods followed. Cyclosporine, but not vehicle caused a dose dependent fall in renal perfusate flow associated with a concomitant increase in renal vascular resistance. Glomerular filtration rate was also decreased in parallel. We also examined whether endogenous endothelin mediates cyclosporine-induced acute renal vasoconstriction. In isolated kidneys pre-exposed to specific anti-endothelin antibody and then challenged with cyclosporine (1.2 mg/min) the renal perfusate flow, renal resistance, and glomerular filtration rate were 22.3 +/- 1.8 ml/min, 4.50 +/- 0.36 mmHg/ml.min-1, 1.06 +/- 0.05 ml/min, respectively, as compared with 12.9 +/- 1.2 ml/min, 7.8 +/- 1.2 mmHg/ml.min-1, 0.55 +/- 0.06 ml/min (P less than 0.01) measured in isolated kidneys pre-exposed to a non-immunized rabbit serum. The effectiveness and specificity of anti-endothelin antibody were confirmed by its capability of preventing the renal function deterioration caused by a single bolus dose (150 pmol) of synthetic endothelin, but not by infusion of angiotensin II, norepinephrine, or thromboxane A2 mimetic U-46619 in isolated kidneys. To test further the relationship between endogenous endothelin and cyclosporine-induced renal vasoconstriction, a second series of in vivo studies was performed in normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Perico
N
N
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Dadan
J
J
Remuzzi
G
G
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D003524:Cyclosporins / Q000633:toxicity*; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D000906:Antibodies; D003524:Cyclosporins; D016232:Endothelins