title: Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat.
abstract: 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)
authors.affiliation: Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Perico
authors.forename: J
authors.initials: J
authors.lastname: Dadan
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: 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
chemical_list: D000906:Antibodies; D003524:Cyclosporins; D016232:Endothelins