Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat

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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 <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. The infusion of specific endothelin anti-serum partially but significantly prevented the reduction of renal plasma flow and glomerular filtration rate induced by cyclosporine administration (20 mg/ kg i.v.), whereas the infusion of non-immune serum had no effect. We suggest that endothelin is an important mediator of cyclosporine-induced acute vasoconstriction in the rat.

Original languageEnglish
Pages (from-to)76-83
Number of pages8
JournalJournal of the American Society of Nephrology
Volume1
Issue number1
Publication statusPublished - Jul 1990

Keywords

  • Anti-endothelin antibody
  • Glomerular filtration rate
  • Isolated perfused kidney
  • Renal plasma flow
  • Renal vascular resistance

ASJC Scopus subject areas

  • Nephrology

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