The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance

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Abstract

We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1,6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 μM) or CsA (0.5, 10 μM). No significant changes in TxB2 and 6-keto-PGF2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGFia, and endothelin release that reached statistical significance after incubation with 10 μM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 μM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/ kg to 2.8 Mg/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.

Original languageEnglish
Pages (from-to)775-780
Number of pages6
JournalTransplantation
Volume54
Issue number5
Publication statusPublished - 1992

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Tacrolimus
Vascular Resistance
Cyclosporine
Endothelial Cells
Kidney
Endothelins
Injections
Eicosanoids
Epoprostenol
Immunosuppressive Agents
Cell Culture Techniques
Cell Count
Wounds and Injuries
In Vitro Techniques

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

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title = "The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance",
abstract = "We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1,6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 μM) or CsA (0.5, 10 μM). No significant changes in TxB2 and 6-keto-PGF1α2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGFia, and endothelin release that reached statistical significance after incubation with 10 μM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 μM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/ kg to 2.8 Mg/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.",
author = "Ariela Benigni and Marina Morigi and Norberto Perico and Carla Zoja and Amuchastegui, {Carmen S.} and Antonella Piccinelli and Roberta Donadelli and Giuseppe Remuzzi",
year = "1992",
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T1 - The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance

AU - Benigni, Ariela

AU - Morigi, Marina

AU - Perico, Norberto

AU - Zoja, Carla

AU - Amuchastegui, Carmen S.

AU - Piccinelli, Antonella

AU - Donadelli, Roberta

AU - Remuzzi, Giuseppe

PY - 1992

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N2 - We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1,6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 μM) or CsA (0.5, 10 μM). No significant changes in TxB2 and 6-keto-PGF1α2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGFia, and endothelin release that reached statistical significance after incubation with 10 μM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 μM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/ kg to 2.8 Mg/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.

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