Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with endothelin-mediated decrease in local...

Area of Science:

• Pharmacology
• Toxicology
• Hepatology

Background:

• Cyclosporine A (CsA) is an immunosuppressant with known hepatotoxicity.
• The precise mechanisms underlying CsA-induced liver injury remain incompletely understood.
• The role of endothelin (ET) and its receptors in CsA's effects requires further investigation.

Purpose of the Study:

• To elucidate the mechanism of CsA-induced hepatotoxicity.
• To investigate the acute effects of CsA on local hepatic blood flow (LHBF) and systemic hemodynamics.
• To determine the involvement of ET and Cremophor-EL (C-EL) in CsA's toxic effects.

Main Methods:

• Guinea pigs were divided into five groups: control, CsA, C-EL, Bosentan+CsA, and BQ-123+CsA.
• CsA was administered intravenously, with or without ET receptor antagonists (Bosentan, BQ-123).
• Local hepatic blood flow (LHBF), mean arterial blood pressure (MAP), and liver pathology were assessed.

Main Results:

• CsA significantly decreased LHBF by 53.3% within 30 minutes, independent of MAP changes.
• Pre-treatment with ET antagonists (Bosentan and BQ-123) completely prevented the CsA-induced reduction in LHBF.
• CsA, but not its vehicle C-EL, induced significant acute pathological changes in liver morphology.

Conclusions:

• CsA exerts its acute hepatotoxic effects through endothelin (ET)-related mechanisms.
• ET receptor antagonism effectively mitigates CsA-induced reductions in hepatic blood flow and acute liver injury.
• These findings highlight a critical role for the ET system in mediating CsA's toxicity.