Cumulative damaging effect of liver hypoperfusion and cyclosporine A on the peribiliary capillary plexus - A study in an isolated dually perfused ratmodel

Background, Cyclosporine (CsA) is an essential posttransplantation immunosu ppressive drug. It may cause hepatotoxicity, mostly cholestasis, by unknown mechanism. CsA causes nephrotoxicity mainly by increased vascular resistan ce. We investigated the effects of CsA on the peribiliary capillary plexus, in an isolated, dually perfused (i.e., via the hepatic artery and the port al vein) rat liver preparation. Methods. After 30 min of stabilization with optimal flow (4 ml/min/g liver) , four liver groups were perfused (control, n=5 each) and four groups were hypoperfused (n=5 each, 1 ml/min/g) for 120 min. This was followed by a 30- min optimal reperfusion phase, during which the controls and the hypoperfus ed groups were injected (60 sec) via the hepatic artery with CsA at high (3 mg/kg body weight in 1 ml) or low dose (0.03 mg/kg), cremophore (130 mg/kg ), or saline (1 ml). A ninth group (n=5) underwent 2-hr ischemia and 30-min reperfusion to standardize liver damage. Dark nonradioactive microspheres (similar to 10 mu m diameter) were injected via the hepatic artery 15 min a fter drug or saline injection. Results. Neither of the two CsA doses, nor cremophore controls, nor hypoper fusion alone caused entrapment of microspheres in the peribiliary circulati on as assessed by light microscopy; perfusion pressures and resistances wer e also not altered. Significant arteriolar impaction and vasculature engorg ement occurred in the hypoperfused plus high-dose CsA livers; hypoperfusion plus low-dose CsA or cremophore groups were minimally tainted. Vascular no table obstruction was associated with 15-40% increase in portal and arteria l perfusion pressures and resistances, 50% decrease in oxygen extraction, a nd increase in lactate/pyruvate ratio, hepatocellular damage, and wet-to-dr y weight ratio. Such findings were superior to those detected in the ischem ic livers. Conclusions. Acute single high-dose CsA injection, but not low-dose or crem ophore, if combined with decreased flow, alters hepatic microcirculatory re sistance. Possible correlations between such changes and clinical implicati ons in organ transplantation are discussed.