USE OF ETA AND ETA +B RECEPTOR ANTAGONISTS IN ATTENUATING HEPATIC ISCHEMIA/REPERFUSION INJURY

Abstract

162 Liver dysfunction and injury can occur following liver transplantation because of ischemia/reperfusion injury (I/R). The potent vasoconstrictor, endothelin (ET-1), may contribute to this injury. The purpose of this study was to test the hypothesis that ET-1 contributes to I/R injury in the liver by blocking its action with specific antagonists to ET-1. This was done in a rat model of 70% liver ischemia created by occluding the blood supply to the medial and left lateral lobe for 60 min. Hepatic injury was determined by alanine amino-transferees (ALT) levels. All animals were subjected to hepatic ischemia. Group 1 (n=6) was not pretreated with an ET-1 antagonist. In Group 2 (n=5), the combined ETA and ETB receptor subtype antagonist, Ro 61-0612 and in Group 3 (n=7), the specific ETA receptor antagonist Ro 61-1790 (both antagonists provided by Hoffman LaRoche) was infused for 30 min (0.5 mg/kg/min, iv) prior to the ischemic period. Twenty-four hrs after ischemia, the animals were anesthetized and catheters placed into the carotid artery for blood pressure measurements and into the vena cava for blood samples. Hepatic injury in Group 1 was manifested by an increase in ALT from a baseline value of 4±1 units/ml (mean ± SEM) to a level of 263± 41 units/ml measured 24 hrs after ischemia. In contrast, the ALT levels in Group 2 changed from 10 ±2 unit /ml to only 66 ± 17 units/ml. In Group 3, the ALT levels at 24 hrs were 204 ± 66 units/ml a value not different from the ischemia only group (Group 1). The ALT levels at 24 hrs in group 2 were significantly different from the untreated Group 1 (66± 17 vs 263 ± 41 units/ml, p<0.05). in conclusion, the use of a combined ETA and ETB receptor antagonist significantly attenuated hepatocellular damage. The ETA receptor antagonist, by itself did not offer significant protection when compared to the ETA + ETB receptor antagonist. Thus blockade of both receptors may be necessary to inhibit the action of ET-1. The ETA and ETB combined receptor antagonists may have a potential role in reducing I/R injury especially in organ transplantation where the drug can be given prior to harvesting.