THE EFFECT OF A THROMBOXANE A(2) RECEPTOR ANTAGONIST (ONO-3708) ON ISCHEMIA-REPERFUSION INJURY OF THE DOG PANCREAS

The effects of a thromboxane A(2) receptor antagonist, ONO 3708, on is chemia-reperfusion injury of the pancreas were evaluated using an isol ated in-vivo-perfused dog pancreas model. Pancreatic endocrine and exo crine function were stimulated with cholecystokinin octapeptide (10(-1 2) mol). This dose significantly increased endogenous prostaglandin I- 2 and thromboxane A(2) production by the pancreas (both P<0.001). A pe riod of 60 min of ischemia and subsequent reperfusion induced an incre ase of pancreatic amylase release (P<0.01) and a decrease of insulin r elease (P<0.01). There was also a decrease of pancreatic juice and pan creatic bicarbonate and amylase output (au P<0.01), suggesting damage to the acinar, ductular, and beta cells. Intravenous administration of ONO 3708 (200 mu g/kg/min) throughout the experiment prevented these abnormalities of pancreatic secretion. It also reduced the plasma lipi d peroxide level in the venous drainage (P<0.01) and elevated the pros taglandin I-2 level (P<0.01) without changing thromboxane A(2) levels. ONO 3708 thus appeared to protect the pancreas from ischemia-reperfus ion injury by reducing the perioxidation of cell membrane lipids and b y decreasing the thromboxane A(2)/prostaglandin I-2 ratio, which is a predictor of cellular injury.