PATHOPHYSIOLOGY OF DOGS AFTER 84-PERCENT HEPATECTOMY WITH EMPHASIS ON PROSTAGLANDIN METABOLITES AND THE EFFECT OF A THROMBOXANE A(2) SYNTHESIS INHIBITOR AND A PROSTAGLANDIN I-2 ANALOG

The pathophysiological conditions following 84% hepatectomy were examined in terms of the changes in thromboxane A(2) (TxA(2)) and prostaglandin I-2 (PGI(2)) in a canine model. OKY-046, a TxA(2) inhibitor, and OP-2507, a PGI(2) analog, were administered to evaluate the possibility of extending hepatic resection. The 2-week survival rate following 84% hepatectomy significantly improved after the administration of OKY-046 and OP-2507, from 12.5% to 58.3% and 75.0%, respectively. Furthermore, OP-2507 significantly improved impaired hepatocyte and sinusoidal endothelial cell function after 84% hepatectomy, resulting in a satisfactory recovery to the preoperative levels. Within 24 h after 84% hepatectomy, the plasma levels of thromboxane B-2 (TxB(2)) increased significantly, and the 6-keto-prostaglandin F-1 alpha, (6-KF) levels became slightly elevated. OKY-016 and OP-2507 decreased TxB(2) and increased 6-KF in the plasma, resulting in the maintenance of sufficient blood how in the portal vein and hepatic tissue and the mitigation of microcirculatory disorders. Moreover, the cytoprotective effects of the two drugs inhibited functional impairment of the residual liver. In conclusion, abnormal prostaglandin metabolites were produced after 84% hepatectomy, being involved in residual liver disorders. However, the administration of either an inhibitor of TxA(2) synthesis or a PGI(2) analog ameliorated the functional impairment of the residual liver, which suggests their potential value for extending the resectability of the liver from what is presently feasible.