JOURNAL OF SURGICAL RESEARCH 68, 56–62 (1997) ARTICLE NO. JR975012 Prostaglandin E 1 Resuscitates Hepatic Organic Anion Transport Independent of Its Hemodynamic Effect after Warm Ischemia HISASHI SHINOHARA, M.D.,* AKIRA TANAKA, M.D.,* TOYOSHI FUJIMOTO, M.D.,† AKIYOSHI KANAZAWA, M.D.,* SEIJI SATOH, M.D.,* ETSURO HATANO, M.D.,* AND YOSHIO YAMAOKA, M.D.* *Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, 54 Kawaracho, Shogoin, Sakyoku, Kyoto 606, Japan; and †Department of Anatomy and Cell Biology, School of Medicine, Gunma University, Maebashi 371, Japan Submitted for publication October 7, 1996 success of the operation and complicate the postopera- Prostaglandin E 1 (PGE 1 ) is a promising agent against tive course [1]. Therefore, different chemicals have ischemic liver damage, but direct evidence of the bene- been applied to improve the warm ischemic tolerance fit to intrinsic hepatocyte function has been lacking. of the hepatocyte [5, 6]. Of those, prostaglandins may We demonstrate here that organic anion transport can be the most promising agents against ischemic liver be supported by treatment with PGE 1 even at a lower damage, considering their biological activities such as dose which does not affect hepatic microcirculation inhibition of cytokine release from activating macro- in rabbits with liver inflow occlusion. Near-infrared phages [7], inhibition of oxyradical generation from ac- spectroscopy was applied to directly measure hepatic tivated polymorphonuclear leukocytes [8], as well as clearance of indocyanine green (ICG), an exogenous increasing hepatic blood flow by relaxing vascular organic anion, and to estimate microcirculation as smooth muscle [9]. Indeed, the use of prostaglandin E 1 measured by oxygen saturation and the content of he- (PGE 1 ) in experimental animals has been reported to moglobin in the sinusoid. Also, morphological changes produce what is called a cytoprotective effect on the in microtubules, the cytoskeleton which is known to be liver following ischemic insults [10 – 12]. Also, a few associated with organic anion transport, and energy clinical trials have successfully reduced primary graft status, as measured by adenine nucleotide levels, were nonfunction with PGE 1 after liver transplantation [3, observed. ICG removal rate in hepatocytes decreased 4]. Nevertheless, to date there has been no direct evi- significantly from 0.100 { 0.018 to 0.027 { 0.019 min 01 dence that PGE 1 resuscitates intrinsic hepatocyte func- (mean { SD, P õ 0.01) by 60-min warm ischemia, whereas tion impaired by warm ischemia. Moreover, the site of the value increased to 0.082 { 0.030 min 01 (P õ 0.05) when PGE 1 was given at a dose of 0.05 mg/kg/min. The treated action, i.e., whether the benefit stems predominantly livers also showed early reorganization of microtubules, from the direct action of PGE 1 on hepatocytes or ensues as well as amelioration of ATP resynthesis after reperfu- from the vasodilator action which improves microcircu- sion. However, there were no significant differences in lation, remains unclear. In previous investigations intraoperative changes in oxygen saturation and the dealing with the cytoprotective effect of PGE 1 , the ad- content of hemoglobin in the sinusoid between PGE 1 - ministered doses of PGE 1 have varied from 0.02 to 0.75 treated and untreated groups, indicating that the influ- mg/kg/min [10 – 12], and the contribution of hemody- ence of PGE 1 at this dose on hemodynamic changes is namic changes has not been fully discussed. not considerable. These results indicate that PGE 1 resus- Tissue near-infrared (NIR) spectroscopy, which mea- citates an inherent hepatocyte function of organic anion sures the absorption spectrum from 700 to 2500 nm, transport on reperfusion after warm ischemia and sug- provides biochemical and biophysical information on gest that the benefit could be attributed solely to direct deep tissue, since NIR light penetrates deeply into or- action on hepatocytes.  1997 Academic Press gans [13]. With NIR spectroscopy, we have previously developed methods for the evaluation of liver hemody- namics and function. Quantitative detection of oxygen INTRODUCTION saturation and the content of hemoglobin reveals the hepatic microcirculatory condition in the sinusoid level [14]. Direct measurement of hepatic clearance of indo- Interruption of hepatic blood flow is sometimes re- cyanine green (ICG), a representative exogenous or- quired to control hemorrhage during extensive resec- ganic anion dye [15], provides us with information tion for tumors or during repair of liver trauma [1, 2] about anion-transport profile in the hepatocytes, using and is always necessary in liver transplantation [3, 4]. two rate constants reflecting dye uptake and removal In these situations, prolonged inflow occlusion results [16]. Thus NIR spectroscopy is a useful technique in in parenchymal liver cell injury with impaired energy metabolism and function, which can compromise the studying the effects of PGE 1 on liver hemodynamics 56 0022-4804/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved. AID JSR 5012 / 6n1b$$$$41 03-15-97 06:22:48 srga