EFFECTS OF SELECTIVE PHOSPHODIESTERASE-3 INHIBITION IN THE PERFUSED LIVER OF THE RAT AFTER ENDOTOXIN TREATMENT

1 This study was designed to investigate the role of rat phosphodieste rase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, al one and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP leve ls were determined in the effluate and bile by radio immunoassay metho ds. 2 After endotoxin treatment, infusion of enoximone at three concen trations (1 mu M, 10 mu M) resulted in an increased glucose output fro m -1.4+/-0.9 to 7.8+/-2.5 mu mol l(-1) 20 min(-1). Bile acid-independe nt bile how increased also, in a dose-dependent manner. 3 In untreated livers, cyclic AMP release increased in the effluate from 1000+/-73 f mol g(-1) min(-1) to 1710+/-143 fmol g(-1) min(-1) when enoximone (10 mu M) was administered. In bile from untreated livers, the level of cy clic AMP was also significantly increased by enoximone. After endotoxi n treatment, the enoximone (10 mu M) effect on cyclic AMP levels in ef fluate and bile was greatly reduced. Levels of cyclic GMP in the efflu ate and bile appeared unchanged in the presence of enoximone. 4 During co-infusion of glucagon (1 nM) and enoximone (10 mu M), cyclic nucleo tide levels in the effluate and bile of livers after endotoxin treatme nt were determined. In the effluate, cyclic AMP release increased from 827+/-144 fmol g(-1) min(-1) to 17802+/-2821 fmol g(-1) min(-1) when glucagon was administered. The presence of enoximone enhanced cyclic A MP further to 41696+/-920 fmol g(-1) min(-1). The same changes in cycl ic AMP release were found in bile. Levels of cyclic GMP in the effluat e and bile were not significantly affected by the administration of gl ucagon and the PDI. 5 Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to gluca gon increased glucose release by 8.2+/-2.8 mu mol g(-1) 20 min(-1), wi thout alteration of lactate balance. The PDI enhanced the glycogenolyt ic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production. 6 Enoximone significantly enhanced t he bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was una ffected by the PDI. The vasoconstrictor effect of nerve stimulation wa s reduced by the PDI. 7 We conclude that endotoxin treatment reduces t he ability of the PDI, enoximone, to increase cyclic AMP release in th e perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 i s involved in the degradation of cyclic AMP in the liver after exposur e to endotoxin. Additionally, the inhibition of the RPDE3 results in g lucose release, vasodilatation and choleresis in endotoxin pretreated livers.