HEPATOCYTE HETEROGENEITY IN RESPONSE TO EXTRACELLULAR ADENOSINE

Metabolic and haemodynamic effects of adenosine were studied in antegr ade and retrograde rat liver perfusions with influent nucleoside conce ntrations either below (i.e. 20 muM) or exceeding (i.e. 200-300 muM) t he single-pass clearance capacity of the liver. Adenosine (20 muM) inc reased in antegrade perfusions the perfusion pressure and markedly sti mulated prostaglandin D2, thromboxane B2 and glucose output, whereas i n retrograde perfusions no pressure and eicosanoid response occurred a nd glucose output was stimulated, only slightly. The perfusion-directi on-dependent differences in the glucose and pressure response to adeno sine (20 muM) were fully abolished in presence of ibuprofen (50 muM). When the adenosine concentration in influent was raised to 200-300 muM , i.e. to a concentration exceeding single-pass clearance of the nucle oside, the adenosine-induced prostaglandin D2 release was about 10-fol d higher in retrograde perfusions than in antegrade perfusions. On the other hand, both adenosine (20-300 muM)-induced cyclic AMP (cAMP) and K+ release from the liver were not affected by the direction of perfu sion, and maximal effects on cAMP release were observed at influent ad enosine concentrations of 100 muM. The basal rate (adenosine absent) o f prostaglandin D2 and thromboxane B2 release was about 10-fold higher in retrograde than in antegrade perfusion experiments, whereas the ba sal cAMP release from the liver was not affected by the direction of p erfusion. Maximal adenosine-stimulated glucose output was significantl y higher in antegrade than in retrograde perfusions at all adenosine c oncentrations tested (range 10-300 muM). Ibuprofen abolished this diff erence, indicating that eicosanoids liberated under the influence of a denosine contribute to the glycogenolytic response in antegrade, but n ot in retrograde, perfusion. Desensitization occurred following repeti tive adenosine infusion; this was more pronounced for adenosine-induce d prostaglandin release than for cAMP or K+ efflux. The data suggest t he following. (i) Both cAMP and eicosanoids are involved in the stimul ation of glycogenolysis by adenosine. (ii) Eicosanoids are probably li berated under the influence of extracellular adenosine from a portal p re-sinusoidal compartment and accordingly stimulate glycogenolysis onl y in antegrade perfusions. Thus signals derived from portal vein struc tures can modulate hepatocellular function. (iii) Contractile elements are probably located also inside the liver acinus. (iv) Eicosanoids r eleased into the hepatic vein reflect less than 10 % of hepatic eicosa noid formation, because of marked clearance by perivenous hepatocytes.