Production, uptake, and metabolic effects of cyclic AMP in the bivascularly perfused rat liver

Production, uptake, and metabolic effects of cyclic AMP (cAMP) were measured in the bivascularly perfused rat liver in anterograde and retrograde perfusion. Glucagon, cAMP, N6,2'-O-dibutyryl cAMP and N6-monobutyryl cAMP were infused into the portal vein (anterograde perfusion), the hepatic vein (retrograde perfusion), or the hepatic artery (anterograde and retrograde perfusion) in order to reach different cell populations. The following results were obtained: (1) cAMP release caused by glucagon was directly proportional to the cell spaces that were accessible via the hepatic artery in anterograde and retrograde perfusion; since the metabolic effects of glucagon were not proportional to the accessible cell spaces, this observation also implies a disproportion between cAMP release and metabolic effects of the hormone; (2) when cAMP and N6,2'-O-dibutyryl cAMP were given to all liver cells (e.g. when infused into the portal vein), their metabolic effects were qualitatively and quantitatively the same and qualitatively equal to the effects of glucagon; (3) the changes caused by cAMP were a function of the cell spaces that can be reached via the hepatic artery in anterograde and retrograde perfusion; this behaviour contrasts markedly with that of glucagon, whose metabolic effects were practically independent of the accessible cell spaces; and (4) the effects of N6,2'-O-dibutyryl cAMP and N6-monobutyryl cAMP were independent of the cell spaces that were accessible via the hepatic artery in anterograde and retrograde perfusion; in this respect their behaviour was equal to that of glucagon. It is apparent that exogenously added cAMP mimicked the metabolic effects of glucagon in the liver only when it was supplied to all liver cells. Since glucagon, N6,2'-O-dibutyryl cAMP, and N6-monobutyryl cAMP were able to produce a full response even when given to only 30% of the liver parenchyma, it was concluded that cAMP production under the stimulus of glucagon or in consequence of the metabolic transformation of N6,2'-O-dibutyryl cAMP and N6-monobutyryl cAMP occurs in a compartment to which exogenous cAMP has no access. cAMP generated within this compartment is possibly able to diffuse from cell to cell.