Stimulation of
adenylyl cyclase causes cellular efflux of cAMP, and cAMP (unlike
adenosine) is stable in blood. Therefore, it is conceivable that cAMP could function as a circulating
adenosine prohormone by local target-organ conversion of distally released cAMP to
adenosine via the sequential actions of ectophosphodiesterase and
ecto-5'-nucleotidase (cAMP==>
AMP==>
adenosine; called the cAMP-
adenosine pathway). A possible specific representation of this general concept is the pancreatohepatorenal cAMP-
adenosine mechanism. The pancreas secretes
glucagon into the portal circulation, and
glucagon is a stimulant of hepatic
adenylyl cyclase. Therefore, we hypothesize that the pancreas, via
glucagon, stimulates hepatic cAMP production, which provides circulating cAMP for conversion to
adenosine in the kidney via the cAMP-
adenosine pathway. In normal rats, intravenous cAMP increased urinary and renal interstitial (assessed by renal microdialysis) cAMP and
adenosine. Intraportal infusions of
glucagon increased plasma cAMP 10-fold, it did not affect plasma
adenosine, and it increased urinary and renal interstitial cAMP and
adenosine. Local renal interstitial blockade (by adding inhibitors directly to the microdialysis perfusate) of ectophosphodiesterase (using 3-isobutyl-1-methylxanthine or 1,3-dipropyl-8-p-sulfophenylxanthine) or
ecto-5'-nucleotidase (using alpha,beta-methyleneadenosine-5'-diphosphate) prevented the cAMP-induced and
glucagon-induced increases in renal interstitial
adenosine, but not cAMP. In ZSF1 rats with the
metabolic syndrome, an oral
glucose load increased plasma
glucagon and urinary cAMP and
adenosine excretion. We conclude that circulating cAMP is a substrate for local conversion to
adenosine via the cAMP-
adenosine pathway. A specific manifestation of this is the pancreatohepatorenal cAMP-
adenosine mechanism (pancreas==> portal
glucagon==> liver==> circulating cAMP==> kidney==> local cAMP-
adenosine pathway).