The pancreatohepatorenal cAMP-adenosine mechanism

Edwin K. Jackson, Zaichuan Mi, Lefteris C. Zacharia, Stevan P. Tofovic, Raghvendra K. Dubey

Research output: Contribution to journalArticlepeer-review


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 α,β-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).

Original languageEnglish
Pages (from-to)799-809
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
Publication statusPublished - May 2007


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