title: The pancreatohepatorenal cAMP-adenosine mechanism.
abstract: 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).
authors.affiliation: Department of Medicine, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Dr., Suite 450, Pittsburgh, PA 15219-3130, USA, and Clinic for Endocrinology, University Hospital Zurich, Switzerland. edj@pitt.edu
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.forename: Lefteris C
authors.initials: LC
authors.lastname: Zacharia
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.forename: Raghvendra K
authors.initials: RK
authors.lastname: Dubey
mesh_terms: D000241:Adenosine / Q000652:urine*; D000249:Adenosine Monophosphate / Q000652:urine; D000818:Animals; D000242:Cyclic AMP / Q000008:administration & dosage / Q000378:metabolism*; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007288:Inosine / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010179:Pancreas / Q000502:physiology*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats
chemical_list: D000249:Adenosine Monophosphate; D007288:Inosine; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose; D000241:Adenosine; D011339:Probenecid