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-5Ј-nucleotidase (cAMP f AMP f 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-5Ј-nucleotidase (using ␣,␤-methyleneadenosine-5Ј-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

Extracellular cAMP-adenosine pathways in the mouse kidney

“…These results imply the presence of ecto-5=-nucleotidases that metabolize 5=-AMP to adenosine. Thus, as with the rat kidney (15,19,27,28), the mouse kidney also supports a robust extracellular 3=,5=-cAMP-adenosine pathway (extracellular 3=,5=-cAMP ¡ 5=-AMP ¡ adenosine).…”

“…ments of extracellular adenosine in the kidney. Also, in anesthetized rats, intraportal glucagon increases plasma levels of 3=,5=-cAMP by 10-fold and this is associated with a 2-fold increase in renal interstitial levels of adenosine (assessed by microdialysis) and a 2-fold increase in the urinary excretion of adenosine (15). Therefore, during hormonal stimulation of adenylyl cyclase, the contribution of the 3=,5=-cAMP-adenosine pathway to renal adenosine is higher.…”

“…No doubt, robust vascular metabolism of these cAMPs contributes importantly to their high renal clearance. Nonetheless, 3=,5=-cAMP is filtered by the glomerulus and is metabolized in the tubular compartment (15), so urinary excretion of unchanged cAMPs and metabolism of cAMPs in the tubular compartment likely also contribute to the high degree of clearance of cAMPs by the kidney. Because the urine flow rate in a mouse kidney is only 0.7 l/min (38) and we infused the cAMPs for 5 min only, we did not attempt to quantify the cAMPs and their metabolites in the minute volumes of urine.…”

The 2′,3′-cAMP-adenosine pathway

“…The extracellular 3=,5=-cAMP-adenosine pathway may also provide a chemical connection by which the liver can affect the kidney (48), and very recent studies by Kuzhikandathil et al (61) support the concept that the extracellular 3=,5=-cAMP-adenosine pathway is also involved in regulating renal D1 dopamine receptor expression.…”

In Vivo Cardiovascular Pharmacology of 2′,3′-cAMP, 2′-AMP, and 3′-AMP in the Rat

“…Our previous work shows that the kidney converts extracellular 39,59-cAMP to extracellular 59-AMP, which in turn is metabolized to adenosine (Jackson, 2011). Moreover, our previously published findings show that intravenously infused 39,59-cAMP increases both renal interstitial adenosine and urinary adenosine excretion (Jackson et al, 2007). A potentially important aspect of the present findings is that intravenous 39,59-cAMP increases urinary adenosine excretion more so than does an equivalent dose of adenosine, 59-AMP, 39-AMP, or 29-AMP.…”