Metabolism of cAMP to adenosine in the renal vasculature.
We recently demonstrated that cAMP added to the perfusate increased the renal venous recovery of adenosine in the isolated rat kidney, an effect blocked by inhibition of ecto-phosphodiesterase and ecto-5'-nucleotidase. Although our previous study established the cAMP-adenosine pathway, i.e., the conversion of cAMP to adenosine, as a viable metabolic pathway within the kidney, that study did not determine whether conversion of arterial cAMP to adenosine recoverable in the venous effluent occurred in the tubules versus nontubular sites. In the current study, we addressed this issue by determining the effects of blocking cAMP transport into the renal tubules with probenecid (0.1, 0.3 and 1 mM) on the increase in renal venous output of adenosine induced by adding cAMP (30 microM) to the perfusate of isolated rat kidneys. Addition of cAMP to the perfusate caused a marked increase in renal venous secretion of adenosine, an effect that was augmented, rather than inhibited, by probenecid. To test the hypothesis that the renal vasculature supports a cAMP-adenosine pathway, cultured rat preglomerular vascular smooth muscle cells were incubated with cAMP (30 microM) for 1 hr in the presence and absence of 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor). Incubation with cAMP increased extracellular adenosine levels 41-fold, and this effect was abolished by 3-isobutyl-1-methylxanthine. In a third experimental series, addition of cAMP (0.3, 1, 3, 10 and 30 microM) to the perfusate of isolated rat kidneys and mesenteric vascular beds increased the renal venous, but not mesenteric venous, output of AMP, adenosine and inosine. We conclude that the renal vasculature supports a cAMP-adenosine pathway, that administering cAMP into the renal artery and measuring adenosine in the venous effluent of the perfused rat kidney most likely monitors primarily the renal vascular cAMP-adenosine pathway and that the quantitative importance of the cAMP-adenosine pathway is not equivalent in all vascular compartments.
Jackson
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EK
Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA.
Mi
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Gillespie
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DG
Dubey
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012082:Renal Veins / Q000378:metabolism*
D000242:Cyclic AMP; D000241:Adenosine; D011339:Probenecid; D015056:1-Methyl-3-isobutylxanthine