Endogenous luminal surface adenosine signaling regulates duodenal bicarbonate secretion in rats.
Luminal ATP increases duodenal bicarbonate secretion (DBS) via brush border P2Y receptors. Because ATP is sequentially dephosphorylated to adenosine (ADO) and the brush border highly expresses adenosine deaminase (ADA), we hypothesized that luminal [ADO] regulators and sensors, including P1 receptors, ADA, and nucleoside transporters (NTs) regulate DBS. We measured DBS with pH and CO(2) electrodes, perfusing ADO ± adenosine receptor agonists or antagonists or the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR(inh)-172 on DBS. Furthermore, we examined the effect of inhibitors of ADA or NT on DBS. Perfusion of AMP or ADO (0.1 mM) uniformly increased DBS, whereas inosine had no effect. The A(1/2) receptor agonist 5'-(N-ethylcarboxamido)-adenosine (0.1 mM) increased DBS, whereas ADO-augmented DBS was inhibited by the potent A(2B) receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide (MRS1754) (10 μM). Other selective adenosine receptor agonists or antagonists had no effect. The A(2B) receptor was immunolocalized to the brush border membrane of duodenal villi, whereas the A(2A) receptor was immunolocalized primarily to the vascular endothelium. Furthermore, ADO-induced DBS was enhanced by 2'-deoxycoformycin (1 μM) and formycin B (0.1 mM), but not by S-(4-nitrobenzyl)-6-thioinosine (0.1 mM), and it was abolished by CFTR(inh)-172 pretreatment (1 mg/kg i.p). Moreover, ATP (0.1 mM)-induced DBS was partially reduced by (1R,2S,4S,5S)-4-2-iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (MRS2500) or 8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine (PSB603) and abolished by both, suggesting that ATP is sequentially degraded to ADO. Luminal ADO stimulates DBS via A(2B) receptors and CFTR. ATP release, ecto-phosphohydrolases, ADA, and concentrative NT may coordinately regulate luminal surface ADO concentration to modulate ADO-P1 receptor signaling in rat duodenum.
Ham
Maggie
M
Department of Medicine, School of Medicine, University of California, Los Angeles, California, USA.
Mizumori
Misa
M
Watanabe
Chikako
C
Wang
Joon-Ho
JH
Inoue
Takuya
T
Nakano
Takanari
T
Guth
Paul H
PH
Engel
Eli
E
Kaunitz
Jonathan D
JD
Akiba
Yasutada
Y
D000241:Adenosine / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D033705:Equilibrative Nucleoside Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D010477:Perfusion; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D001639:Bicarbonates; D033705:Equilibrative Nucleoside Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058912:Purinergic P2Y Receptor Agonists; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; C065171:cif nucleoside transporter; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; C548484:Ada protein, rat; D000243:Adenosine Deaminase; D000241:Adenosine
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