ADENOSINE SCAVENGING - A NOVEL MECHANISM OF CHLORIDE SECRETORY CONTROL IN INTESTINAL EPITHELIAL-CELLS

Background, Adenosine released by cells during ischemia typically serv es as a feedback inhibitor of further organ work. However, in ischemic intestine, adenosine appears to act via stimulatory A(2b) receptors t o increase work in the form of chloride ion (Cl-) secretion. This unus ual response may contribute to luminal fluid sequestration in intestin al ischemia. In nonischemic cells feed-forward activation of Cl- secre tion does not occur despite the fact that adenosine may be continuousl y generated during normal cell metabolism. Thus we postulated that int estinal epithelia normally control the disposition of adenosine to pre vent inappropriate activation of secretion. Methods, Model T84 intesti nal epithelia were studied by means of electrophysiologic and isotopic techniques. Results, Dipyridamole and nitrobenzylthioinosine (inhibit ors of nucleoside transport) and iodotubercidin (an inhibitor of adeno sine kinase) caused adenosine to accumulate extracellularly and induce d a Cl- secretory response that was prevented by adenosine receptor bl ockade. Uptake of exogenous adenosine was restricted to the basolatera l compartment and was blocked by nucleoside transport inhibitors. Conc lusions, Adenosine released from nonischemic intestinal epithelial cel ls is scavenged by a basolaterally restricted adenosine transporter Th is system maintains extracellular adenosine levels below the prosecret ory threshold and thus limits adenosine-elicited activation of Cl- sec retion (and hence diarrhea) under normal conditions.