Activation of Cl secretion during chemical hypoxia by endogenous release of adenosine in intestinal epithelial monolayers.
Intestinal ischemia is characterized by rapid early inhibition of absorptive function and the appearance of net secretion, although why active secretion persists in the setting of a mucosal energy deficit is unknown. The cryptlike epithelial line T84, a well-characterized model of intestinal Cl- secretion, develops a prominent increase in short-circuit current (Isc, indicative of active Cl- transport) in response to "hypoxia" induced by metabolic inhibitors. The increased Isc is associated with the initial decrease in monolayer ATP content. The Isc is transient and disappears with progressive energy depletion, although graded degrees of ATP depletion induce a more sustained Isc response. Chromatographic analysis and secretory bioassays show that the Isc response to metabolic inhibitors is related to the endogenous release of adenosine into the extracellular space in quantities sufficient to interact locally with stimulatory adenosine receptors. Unlike its classical role as a metabolic feedback inhibitor, adenosine appears to function as an autocrine "feed-forward" activator of active intestinal Cl- secretion. These studies suggest a novel role for adenosine in the conversion of the gut from an absorptive to a secretory organ during ischemic stress, thus contributing to the initial diarrheal manifestation of intestinal ischemia.
Matthews
J B
JB
Department of Surgery, Beth Israel Hospital Harvard Medical School, Boston, Massachusetts, USA.
Tally
K J
KJ
Smith
J A
JA
Zeind
A J
AJ
Hrnjez
B J
BJ
D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000032:analysis; D001692:Biological Transport; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D003847:Deoxyglucose / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology
D002712:Chlorides; D009840:Oligomycins; C031004:oligomycin A; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000241:Adenosine