HCO3- potentiates the cAMP-dependent secretary response of the human distal colon through a DIDS-sensitive pathway

We used the Ussing short-circuit technique to investigate the role of HCO3- in the adenosine 3 ' ,5 ' -cyclic monophosphate (cAMP)-dependent secretory response of the human distal colon In HCO3--free 4-(2-hydroxyethyl)-1 -pip erazineethanesulphonic acid (HEPES)Ringer's, forskolin (10 mu mol l(-1) muc osal and serosal) evoked a sustained increase in short-circuit current (I-S C) (DeltaI(SC)=24 +/-3 muA cm(-2), n=57). However, this was only 25% of the forskolin-stimulated I-SC response in HCO3--Ringer's (DeltaI(SC)=84 +/-8 m uA cm(-2), n=57). The reduced response to forskolin in HCO3--free HEPES-Rin ger's was not due to inhibition of the secretory mechanism by HEPES, as rep lacing HCO3- with a different buffer, N-tris[hydroxymethyl)methyl-2-aminoet hanesulphonic acid (TES), had a similar effect and inclusion of HEPES in th e HCO3--Ringer's did not reduce the secretory response. Similarly, it was n ot due to an indirect modulation of electrogenic Cl- secretion, as the fors kolin-stimulated bumetanide-sensitive I-SC was comparable in the two Ringer 's. Rather it was due to the activation of a HCO3--dependent I-SC which was inhibited by serosal 4,4 ' -diisothiocyano-stilbene-2,2 ' -disulphonate (D TDS). This DIDS-sensitive I-SC was not inhibited by acetazolamide, but it w as inhibited by the replacement of bathing solution Cl- with gluconate, sug gesting a role for a Na+-dependent Cl-/HCO3- exchanger in the cAMP-dependen t secretory response of the human distal colon.