The aim of the present study was to study the effect of secretin on the electrophysiological response of pancreatic ducts. Furthermore, we investigated the effects of lipid-soluble buffers and inhibitors of HCO3-/H+ transport. Ducts obtained from fresh rat pancreas were perfused in vitro. Secretin depolarized the basolateral membrane voltage, Vbl, by up to 35 mV (n = 37); a half-maximal response was obtained at 3 x 10(-11) mol/l. In unstimulated ducts a decrease in the luminal Cl- concentration (120 to 37 mmol/l) had a marginal effect on Vbl, but after maximal secretin stimulation it evoked a 14 +/- 2 mV depolarization (n = 6), showing that a luminal Cl- conductance (GCl-) was activated. The depolarizing effect of secretin on Vbl was often preceded by about a 6 mV hyperpolarization, most likely due to an increase in the basolateral GK+. Perfusion of ducts with DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid, 0.01 mmol/l) or addition of ethoxzolamide (0.1 mmol/l) to the bath medium diminished the effect of secretin. Acetate or pre-treatment of ducts with NH4+/NH3 (10 mmol/l in the bath) depolarized the resting Vbl of -65 +/- 2 mV by 16 +/- 4 mV (n = 7) and 19 +/- 3 mV (n = 10), respectively. The fractional resistance of the basolateral membrane (FRbl) doubled, and the depolarizing responses to changes in bath K+ concentrations (5 to 20 mmol/l) decreased from 22 +/- 1 to 11 +/- 2 mV.(ABSTRACT TRUNCATED AT 250 WORDS)