Interstitial cells of Cajal (ICC) pace gastrointestinal phasic activity and transmit nerve activity. Gap junctions may couple these cells to smooth muscle, but no functional evidence exists. The objective of this study was to use uncouplers of gap junctions, 18 alpha-glycyrrhetenic acid and its water-soluble analogue carbenoxolone, to evaluate if gap junctions function in pacing and neurotransmission. After inhibition of nerve function with tetrodotoxin (TTX) and N(G)-nitro-L-arginine (L-NOARG), ionomycin- or carbachol-initiated regular phasic activities of circular muscle strips from canine colon and ileum. In some cases, the primary ICC network responsible for pacing was removed. The effects of inhibitors of gap junction conductance (10(-5)-10(-4) mol L(-1)) on frequencies and amplitudes of contraction were compared to appropriate time controls. Lower oesophageal sphincter (LOS) relaxations to nerve stimulation were studied before and after inhibition of gap junction functions. No major changes in LOS relaxations or frequencies of colonic or ileal contractions occurred, but amplitudes of contractions decreased from these agents. Similar results were obtained when the myenteric plexus-ICC network of ileum was removed. Regular phasic activity was not obtained after removal of the colon submuscular plexus ICC. These findings suggest that mechanisms other than gap junctions couple gut pacemaking activity and nerve transmission.