The traditional herbal medicine, Ge‐Gen‐Tang, inhibits pacemaker potentials by nitric oxide/cGMP dependent ATP‐sensitive K+ channels in cultured interstitial cells of Cajal from the mouse small intestine (LB746)

Abstract

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal (GI) smooth muscle. The effects of Ge‐Gen‐Tang (GGT), a traditional herbal medicine, on pacemaker potentials in cultured ICCs from the mouse small intestine were investigated. The patch‐clamp technique for whole‐cell recording was used in cultured ICCs. Under the current clamping mode, ICC generated pacemaker potentials. The resting membrane potential was ‐ 52 4 mV and the amplitude was 18.3 1.6 mV. GGT (10‐50 mg/ml) decreased the frequency and amplitude of pacemaker potentials in a concentration‐dependent manner, but had no effects on membrane potentials. In the presence of 50 mg/ml GGT, the amplitude was 1.2 0.3 mV and the frequency was 0.3 0.6 cycles/min at 50 mg/ml. However, these effects were blocked by intracellular GDPβS, a G‐protein inhibitor, and glibenclamide, a specific ATP‐sensitive K+ channels blocker. Pretreatment with SQ‐22536, an inhibitor of adenylate cyclase, before the application of GGT had no effect on pacemaker potentials. Similarly, pretreatment with ODQ, an inhibitor of guanylate cyclase, did not inhibit the pacemaker potentials. However, GGT inhibited the pacemaker potentials in the presence of SQ‐22536, not in ODQ. The amplitude was 1.7 0.6 mV in the presence of SQ‐22536 and 17.1 2.6 mV in ODQ at GGT 50 mg/ml. Also, pretreatment with L‐NAME (an inhibitor of nitric oxide (NO) synthase) before the application of GGT abolished its effects on pacemaker potentials, but L‐NAME itself had no effect. In the presence of L‐NAME, the amplitude was 18.7 0.6 mV at GGT 50 mg/ml. Taken together, GGT inhibits pacemaker potentials in ICC in a G protein‐, cGMP‐ and NO‐dependent manner. Our data suggest that the gastroprokinetic effects of GGT are mediated by the induction of pacemaker potentials in ICCs.Grant Funding Source: Supported by the Traditonal Korean Medicine R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C1886, B120008)