Induction of Pacemaker Currents by DA-9701, a Prokinetic Agent, in Interstitial Cells of Cajal from Murine Small Intestine

Abstract

The interstitial cells of Cajal (ICC) are pacemaking cells required for gastrointestinal motility. The possibility of whether DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber, modulates pacemaker activities in the ICC was tested using the whole cell patch clamp technique. DA-9701 produced membrane depolarization and increased tonic inward pacemaker currents in the voltage-clamp mode. The application of flufenamic acid, a non-selective cation channel blocker, but not niflumic acid, abolished the generation of pacemaker currents induced by DA-9701. Pretreatment with a Ca2+-free solution and thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum, abolished the generation of pacemaker currents. In addition, the tonic inward currents were inhibited by U-73122, an active phospholipase C inhibitor, but not by GDP-beta-S, which permanently binds G-binding proteins. Furthermore, the protein kinase C inhibitors, chelerythrine and calphostin C, did not block the DA-9701-induced pacemaker currents. These results suggest that DA-9701 might affect gastrointestinal motility by the modulation of pacemaker activity in the ICC, and the activation is associated with the non-selective cationic channels via external Ca2+ influx, phospholipase C activation, and Ca2+ release from internal storage in a G protein-independent and protein kinase C-independent manner.

Randomized, Controlled, Multi-center Trial: Comparing the Safety and Efficacy of DA-9701 and Itopride Hydrochloride in Patients With Functional Dyspepsia

“…DA-9701 has been shown to improve gastric motility by normalizing delayed gastric emptying and enhancing gastric accommodation in animal models. [7][8][9][10] The aim of this study was to assess the efficacy and safety of DA-9701 compared with itopride in patients with FD.…”

Characteristics of Gintonin-Mediated Membrane Depolarization of Pacemaker Activity in Cultured Interstitial Cells of Cajal

“…To study the roles of extracellular and intracellular Ca 2+ , the effect of gintonin was investigated under extracellular Ca 2+ -free conditions and in the presence of thapsigargin (an inhibitor of Ca 2+ -ATPase) in the endoplasmic reticulum [15,45]. In the presence of an extracellular Ca 2+ -free solution, pacemaker activity was greatly attenuated, and gintonin-induced depolarizations were lower than in Ca 2+ -containing solutions (n = 5; Fig.…”

Characteristics of the Cholecystokinin-Induced Depolarization of Pacemaking Activity in Cultured Interstitial Cells of Cajal from Murine Small Intestine

“…Furthermore, the generation of pacemaking activity is known to be dependent on intracellular Ca 2+ oscillations [24]. To study the roles of external and internal Ca 2+ , CCK was investigated under external Ca 2+ -free conditions and in the presence of thapsigargin, an inhibitor of Ca 2+ -ATPase in the endoplasmic reticulum [25,26]. In the presence of an external Ca 2+ -free solution, pacemaking activity was completely abolished, and CCK-induced depolarizations were lower than in Ca 2+ -containing solutions (n = 7; Fig.…”