Effects of Lubiprostone on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Colon
Han-Yi Jiao1,*, Dong Hyun Kim2,*, Jung Suk Ki1, Kwon Ho Ryu1, Seok Choi1, and Jae Yeoul Jun1
Departments of 1Physiology, 2Radiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
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Lubiprostone is a chloride (Cl−) channel activator derived from prostaglandin E1 and used for managing constipation. In addition, lubiprostone affects the activity of gastrointestinal smooth muscles. Interstitial cells of Cajal (ICCs) are pacemaker cells that generate slow-wave activity in smooth muscles. We studied the effects of lubiprostone on the pacemaker potentials of colonic ICCs. We used the whole-cell patch-clamp technique to determine the pacemaker activity in cultured colonic ICCs obtained from mice. Lubiprostone hyperpolarized the membrane and inhibited the generation of pacemaker potentials. Prostanoid EP1, EP2, EP3, and EP4 antagonists (SC-19220, PF-04418948, 6-methoxypyridine-2-boronc acid N-phenyldiethanolamine ester, and GW627368, respectively) did not block the response to lubiprostone. L-NG-nitroarginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) did not block the response to lubiprostone. In addition, tetraethylammonium (TEA, a voltage-dependent potassium [K＋] channel blocker) and apamin (a calcium [Ca2＋]-dependent K＋ channel blocker) did not block the response to lubiprostone. However, glibenclamide (an ATP-sensitive K＋ channel blocker) blocked the response to lubiprostone. Similar to lubiprostone, pinacidil (an opener of ATP-sensitive K＋ channel) hyperpolarized the membrane and inhibited the generation of pacemaker potentials, and these effects were inhibited by glibenclamide. These results suggest that lubiprostone can modulate the pacemaker potentials of colonic ICCs via activation of ATP-sensitive K＋ channel through a prostanoid EP receptor-independent mechanism.
Keywords: Colon, Interstitial cells of Cajal, Lubiprostone, Pacemaker potentials