Hideyuki Nishiwaki1,2, Noriko Saitoh1, Hideaki
Nishio1, Tadayoshi Takeuchi 1,3 and Fumiaki Hata1,3,*
1Department╩of Veterinary Pharmacology, College of Agriculture and 3Department of Molecular Physiology and Biochemistry,
Research Institute for Advanced Science and Technology, Osaka Prefecture University, Sakai 599-8531, Japan
2Kawanishi╩Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kawanishi 666-0131, Japan
*╩To whom correspondence should be addressed(1).
Abstract: It is known that mu-agonists inhibit electrical field stimulation (EFS)-evoked ACh release from longitudinal muscle myenteric plexus (LMMP) preparation of guinea pig ileum when muscarinic autoinhibition does not fully work. In the present study, the possible role of K+ channels in the mechanisms of mu-agonists-induced inhibition and autoinhibition of ACh release was studied. In the presence of atropine, which blocks the autoinhibition, non-selective K+ channel blockers, tetraethylammonium (TEA) and 4-aminopyridine (4-AP), reversed the inhibitory effect of mu-agonists, morphine and [D-Ala2,╩N-Me-Phe4,╩Gly5-ol] enkephalin, on EFS-evoked ACh release, but not that of kappa-agonist U-50,488. Apamin, iberiotoxin or glibenclamide did not affect the inhibition of ACh release by morphine. On the other hand, in the absence of atropine (under the autoinhibition working condition), 4-AP increased EFS-evoked ACh release, but atropine did not further increase ACh release in the presence of 4-AP. In contrast, although TEA did not affect EFS-evoked ACh release, atropine increased ACh release in the presence of TEA. These results suggest that the inhibitory effects of mu-agonists and muscarinic autoinhibition on the ACh release are associated with activation of different types of K+ channels in the guinea pig LMMP preparations: the former is associated with 4-AP- and TEA-sensitive K+ channels and the latter is associated with 4-AP- but not TEA-sensitive K+ channels.
Keywords: K+ channel, Mu-receptor, Muscarinic autoinhibition, Acetylcholine release, Myenteric plexus