Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits.
Nonadrenergic noncholinergic (NANC) nerves are known to be nitrergic and to have an important role in the regulation of gastrointestinal motility and function. Cardiac antiarrhythmic therapy in humans is accompanied by a high incidence of gastrointestinal side-effects. We investigated the effect of mexiletine, a class Ib antiarrhythmic drug, on NANC lower oesophageal sphincter relaxation. Mexiletine concentration dependently inhibited the NANC relaxation induced by 30 mM KCl (EC(50)=4.4 x 10(-6) M); the production of 3',5'-cyclic guanosine monophosphate (cGMP) after KCl stimulation was concentration dependently decreased. The relaxation induced by the exogenous nitric oxide (NO) donor, diethylamine NONOate (10(-5) M), was not inhibited by mexiletine, and the cGMP production after diethylamine NONOate application was not altered. Mexiletine did not alter the activity of NO synthase. These findings suggest that mexiletine inhibits NANC relaxation via NO-cGMP pathway modulation, possibly by inhibiting myenteric nitrergic neurotransmission in the lower oesophageal sphincter in rabbits.
Kohjitani
Atsushi
A
Department of Dental Anaesthesiology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8525, Japan. atsushik@md.okayama-u.ac.jp
Miyawaki
Takuya
T
Funahashi
Makoto
M
Mitoh
Yoshihiro
Y
Matsuo
Ryuji
R
Shimada
Masahiko
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009589:Nitrogen Oxides; D011817:Rabbits
D000889:Anti-Arrhythmia Agents; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D008801:Mexiletine; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP