Abstract
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 (EC50=4.4×10-6 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.
| Original language | English |
|---|---|
| Pages (from-to) | 145-151 |
| Number of pages | 7 |
| Journal | European Journal of Pharmacology |
| Volume | 465 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Mar 28 2003 |
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Keywords
- 3′,5′-Cyclic guanosine monophosphate
- Lower
- Mexiletine
- Nitric oxide (NO)
- Nitric oxide (NO) synthase
- Oesophageal sphincter
- Smooth muscle
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Pharmacology
Cite this
Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits. / Kohjitani, Atsushi; Miyawaki, Takuya; Funahashi, Makoto; Mitoh, Yoshihiro; Matsuo, Ryuji; Shimada, Masahiko.
In: European Journal of Pharmacology, Vol. 465, No. 1-2, 28.03.2003, p. 145-151.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits
AU - Kohjitani, Atsushi
AU - Miyawaki, Takuya
AU - Funahashi, Makoto
AU - Mitoh, Yoshihiro
AU - Matsuo, Ryuji
AU - Shimada, Masahiko
PY - 2003/3/28
Y1 - 2003/3/28
N2 - 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 (EC50=4.4×10-6 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.
AB - 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 (EC50=4.4×10-6 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.
KW - 3′,5′-Cyclic guanosine monophosphate
KW - Lower
KW - Mexiletine
KW - Nitric oxide (NO)
KW - Nitric oxide (NO) synthase
KW - Oesophageal sphincter
KW - Smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=0037470764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037470764&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(03)01483-3
DO - 10.1016/S0014-2999(03)01483-3
M3 - Article
VL - 465
SP - 145
EP - 151
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-2
ER -