Phenytoin inhibits contractions of rat gastrointestinal and portal vein smooth muscle by inhibiting calcium entry.
BACKGROUND
Phenytoin is widely used as a second-line treatment for status epilepticus. Besides its well-known cardiac pro-arrhythmogenicity, side effects on other organ systems have received less attention.


METHODS
This study investigates the effects of phenytoin on gastrointestinal tissue function using an in vitro model of smooth muscle preparations from rats by combining registrations of pharmacological effects on mechanical contractions, electric field potentials, and dynamic intravital fluorescence microscopy.


RESULTS
When added to the bathing solution at a concentration of 30 μM, phenytoin reduced the frequency of spontaneous activity significantly in antrum and portal vein preparations to 72.2 ± 36.5% (p = 0.022) and 80.7 ± 24.4% (p = 0.037) of control values, respectively. At a concentration of 100 μM, the height of spontaneous contractions declined to 9.8 ± 19.6% (p = 0.005) (antrum), 15.7 ± 28.2% (p = 0.004) (portal vein), and 31.8 ± 31.3% (p = 0.005) (colon) in comparison to the control conditions before the application of phenytoin. Depolarization triggered increases in calcium dependent fluorescence signals were reduced by 52.8 ± 39.1% (p = 0.012) The inhibition of spontaneous activity caused by phenytoin was reduced in the presence of the L-type calcium channel agonist BAY K8644(-).


CONCLUSIONS
Phenytoin exerts strong inhibitory effects on the spontaneous and stimulated contractile activity of smooth muscles from both the upper and lower gastrointestinal tract. The mechanism underlying this effect is not related to the sodium channel blocking activity of phenytoin, but is rather caused by an inhibition of calcium entry through voltage dependent L-type calcium channels. The results of this study should raise vigilance to gastrointestinal complications in patients treated with phenytoin.
Institut für Physiologie, Universitätsmedizin Rostock, Rostock, Germany.
R
R
Patejdl
Institut für Physiologie, Universitätsmedizin Rostock, Rostock, Germany.
A-C
AC
Leroux
Institut für Physiologie, Universitätsmedizin Rostock, Rostock, Germany.
T
T
Noack
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010672:Phenytoin / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011169:Portal Vein / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology*; D011706:Pyloric Antrum / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D053284:Polyunsaturated Alkamides; D011422:Propionates; D010672:Phenytoin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C037512:3,4-dichlorophenyl propenylisobutylamide; D002118:Calcium
BAYK 8644; intestinal smooth muscle; phenytoin; status epilepticus; vascular smooth muscle