Effect of otilonium bromide on contractile patterns in the human sigmoid colon.
BACKGROUND
The mechanism of action of the spasmolytic compound otilonium bromide (OB) on human colonic motility is not understood. The aim of our study was to characterize the pharmacological effects of OB on contractile patterns in the human sigmoid colon.


METHODS
Circular sigmoid strips were studied in organ baths. Isolated smooth muscle cells from human sigmoid colon were examined using the calcium imaging technique.


RESULTS
Otilonium bromide inhibited by 85% spontaneous non-neural rhythmic phasic contractions (RPCs), (IC(50) = 49.9 nmol L(-1)) and stretch-induced tone (IC(50) = 10.7 nmol L(-1)) with maximum effects at micromolar range. OB also inhibited by 50% both on- (IC(50) = 38.0 nmol L(-1)) and off-contractions induced by electrical stimulation of excitatory motor neurons. In contrast, the inhibitory latency period prior to off-contractions was unaffected by OB. OB inhibited acetylcholine-, substance P-, and neurokinin A-induced contractions. The L-type Ca(2+) channel agonist BayK8644 reversed the effects of OB on RPCs, on- and off-contractions. Hexamethonium, atropine, the NK(2) antagonist, or depletion of intracellular Ca(2+) stores by thapsigargin did not prevent the inhibitory effect of OB on RPCs and electrical contractions. KCl-induced calcium transients in isolated smooth muscle cells were also inhibited by OB (IC(50) = 0.2 micromol L(-1)).


CONCLUSIONS
Otilonium bromide strongly inhibited the main patterns of human sigmoid motility in vitro by blocking calcium influx through L-type calcium channels on smooth muscle cells. This pharmacological profile may mediate the clinically observed effects of the drug in patients with irritable bowel syndrome.
Gallego
D
D
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Instituto de Salud Carlos III, Barcelona, Spain.
Aulí
M
M
Aleu
J
J
Martínez
E
E
Rofes
L
L
Martí-Ragué
J
J
Jiménez
M
M
Clavé
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D012809:Colon, Sigmoid / Q000187:drug effects*; D004558:Electric Stimulation; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010812:Physical Stimulation; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012026:Reflex, Stretch / Q000187:drug effects
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018377:Neurotransmitter Agents; D010276:Parasympatholytics; D000644:Quaternary Ammonium Compounds; C013934:octylonium; D002118:Calcium