title: T-type Ca(2+) channel modulation by otilonium bromide.
abstract: Antispasmodics are used clinically to treat a variety of gastrointestinal disorders by inhibition of smooth muscle contraction. The main pathway for smooth muscle Ca(2+) entry is through L-type channels; however, there is increasing evidence that T-type Ca(2+) channels also play a role in regulating contractility. Otilonium bromide, an antispasmodic, has previously been shown to inhibit L-type Ca(2+) channels and colonic contractile activity. The objective of this study was to determine whether otilonium bromide also inhibits T-type Ca(2+) channels. Whole cell currents were recorded by patch-clamp technique from HEK293 cells transfected with cDNAs encoding the T-type Ca(2+) channels, Ca(V)3.1 (alpha1G), Ca(V)3.2 (alpha1H), or Ca(V)3.3 (alpha1I) alpha subunits. Extracellular solution was exchanged with otilonium bromide (10(-8) to 10(-5) M). Otilonium bromide reversibly blocked all T-type Ca(2+) channels with a significantly greater affinity for Ca(V)3.3 than Ca(V)3.1 or Ca(V)3.2. Additionally, the drug slowed inactivation in Ca(V)3.1 and Ca(V)3.3. Inhibition of T-type Ca(2+) channels may contribute to inhibition of contractility by otilonium bromide. This may represent a new mechanism of action for antispasmodics and may contribute to the observed increased clinical effectiveness of antispasmodics compared with selective L-type Ca(2+) channel blockers.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: Lei
authors.initials: L
authors.lastname: Sha
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
authors.forename: Stefano
authors.initials: S
authors.lastname: Evangelista
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Szurszewski
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D020748:Mibefradil / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010276:Parasympatholytics; D000644:Quaternary Ammonium Compounds; C013934:octylonium; D020748:Mibefradil