T-type Ca2+ channel modulation by otilonium bromide

Strege PR, Sha L, Beyder A, Bernard CE, Perez-Reyes E, Evangelista S, Gibbons SJ, Szurszewski JH, Farrugia G. T-type Ca2+ channel modulation by otilonium bromide. Am J Physiol Gastrointest Liver Physiol 298: G706-G713, 2010. First published March 4, 2010; doi:10.1152/ajpgi.00437.2009.-Antispasmodics are used clinically to treat a variety of gastrointestinal disorders by inhibition of smooth muscle contraction. The main pathway for smooth muscle Ca2+ entry is through L-type channels; however, there is increasing evidence that T-type Ca2+ channels also play a role in regulating contractility. Otilonium bromide, an antispasmodic, has previously been shown to inhibit L-type Ca2+ channels and colonic contractile activity. The objective of this study was to determine whether otilonium bromide also inhibits T-type Ca2+ channels. Whole cell currents were recorded by patch-clamp technique from HEK293 cells transfected with cDNAs encoding the T-type Ca2+ channels, CaV3.1 (alpha 1G), Ca(V)3.2 (alpha 1H), or Ca(V)3.3 (alpha 1I) alpha subunits. Extracellular solution was exchanged with otilonium bromide (10(-8) to 10(-5) M). Otilonium bromide reversibly blocked all T-type Ca2+ 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 Ca2+ 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 Ca2+ channel blockers.