T-type Ca²⁺ channel modulation by otilonium bromide

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 C^a+ 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 (α1G), CaV3.2 (α1H), or CaV3.3 (α1I) 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_V3.3 than Ca_V3.1 or Ca_V3.2. Additionally, the drug slowed inactivation in Ca _V3.1 and Ca_V3.3. 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.