T-type Ca2+ channel modulation by otilonium bromide

Peter R. Strege, Lei Sha, Arthur Beyder, Cheryl E. Bernard, Edward Perez-Reyes, Stefano Evangelista, Simon J. Gibbons, Joseph H. Szurszewski, Gianrico Farrugia

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 Ca+ 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 CaV3.3 than CaV3.1 or CaV3.2. Additionally, the drug slowed inactivation in Ca V3.1 and CaV3.3. 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume298
Issue number5
DOIs
StatePublished - May 2010

Fingerprint

Parasympatholytics
Smooth Muscle
HEK293 Cells
Patch-Clamp Techniques
Muscle Contraction
Complementary DNA
octylonium
Pharmaceutical Preparations

Keywords

  • Ammonium
  • Antispasmodic
  • Intestine
  • Smooth muscle
  • Voltage dependence

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

T-type Ca2+ channel modulation by otilonium bromide. / Strege, Peter R.; Sha, Lei; Beyder, Arthur; Bernard, Cheryl E.; Perez-Reyes, Edward; Evangelista, Stefano; Gibbons, Simon J.; Szurszewski, Joseph H.; Farrugia, Gianrico.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 298, No. 5, 05.2010.

Research output: Contribution to journalArticle

Strege, Peter R. ; Sha, Lei ; Beyder, Arthur ; Bernard, Cheryl E. ; Perez-Reyes, Edward ; Evangelista, Stefano ; Gibbons, Simon J. ; Szurszewski, Joseph H. ; Farrugia, Gianrico. / T-type Ca2+ channel modulation by otilonium bromide. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2010 ; Vol. 298, No. 5.
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