T-type Ca2+channel modulation by otilonium bromide

Author:

Strege Peter R.1,Sha Lei1,Beyder Arthur1,Bernard Cheryl E.1,Perez-Reyes Edward2,Evangelista Stefano3,Gibbons Simon J.1,Szurszewski Joseph H.1,Farrugia Gianrico1

Affiliation:

1. Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;

2. Department of Pharmacology, University of Virginia, Charlottesville, Virginia; and

3. Department of Preclinical Development, Menarini Ricerche, Florence, Italy

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 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 (α1G), CaV3.2 (α1H), or CaV3.3 (α1I) alpha subunits. Extracellular solution was exchanged with otilonium bromide (10−8to 10−5M). 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 CaV3.1 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.

Publisher

American Physiological Society

Subject

Physiology (medical),Gastroenterology,Hepatology,Physiology

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