Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA.
Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G706-13. doi: 10.1152/ajpgi.00437.2009. Epub 2010 Mar 4.
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.
抗痉挛药通过抑制平滑肌收缩在临床上用于治疗各种胃肠道疾病。平滑肌 Ca(2+)内流的主要途径是通过 L 型通道；然而，越来越多的证据表明 T 型 Ca(2+)通道也在调节收缩性方面发挥作用。奥替溴铵是一种抗痉挛药，先前已被证明可抑制 L 型 Ca(2+)通道和结肠收缩活性。本研究的目的是确定奥替溴铵是否也抑制 T 型 Ca(2+)通道。通过膜片钳技术从转染编码 T 型 Ca(2+)通道 Ca(V)3.1 (alpha1G)、Ca(V)3.2 (alpha1H)或 Ca(V)3.3 (alpha1I)亚基 cDNA 的 HEK293 细胞中记录全细胞电流。将细胞外溶液用奥替溴铵（10(-8) 至 10(-5) M）交换。奥替溴铵可逆性地阻断所有 T 型 Ca(2+)通道，对 Ca(V)3.3 的亲和力明显大于 Ca(V)3.1 或 Ca(V)3.2。此外，该药物减缓了 Ca(V)3.1 和 Ca(V)3.3 的失活。T 型 Ca(2+)通道的抑制可能有助于奥替溴铵抑制收缩性。这可能代表了抗痉挛药的一种新作用机制，并可能导致与选择性 L 型 Ca(2+)通道阻滞剂相比，观察到抗痉挛药的临床疗效增加。
