Possible antagonistic effects of the TRPC4 channel blocker ML204 on M(2) and M(3) muscarinic receptors in mouse ileal and detrusor smooth muscles and atrial myocardium.
Possible antagonistic effects of the TRPC4 channel blocker ML204 on M(2) and M(3) muscarinic receptors in mouse ileal and detrusor smooth muscles and atrial myocardium.
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DOI：
10.1292/jvms.18-0197
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发表时间：
2018-09-13
期刊：
影响因子：
--
通讯作者：
Unno T
中科院分区：
文献类型：
--
作者：
Alom F;Miyakawa M;Matsuyama H;Nagano H;Tanahashi Y;Unno T
ML204是一种有效的瞬时受体电位规范4 （TRPC4）通道阻滞剂，常被用于阐明TRPC4通道参与内脏平滑肌受体操作的信号传导过程。在本研究中，我们研究了ML204对介导小鼠回肠和逼尿肌平滑肌收缩的M2和M3毒蕈碱受体可能的拮抗作用。在回肠和逼尿肌平滑肌制剂中，ML204（3或10µM）显著抑制电场刺激（EFS）引起的胆碱能收缩。然而，在回肠制剂中，它没有明显抑制高K+诱导和efs诱发的非胆碱能收缩。累积施用毒蕈碱激动剂卡巴乔时，ML204（1、3和10µM）引起卡巴乔浓度-响应曲线向右平行移动。此外，ML204（1、3和10µM）可抑制由M2毒蕈碱受体介导的碳水化合物诱导的心房制剂负性变时反应。此外，ML204显著抑制了由M3毒蕈碱受体介导的碳水化合物诱导的细胞内Ca2+释放引起的收缩。这些结果表明，ML204可能对M2和M3毒蕈碱受体具有拮抗作用；此外，ML204对efs诱导的胆碱能收缩的抑制作用可能归因于这种受体拮抗作用，而不是抑制TRPC4通道活性。因此，当ML204用作TRPC4通道阻滞剂时，应考虑这些影响。
ML204, a potent transient receptor potential canonical 4 (TRPC4) channel blocker, is often used to elucidate the involvement of TRPC4 channels in receptor-operated signaling processes in visceral smooth muscles. In the present study, we investigated the possible antagonistic actions of ML204 on M2 and M3 muscarinic receptors, which mediate contractions in mouse ileal and detrusor smooth muscles. In ileal and detrusor smooth muscle preparations, ML204 (3 or 10 µM) significantly inhibited electrical field stimulation (EFS)-evoked cholinergic contractions. However, it did not significantly inhibit high K+-induced and EFS-evoked non-cholinergic contractions in the ileal preparations. When the muscarinic agonist, carbachol was cumulatively applied, ML204 (1, 3 and 10 µM) caused a rightward parallel shift of the concentration-response curves of carbachol. Additionally, ML204 (1, 3 and 10 µM) inhibited carbachol-induced negative chronotropic response in atrial preparations, which is mediated by M2 muscarinic receptors. Furthermore, ML204 significantly inhibited the contractions evoked by carbachol-induced intracellular Ca2+ release, which is mediated by M3 muscarinic receptors. These results suggested that ML204 might exhibit antagonistic actions on M2 and M3 muscarinic receptors; in addition, the inhibitory effects of ML204 against EFS-induced cholinergic contractions might be attributed to this receptor antagonism rather than inhibition of TRPC4 channel activity. Therefore, these effects should be considered when ML204 is used as a TRPC4 channel blocker.
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影响因子：
7.3
作者：
Unno, T;Kwon, SC;Komori, S
通讯作者：
Komori, S
影响因子：
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作者：
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作者：
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影响因子：
--
作者：
INOUE, R;ISENBERG, G
通讯作者：
ISENBERG, G
影响因子：
7.3
作者：
UYAMA, Y;IMAIZUMI, Y;WATANABE, M
通讯作者：
WATANABE, M