Melnyk Mariia I, Dryn Dariia O, Al Kury Lina T, Dziuba Dmytro O, Zholos Alexander V
A.A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Institute of Pharmacology and Toxicology, National Academy of Medical Science of Ukraine, Kyiv, Ukraine.
Front Pharmacol. 2020 Dec 18;11:594882. doi: 10.3389/fphar.2020.594882. eCollection 2020.
A better understanding of the negative impact of general anesthetics on gastrointestinal motility requires thorough knowledge of their molecular targets. In this respect the muscarinic cationic current (mI carried mainly via TRPC4 channels) that initiates cholinergic excitation-contraction coupling in the gut is of special interest. Here we aimed to characterize the effects of one of the most commonly used "dissociative anesthetics", ketamine, on mI. Patch-clamp and tensiometry techniques were used to investigate the mechanisms of the inhibitory effects of ketamine on mI in single mouse ileal myocytes, as well as on intestinal motility. Ketamine (100 µM) strongly inhibited both carbachol- and GTPγS-induced mI. The inhibition was slow (time constant of about 1 min) and practically irreversible. It was associated with altered voltage dependence and kinetics of mI. In functional tests, ketamine suppressed both spontaneous and carbachol-induced contractions of small intestine. Importantly, inhibited by ketamine mI could be restored by direct TRPC4 agonist (-)-englerin A. We identified mI as a novel target for ketamine. Signal transduction leading to TRPC4 channel opening is disrupted by ketamine mainly downstream of muscarinic receptor activation, but does not involve TRPC4 . Direct TRPC4 agonists may be used for the correction of gastrointestinal disorders provoked by general anesthesia.
要更好地理解全身麻醉药对胃肠蠕动的负面影响，需要深入了解其分子靶点。在这方面，肠道中启动胆碱能兴奋 - 收缩偶联的毒蕈碱阳离子电流（主要通过TRPC4通道传导的mI）特别受关注。在这里，我们旨在表征最常用的“分离麻醉药”之一氯胺酮对mI的影响。采用膜片钳和张力测定技术研究氯胺酮对单个小鼠回肠肌细胞中mI以及肠道蠕动的抑制作用机制。氯胺酮（100 μM）强烈抑制卡巴胆碱和GTPγS诱导的mI。抑制作用缓慢（时间常数约为1分钟）且几乎不可逆。它与mI的电压依赖性和动力学改变有关。在功能测试中，氯胺酮抑制小肠的自发收缩和卡巴胆碱诱导的收缩。重要的是，氯胺酮抑制的mI可被直接TRPC4激动剂（ - ） - 恩格勒因A恢复。我们确定mI是氯胺酮的一个新靶点。导致TRPC4通道开放的信号转导在氯胺酮作用下主要在毒蕈碱受体激活的下游被破坏，但不涉及TRPC4。直接TRPC4激动剂可用于纠正全身麻醉引起的胃肠道紊乱。
