Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Am J Physiol Gastrointest Liver Physiol. 2011 Mar;300(3):G394-400. doi: 10.1152/ajpgi.00493.2010. Epub 2010 Dec 30.
The inhibitory action of hyperglycemia is mediated by vagal afferent fibers innervating the stomach and duodenum. Our in vitro studies showed that a subset of nodose ganglia neurons is excited by rising ambient glucose, involving inactivation of ATP-sensitive K(+) (K(ATP)) channels and leading to membrane depolarization and neuronal firing. To investigate whether nodose ganglia K(ATP) channels mediate gastric relaxation induced by hyperglycemia, we performed in vivo gastric motility studies to examine the effects of K(ATP) channel activators and inactivators. Intravenous infusion of 20% dextrose induced gastric relaxation in a dose-dependent manner. This inhibitory effect of hyperglycemia was blocked by diazoxide, a K(ATP) channel activator. Conversely, tolbutamide, a K(ATP) channel inactivator, induced dose-dependent gastric relaxation, an effect similar to hyperglycemia. Vagotomy, perivagal capsaicin treatment, and hexamethonium each prevented the inhibitory action of tolbutamide. Similarly, N(G)-nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, also blocked tolbutamide's inhibitory effect. To show that K(ATP) channel inactivation at the level of the nodose ganglia induces gastric relaxation, we performed electroporation of the nodose ganglia with small interfering RNA of Kir6.2 (a subunit of K(ATP)) and plasmid pEGFP-N1 carrying the green fluorescent protein gene. The gastric responses to hyperglycemia and tolbutamide were not observed in rats with Kir6.2 small interfering RNA-treated nodose ganglia. However, these rats responded to secretin, which acts via the vagal afferent pathway, independently of K(ATP) channels. These studies provide in vivo evidence that hyperglycemia induces gastric relaxation via the vagal afferent pathway. This action is mediated through inactivation of nodose ganglia K(ATP) channels.
高血糖的抑制作用是通过支配胃和十二指肠的迷走传入纤维介导的。我们的体外研究表明，一部分结状神经节神经元被升高的环境葡萄糖兴奋，涉及 ATP 敏感性 K(+)（K(ATP)）通道失活，导致膜去极化和神经元放电。为了研究结状神经节 K(ATP)通道是否介导高血糖诱导的胃松弛，我们进行了体内胃动力研究，以检查 K(ATP)通道激活剂和失活剂的作用。静脉输注 20%的葡萄糖以剂量依赖性方式诱导胃松弛。这种高血糖的抑制作用被 K(ATP)通道激活剂 diazoxide 阻断。相反，K(ATP)通道失活剂甲苯磺丁脲诱导了剂量依赖性的胃松弛，其作用类似于高血糖。迷走神经切断术、迷走神经周围辣椒素处理和六烃季铵均防止了甲苯磺丁脲的抑制作用。同样，一氧化氮合酶抑制剂 N(G)-硝基-l-精氨酸甲酯也阻断了甲苯磺丁脲的抑制作用。为了表明结状神经节水平的 K(ATP)通道失活诱导胃松弛，我们用电穿孔的方法将 Kir6.2（K(ATP)的亚单位）的小干扰 RNA 和携带绿色荧光蛋白基因的质粒 pEGFP-N1 转染结状神经节。在用 Kir6.2 小干扰 RNA 处理的结状神经节的大鼠中，没有观察到高血糖和甲苯磺丁脲的胃反应。然而，这些大鼠对通过迷走传入途径作用的促胰液素产生反应，而不依赖于 K(ATP)通道。这些研究提供了体内证据，表明高血糖通过迷走传入途径诱导胃松弛。这种作用是通过结状神经节 K(ATP)通道失活介导的。
