Inhibition of gastric motility by hyperglycemia is mediated by nodose ganglia KATP channels

Author:

Zhou Shi-Yi1,Lu Yuanxu1,Song Il1,Owyang Chung1

Affiliation:

1. Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Abstract

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+ (KATP) channels and leading to membrane depolarization and neuronal firing. To investigate whether nodose ganglia KATP channels mediate gastric relaxation induced by hyperglycemia, we performed in vivo gastric motility studies to examine the effects of KATP 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 KATP channel activator. Conversely, tolbutamide, a KATP 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, NG-nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, also blocked tolbutamide's inhibitory effect. To show that KATP 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 KATP) 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 KATP 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 KATP channels.

Publisher

American Physiological Society

Subject

Physiology (medical),Gastroenterology,Hepatology,Physiology

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