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.