Vagal afferent innervation and regulation of gastric function.

In this article, we have presented evidence that vagal capsaicin-sensitive afferent fibers are involved in the regulation of gastric mucosal and motor function. Gastric acid secretion stimulated by gastric distension, histamine and central injection of TRH analog are all partly dependent on vagal capsaicin-sensitive afferent mechanisms. It is possible that as vagal efferent activity releases histamine, the common final pathway is the reduction in the response to histamine. At present, it is unclear as to the mechanism by which capsaicin-sensitive afferents are involved in the secretory response to histamine. With regard to the gastric acid and mucosal blood flow responses to TRH, it is not clear whether the sensory neurons represent a component of the efferent pathway that is activated by TRH or whether their role is to set the sensitivity of, or exert feedback control on this efferent pathway. As perineural capsaicin application decreases peptide content in the peripheral terminal fields of sensory neurons and these peptides may produce local effector functions within the tissue, it is possible that alterations in the gastric responses to TRH result from a decrease in the local effector functions of vagal neurons. From the experiments on electrical stimulation of the vagus nerve, it is evident that antidromic stimulation of vagal afferents can stimulate gastric mucosal blood flow, although under these experimental conditions there was no evidence for a capsaicin-sensitive stimulation of gastric acid secretion. The physiological relevance of this stimulation of gastric mucosal blood flow is at present unclear, but it is possible that physiological stimuli, such as distension or nutrients, may stimulate afferents and signal for an increase in gastric mucosal blood flow. In addition, pathophysiological or noxious stimulation of vagal afferents may also signal for an increase in gastric mucosal blood flow and may play a role in the response of the mucosa to injury.

Duodenal acid-induced inhibition of gastric motility and emptying in rats.

The mechanism by which acid in the duodenum inhibits proximal gastric motor function and delays emptying was investigated in urethan-anesthetized and awake rats. Gastric motility inhibited by duodenal acid (0.2 N HCl) in urethan-anesthetized rats was attenuated by 68 and 54%, respectively, by functional ablation of the vagal or spinal sensory innervation with capsaicin. 5-Hydroxytryptamine3 receptor blockade with zacopride (0.2 mg/kg ip) or cholecystokinin (CCK)-A-type receptor blockade with MK-329 (1 mg/kg ip) had no effect on the motility response to acid. In awake rats with chronically implanted gastric and duodenal cannulas, perfusion of the duodenum with acid (0.1 and 0.2 N HCl) inhibited gastric emptying of a nonnutrient liquid (38 and 59%, respectively). Blockade of CCK-A-type receptors reduced by 30% inhibition of gastric emptying induced by 0.1 N HCl. However, functional ablation of the vagal or spinal sensory innervation, 5-hydroxytryptamine3 receptor blockade, or immunoneutralization of secretin by systemic administration of a polyclonal antibody (no. 7842, 1 ml ip) had no effect on acid-induced (0.1 N HCl) inhibition of gastric emptying. Perfusion of the duodenum with 0.2 N HCl but not 0.1 N HCl inhibited proximal gastric motility in awake rats. These results suggest that 1) a duodenal acid load inhibits gastric emptying in part by a mechanism involving CCK and 2) decreased proximal gastric motility plays a minor role in inhibition of gastric emptying in response to acid.

Vagal and splanchnic sensory pathways mediate inhibition of gastric motility induced by duodenal distension.

Afferent pathways mediating gastric corpus relaxation after duodenal distension were studied in urethan-anesthetized rats in which the sensory neurotoxin capsaicin (1%) or its vehicle was applied directly to the cervical vagus nerve trunks or the celiac-superior mesenteric ganglia 10-20 days before experiments. Distension (0.05-0.5 ml) of a closed loop of proximal duodenum decreased gastric intraluminal pressure. Perineural capsaicin treatment to the vagus nerves decreased by 73 and 80% the response to low volumes of distension (0.05 and 0.1 ml). Perineural capsaicin treatment of the celiac-superior mesenteric ganglia significantly attenuated by 46-88% the response to all volumes of distension. Bilateral cervical vagotomy or ganglionectomy reduced the response to all volumes of duodenal distension and, in combination, abolished the response. It is concluded that the decrease in gastric corpus motility after duodenal distension is dependent on the extrinsic innervation to the upper gastrointestinal tract and is mediated by both vagal and spinal capsaicin-sensitive afferents. Capsaicin-sensitive vagal afferents mediate responses to low volumes of distension that may be physiological. Capsaicin-sensitive spinal afferents mediate the gastric response to higher volumes of distension and may be involved in mediating visceral and somatic responses to pathophysiological intestinal obstruction.

Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats.

The mechanism by which lipid in the duodenum inhibits gastric emptying was investigated in awake rats fitted with chronic gastric and duodenal cannulas. Perfusion of the duodenum with lipid (Intralipid, 5 and 10%; total amount 50 and 100 mg) caused a significant inhibition (26 and 78%, respectively) of gastric emptying of a nonnutrient liquid (0.9% saline). Functional ablation of the capsaicin-sensitive vagal, but not the spinal, sensory innervation to the upper gastrointestinal tract significantly attenuated by 57% lipid-induced inhibition of gastric emptying. In intact rats, administration of a specific cholecystokinin (CCK)-A receptor antagonist, devazepide, significantly attenuated by 66% the response to lipid. Administration of devazepide in perivagal capsaicin-treated rats did not further reduce the response to lipid. These results suggest that lipid in the duodenum inhibits gastric emptying via a mechanism involving an action of CCK at type A receptors and capsaicin-sensitive vagal afferents.

Duodenal lipid inhibits gastric acid secretion by vagal, capsaicin-sensitive afferent pathways in rats.

Neural and endocrine pathways mediate the inhibitory effects of intestinal fat on gastric acid secretion. To study whether vagal and/or spinal afferent nerves contribute to the neural component of the enterogastric reflex, the sensory neurotoxin capsaicin was applied topically either to the vagus nerves bilaterally or to the celiac-superior mesenteric ganglia in rats with chronic gastric and duodenal fistulas. In lightly restrained, awake rats acid secretion was stimulated for 2 h by continuous intragastric perfusion with 8% peptone and was measured by extragastric titration to pH 5.5. Duodenal lipid perfusion (0-20%) during the 2nd h caused inhibition of peptone-stimulated acid output. Acid output was inhibited by 81% during 5% lipid perfusion of the duodenum and was restored after capsaicin treatment of the vagus nerves. In contrast, capsaicin treatment of the celiac ganglion did not alter the acid inhibitory response to any dose of intestinal lipid. Basal and maximum acid outputs were not significantly different among rats treated by either method with capsaicin. The neural component of the enterogastric reflex in awake rats is mediated in part by a capsaicin-sensitive, vagal-afferent neural reflex.

Gastroduodenal sensory mechanisms and CCK in inhibition of gastric emptying in response to a meal.

The ability of nutrients in the intestinal lumen to exert feedback control over the proximal gastrointestinal tract function is well recognized, yet the control mechanisms are poorly defined. There is evidence that extrinsic sensory pathways from the intestine are required to initiate this regulatory process. Furthermore, CCK appears to be involved in the gastric response to several intestinal stimuli, such as fat, carbohydrate and protein. Our hypothesis is that nutrients release CCK from the intestine, which then stimulates intestinal mucosal afferents to signal reflex changes in gastric motor function and thus inhibit gastric emptying.