Apelin-13 inhibits gastric motility through vagal cholinergic pathway in rats

Abstract

The expression of apelin and its receptors (APJ) in central autonomic networks suggests that apelin may regulate gastrointestinal motor functions. In rodents, central administration of apelin-13 has been shown to inhibit gastric emptying; however, the mechanisms involved remain to be determined. Using male adult Sprague-Dawley rats, the aims of the present study were 1) to determine the expression of APJ receptor in the dorsal vagal complex (DVC), 2) to assess the effects of central application of apelin-13 into the DVC on gastric tone and motility, and 3) to investigate the neuronal pathways responsible for apelin-induced alterations. APJ receptor immunoreactivity was detected in gastric-projecting and choline acetyltransferase-positive neurons of the DVC. Microinjection of apelin-13 into the DVC significantly decreased gastric tone and motility in both corpus and antrum. The apelin-induced reduction in gastric tone and motility was prevented by surgical vagotomy or fourth ventricular application of the APJ receptor antagonist, [Ala13]apelin-13 (F13A). Systemic administration of the muscarinic receptor antagonist atropine, but not the nitric oxide synthase inhibitor nitro-l-arginine methyl ester (l-NAME), abolished the apelin-induced inhibitory responses. The present results indicate a central modulatory role of apelin in the vagal neurocircuitry that controls gastric motor functions via withdrawal of the tonically active cholinergic pathway. NEW & NOTEWORTHY This is the first study investigating the effects induced by brain stem application of apelin-13 while monitoring gastric tone and motility in rats. We have found that gastric-projecting neurons of the dorsal vagal complex express apelin receptors (APJ), which mediate the inhibitory actions of apelin-13. The inhibitory effects of apelin were abolished by systemic preadministration of atropine, but not nitro-l-arginine methyl ester (l-NAME). Apelin seems to modulate gastric motility via withdrawal of the tonically active vagal cholinergic pathway.

Novel transmitters in brain stem vagal neurocircuitry: new players on the pitch

“…The APJ receptor is expressed robustly in hypothalamic nuclei [PVN and supraoptic nucleus (SON)] (54, 64, 73) and brain stem structures, including rostral ventrolateral medulla (RVLM), NTS (15,64), DMV, and hypoglossal nucleus (HGN) (15).…”

“…In the rodent brain, apelin-producing cells have been detected in several hypothalamic structures, including the PVN, preoptic, ventromedial (VMN), dorsomedial (DMN), and arcuate (ARC) nuclei, the reticular tegmental pontine nucleus, lateral reticular nucleus, spinal trigeminal nucleus, HGN, nucleus ambiguus (NA), and retrofacial nucleus (46,54,77). Apelinergic projections have been found to innervate the periaqueductal gray matter, locus coeruleus (LC), Barrington's nucleus, medial and lateral parts of the parabrachial nucleus, and circumventricular structures, including the organum vasculosum of the lamina terminalis, the subfornical organs (SFO), the subcommissural organ, and the area postrema (AP) (13,15,77).…”

“…The apelin/APJ receptor system has been demonstrated to play a role in hypothalamic regulatory functions such as food intake (90), drinking behavior, fluid homeostasis (59,65,76,90), neuroendocrine control (38,61,62,90), and autonomic/ visceromotor signaling, including cardiovascular, gastrointestinal motor, and respiratory functions (4,12,13,15,27,52,53,59,85,101,102,104). A growing body of evidence suggests the central apelinergic system is involved in the regulation of gastrointestinal motor functions.…”

“…In rodents, for example, central (icv) administration of apelin inhibits solid gastric emptying (4, 13, 52), colonic transit (13,101), and postprandial colonic contractions (13) and increases the antral interdigestive migrating motor complex (51). More importantly, microinjection of apelin-13 in the DMV inhibits gastric tone and motility in anesthetized rats (15). In fact, the APJ receptor is known to be expressed in a subgroup of gastric-projecting DMV neurons, and the gastroinhibition resulting from fourth-ventricular application of apelin is abolished by vagotomy and atropine pretreatment, suggesting that, in the rat, apelin inhibits gastric motor functions through withdrawal of the vagally dependent cholinergic postganglionic pathway (4,15).…”

“…More importantly, microinjection of apelin-13 in the DMV inhibits gastric tone and motility in anesthetized rats (15). In fact, the APJ receptor is known to be expressed in a subgroup of gastric-projecting DMV neurons, and the gastroinhibition resulting from fourth-ventricular application of apelin is abolished by vagotomy and atropine pretreatment, suggesting that, in the rat, apelin inhibits gastric motor functions through withdrawal of the vagally dependent cholinergic postganglionic pathway (4,15).…”