Mechanism of bombesin-induced tonic contraction of the porcine lower esophageal sphincter.

Ching-Chung Tsai,Yu-Tsun Su,Tong-Rong Tsai,Shu-Leei Tey,Ching-Wen Liu,Li-Ching Chang,Shih-Che Huang,Kai-Jen Lin

doi:10.1038/srep15879

Abstract

Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES). Previous studies showed that bombesin could increase LES pressure in humans and opossums. The aim of the present study was to characterize the effects of bombesin on porcine LES contraction. We used the selective agonists, neuromedin B (NMB), gastrin-releasing peptide (GRP), and [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) (DTACPN-BN), as well as receptor antagonists of bombesin receptor subtype 2 (BB2), and 3 (BB3) for ex vivo contraction studies. Atropine, nifedipine, tetrodotoxin, and ω-conotoxin GVIA were used to explore the agonist-induced LES contraction mechanism. Reverse transcription polymerase chain reaction and immunohistochemistry were applied to detect bombesin receptor expression. Our results indicate that GRP and DTACPN-BN, but not NMB, induced tonic contractions of the porcine LES in a dose-dependent manner, and the contractions were inhibited with selective BB2 and BB3 antagonists. The GRP-induced contraction is mainly caused by L-type Ca2+ channel-mediated Ca2+ influx. However, DTACPN-BN-induced contractions are associated with neuronal conduction. RT-PCR and immunohistochemistry revealed that BB2 and BB3 were expressed in the porcine LES. Bombesin-induced tonic contraction of the LES is mediated through BB2 and BB3. Bombesin, BB2, and BB3 agonists might have the potential to treat GERD.

Highlights

Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES)
The structure of the porcine LES is similar to that of the human LES. It is composed of sling muscle fibers at the greater curvature (GC) and clasp muscle fibers at the lesser curvature (LC)
Bombesin receptor agonists including a bombesin receptor subtype 1 (BB1) agonist, neuromedin B (NMB), a bombesin receptor subtype 2 (BB2) agonist, gastrin-releasing peptide (GRP), and a bombesin receptor subtype 3 (BB3) agonist, [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) (DTACPN-BN), were used to elucidate which bombesin receptor subtype or subtypes are involved in bombesin-induced LES contraction

Summary

Introduction

Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES). Gastroesophageal reflux disease (GERD) is caused by acid- or other irritant-induced injury from stomach backflow to the esophagus. Long-term PPI use may cause some side effects, such as micronutrient absorption, drug interference and microscopic colitis[3]. Surgical procedures, such as Nissen fundoplication, increase the LES resting tone and can lead to an improved esophageal contraction amplitude[4]. Neither the effects of vagal cholinergic agents nor the release of gastrointestinal hormones caused by bombesin are considered to be related to the mechanism of action of bombesin on esophageal motility in humans[14]

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