The PI's hypothesis is that the crural diaphragm interacts with the intrinsic lower esophageal sphincter in a very complex manner. These interactions take two forms: 1) space-time interactions in which the crural diaphragm and intrinsic lower esophageal sphincter (LES) are displaced from each other both in space and in time; and 2) mechanical interactions in which each component of the LES and CD contributes to the pressure generated at the gastroesophageal junction high-pressure zone (GEJHPZ) individually and in combination. When there are abnormalities in either of these interactions, at the GEJHPZ reflux events and retrograde flow of fluids will occur. The purpose of this proposal is to determine the relative physiologic roles of the intrinsic LES and CD in providing an anti-reflux barrier at the GEJHPZ. The PI plans to define the relative motion of the CD to the intrinsic LES the relaxation and contraction of the CD in relationship to the LES, the compressive effect and forces of the CD on the distal esophagus, the role of the CD in antegrade movement of liquids and the role of the CD in induced relaxation of the GEJHPZ and retrograde movement of liquids from the stomach to the esophagus. Simultaneous high-resolution ultrasound and manometry will be utilized to correlate anatomical position (structure) with pressure (function). To achieve these specific aims the PI plans to: 1) determine the effect of respiration on the position and pressure relationships of the intrinsic LES and CD as components of the GEJHPZ. The investigators hypothesize that respiration causes movement of the crural diaphragm relative to the intrinsic LES and, therefore, effects the anatomical relationship of these two structures to each other; 2) separate the intrinsic LES from the crural diaphragm using physiologic and pharmacologic manipulations. The manometric contribution of the CD to the GEJHPZ will be determined by using pharmacologic and physiologic maneuvers to strengthen, diminish and even ablate the effects of the CD in order to better define the contribution of the CD to the GEJHPZ: 3) determine the effect of esophageal shortening during swallowing on the antireflux barrier GEJHPZ. This will be done by quantitating, the relative displacement of the intrinsic LES and CD to each other, in response to esophageal shortening, during swallowing of various bolus volumes of water; and 4) utilize several conditions in which the CEJHPZ structure and function are distorted to study the relative roles of the LES and CD. These conditions include hiatal hernia (displacement of the LES); Nissen fundoplication (reinforced HPZ) prior resection of the gastroesophageal junction (loss of the intrinsic LES); and GERD with and without hypotensive LES.
Aim 5 Study the effect of retrograde flow at the GEJHPZ by inducing relaxation of the GEJHPZ and eliciting reflux events. This will be achieved by distending the fluid filled stomach with an air filled balloon, or distending the esophagus with an air filled balloon to induce relaxation of the GEJHPZ and elicit retrograde fluid movement from the stomach to the esophagus in normal controls and patients with GERD with and without a hypotensive LES. They will delineate both the normal and abnormal interactions of the LES and CD, using simultaneous ultrasound and manometry to define the physiology and pathophysiology of the GEJHPZ.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Vegesna, A K; Sloan, J A; Singh, B et al. (2013) Characterization of the distal esophagus high-pressure zone with manometry, ultrasound and micro-computed tomography. Neurogastroenterol Motil 25:53-60.e6
Vegesna, Anil K; Chuang, Keng-Yu; Besetty, Ramashesai et al. (2012) Circular smooth muscle contributes to esophageal shortening during peristalsis. World J Gastroenterol 18:4317-22
Braverman, Alan S; Vegesna, Anil K; Miller, Larry S et al. (2011) Pharmacologic specificity of nicotinic receptor-mediated relaxation of muscarinic receptor precontracted human gastric clasp and sling muscle fibers within the gastroesophageal junction. J Pharmacol Exp Ther 338:37-46
Vegesna, Anil K; Braverman, Alan S; Miller, Larry S et al. (2010) Comparison of human and porcine gastric clasp and sling fiber contraction by M2 and M3 muscarinic receptors. Am J Physiol Gastrointest Liver Physiol 298:G530-4
Braverman, Alan S; Miller, Larry S; Vegesna, Anil K et al. (2009) Quantitation of the contractile response mediated by two receptors: M2 and M3 muscarinic receptor-mediated contractions of human gastroesophageal smooth muscle. J Pharmacol Exp Ther 329:218-24
Miller, L; Dai, Q; Vegesna, A et al. (2009) A missing sphincteric component of the gastro-oesophageal junction in patients with GORD. Neurogastroenterol Motil 21:813-e52
Brasseur, James G; Ulerich, Rhys; Dai, Qing et al. (2007) Pharmacological dissection of the human gastro-oesophageal segment into three sphincteric components. J Physiol 580:961-75
Miller, Larry; Vegesna, Anil; Kalra, Amit et al. (2007) New observations on the gastroesophageal antireflux barrier. Gastroenterol Clin North Am 36:601-17, ix
Dai, Qing; Korimilli, Annapurna; Thangada, Vinod K et al. (2006) Muscle shortening along the normal esophagus during swallowing. Dig Dis Sci 51:105-9
Miller, Larry S; Dai, Qing; Sweitzer, Brett A et al. (2004) Evaluation of the upper esophageal sphincter (UES) using simultaneous high-resolution endoluminal sonography (HRES) and manometry. Dig Dis Sci 49:703-9

Showing the most recent 10 out of 11 publications