A high incidence of gastroesophageal reflux (GER) is reported in a wide variety of chronic respiratory disorders in children and adults. To examine the mechanisms of GER in pulmonary disease, we have utilized and validated an animal model in cats which permits simultaneous measurements of cardiovascular, pulmonary, and esophageal function. Preliminary studies indicate that chemical activation of vagal afferent receptors in the lung evoke a transient relaxation of lower esophageal sphincter (LES) pressure which is independent of esophageal body motor events. The pattern and time course of this LES relaxation is identical to isolated transient LES relaxations which are reported to be the major mechanism of GER in humans, including several children whom we have studied with chronic lung disorders.
The specific aims of the present proposal are designed to further our understanding of the extrinsic regulation of LES tone, and of pulmonary factors which modulate threshold, magnitude, and duration of LES inhibitory reflexes. Peripheral afferent mechanisms for evoking reflex change in LES pressure will be evaluated by measuring intraluminal LES pressure changes following activation of afferent fibers accessible to the circulation, and to the serosal surface of abdominal viscera, both by foreign chemicals (phenylbiguanide, capsacin) and endogenous autocoids (bradykinin, histamine, and serotonin). The central circuitry that mediates reflex change in LES pressure will be studied. The importance of spinal cord and suprapontine structures will be determined. Established neuroanatomical techniques of retrograde transport of horseradish peroxidase will be used to identify location of vagal preganglionic neurons innervating the LES, and established neurophysiological techniques of electrical stimulation and microinjection of excitatory amino acids used to establish a functional role of specific neuronal loci in reflex reduction in LES pressure evoked by pulmonary afferent receptors. We will then determine how physiological stimuli which elicit chemical changes in the brain (hypercapnea and hypoxia), or specifically activate peripheral airway receptors (bronchoconstriction and microembolism) affect LES tone or reflexes which affect LES tone. Data generated by this proposal will provide new insights into causal mechanisms which associate chronic lung disease and GER by expanding our knowledge of extrinsic control of LES tone.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035687-08
Application #
2217885
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1987-09-01
Project End
1996-06-30
Budget Start
1993-12-01
Budget End
1996-06-30
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106