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Intraduodenal lipid inhibits central vagal stimulation of gastric acid secretion through activation of CCK a receptor in rats
GASTROENTEROLOGY Vol. 118, No.4
A132 AGA ABSTRACTS
801
803
INTRADUODENAL LIPID INHIBITS CENTRAL VAGAL STIMULATION OF GASTRIC ACID SECRETION THROUGH ACTIVATION OF CCK A RECEPTOR IN RATS. Hong Yang, Yvtte F. Tache, Ming-Luen Doong, John H. Walsh, Curel Ddrc., UCLA, Los Angeles, CA. Background: Intestinal lipids inhibit gastric acid secretion induced by meal in dogs and gastric emptying in rats via CCK and vagal capsaicin-sensitive afferent pathway (Lloyd et al: Gastroenterology, 102: 131,1992. Holzer et al: Am J Physiol267: G625, 1994). Intracisternal injection (ic) ofTRH is widely used to stimulate vagal efferent activity and mimics the cephalic phase of acid secretion. Aim: To investigate I) whether intraduodenal lipids inhibit central vagal gastric acid stimulation-induced by ic TRH analog; 2) whether CCK receptors are involved in these responses. Methods: Male SD rats (270-310 g) fasted for 24 h were anesthetized with urethane. Gastric acid secretion was induced by ic TRH analog, RX 77368 (5 ng) and measured by flushing the stomach through a gastric cannula. Intraduodenal (id) intralipid (0.5 ml) was administered through a duodenal fistula. Results: RX 77368 ic induced a net acid output of 56.8 ± 8.0 /Lmo1/90 min. CCK-8S (0.5 and 1 nmol/kg/h) iv infusion started 10 min before the ic RX 77368 inhibited the acid secretion by 23% and 82% respectively. The inhibitory action of CCK-8S was completely prevented by the CCK A receptor antagonist devazepide (l mg/kg) injected iv 10 min before the CCK-8S infusion. Intraduodenal intralipid (5%, 10% and 20%) administered 20 min before ic RX 77368 dose-dependently reduced by 24%, 83% and 100% the acid response and the inhibitory effect of intralipid was completely prevented by devazepide(l mg/kg). The CCK B receptor antagonist L-365260 (l mg/kg) had no effect on the inhibitory effect of intraduodenal lipid (Table). Conclusion: Intraduodenal lipid inhibits central TRH-induced gastric acid secretion through releasing endogenous CCK and the inhibitory action is mediated by CCK A receptors.
CONCURRENT EVALUATION OF INTRALUMINAL PRESSURES AND AXIAL ESOPHAGEAL MOVEMENT USING TOPOGRAPHIC METHODS IN THE OPOSSUM. Ray E. Clouse, Chandra Prakash, Robert A. Underwood, Annamaria Staiano, Laura R. Haroian, Nathaniel 1. Soper, Gastroenterology Div, Washington Univ, St. Louis, MO; Dept of Surg WUIMIS, Washington Univ, St. Louis, MO; astroenterology Div, Washington Univ, St. Louis, MO; Barnes-Jewish Hosp, St. Louis, MO; Dept of Surg - WUIMIS, Washington Univ, St. Louis, MO. Topographic methods consider spatial relationships of pressure data and are well suited for comparing intraluminal manometry with axial organ movement. These methods were used in 4 North American opossums (3.8-5.5 kg) to establish regional changes in esophageal length in relation to the topographically defined pressure segments comprising peristalsis. Using a transabdominal approach, up to 7 radiopaque clips were placed along the serosal esophageal surface in anesthetized animals. The clips began near the LES and extended into the proximal half of the esophagus. At least 4 weeks following surgery, manometry was performed using a 21-lumen system capable of creating 3-dimensional topographic plots and exporting data for additional topographic analysis (MMS, Enschede, Holland). Clip movement was extracted from digitized images obtained from concurrent videofluoroscopy that was synchronized with manometry. Clip locations were converted to percent esophageal length using topographically defined landmarks. All data from each swallow were analyzed and displayed using topographic methods. RESULTS: Three sequential pressure segments in the esophageal body that merged with a 4th segment at LES aftercontraction were found in each animal, as previously described. The entire esophagus shortened with the onset of swallowing to a maximum of 3.5 ±2.0% at 3.0s. In the proximal esophagus, shortening began with swallowing and progressively reached a maximum of 3.3 ± 1.6% of baseline at 1.8s after the swallow. This shortening occurred in concert with the 1st and early part of the 2nd topographic segments and was not appreciated in distal esophageal regions. With further development of the 2nd segment, shortening abruptly occurred simultaneously across more distal regions, compressing the distal esophageal half by 5.3 ±3.9%. Although this abrupt shortening preceded onset of distal contraction, shortening persisted until the topographic segment passed through each distal region. CONCLUSIONS: Regional axial esophageal movements can be identified that both precede and occur concurrently with the muscle contractions responsible for the peristaltic sequence. The most pronounced distal axial movement precedes peristalsis and coincides with development of the 2nd topographic segment, an effect that would improve bolus transit in response to pump action of this segment. Topographic methods are helpful in understanding the physiologic events involved in esophageal motility.
Effect of CCK receptor antagonists on the inhibition oficTRH analog induced gastric acid secretion by intraduodenal lipid iv id
acid
vehicle saline
vehicle lipid
vehicle lipid
vehicle lipid
13
5% 9
10% 8
20% 10
66+13
50+21
11±10
-2+3
devaze. saline
devaze. L·365260 L·365260 saline lipid lipid
20% 9 50+17
53+16
20% 5 57+19
-1+3
802 THE NOCICEPTIVE RESPONSE TO ACUTE PANCREATITIS: CHANGES IN BEHAVIOR, REFERRED HYPERALGESIA AND SPINAL C·FOS EXPRESSION. Lei Zou, John H. Winston, Mohan Shenoy, Pankaj Jay Pasricha, UTMB, Galveston, TX. Pain is the cardinal symptom of pancreatitis but little is known about its pathogenesis or its processing at the spinal or higher levels of the CNS. Methods: Pancreatitis was induced in rats by either intraperitoneal injection of L-arginine or intraductal taurocholate 5%. In order to assess global pain responsiveness in rats with pancreatitis we measured their activity in a caged environment, which was markedly decreased for the first 24 hours. We also studied the degree of referred hyperalgesia to the abdominal wall by stimulation with von Frey filaments. In other rats, spinal segments T6-Til were isolated and were processed for c-fos imrnunostaining. C-fos immunoreactive neurons were counted and were averaged for each segment. Results: Acute pancreatitis was associated with significant and measurable changes in home cage activity and response to abdominal stimulation with von Frey filaments. In addition, acute pancreatitis was associated with a significant increase in the number of c-fos staining nuclei per section per segment compared with controls: T6 (42 +1- 15 vs 29 +18; P <0.01 ), T7 (61 +1- 10 vs 39 +1- 7; P <.001), T8 (79 +1- 12 vs 52 +1- 14; P <0.001); T9 (72 +1- 12 vs 46 +1- 8; P
804 DOES HIGH RESOLUTION MANOMETRY DETECT ESOPHAGEAL MOTILITY DISORDERS MORE RELIABLE THAN CONVENTIONAL MANOMETRY? Patrick O. Janiak, Sudip K. Ghosh, Miriam Thumshim, James G. Brasseur, Michael Fried, Geoff S. Hebbard, Werner Schwizer, Univ Hosp Zurich, Zurich, Switzerland; Penn State Univ, University Park, PA; Repatriation Gen Hosp, Adelaide, Australia. Assessment of esophageal motility disorders by conventional manometry (CM) may be hampered by the lack of sufficient spatial resolution. High resolution manometry (HRM) provides greater detail of the space-time structure and may show motility patterns not detected with CM. Aim: To analyze quantitatively whether HRM gives sufficiently more information to improve assessment of motility compared to CM. Method: 10 normal volunteers and 9 patients with dysphagia (systemic scleroderma, n=5; reflux esophagitis, n=4) underwent HRM using a 21-channel catheter(l1.5 em spacing). A series of 5 lower resolution "catheters" were computer generated by different groupings of the sideholes of the HRM varying from 4 (spaced 6-8 cm) to 8 (spaced 3 em) sideholes. HRM contour plots of 95 swallows were compared to CM plots of a 6 sidehole catheter for motility disorders with blinded analysis by two clinicians. Using a computer based analysis we compared each lower resolution "catheter" to HRM by evaluating a) correlation coefficients in interpolated pressures, b)peristaltic wave speeds and c)space-time isocontours, Results: By clinical judgement 76% of swallows in dysphagic patients were classified as "disturbed" by CM compared to 92% by HRM. ROC analysis revealed for HRM at a sensitivity level of 90% a specificity of 100% whereas for CM a specificity of 89% was associated with a sensitivity of 70%. Computer analysis showed that the correlation in pressure decreased from 1.00 with HRM to 0.65 with the lowest resolution CM. Important details such as segmental and multiple contractions, abnormally displaced transition zone, variation of wave-speed, which were common motility features in patients, were resolved with HRM but not CM. Conclusion: Potentially important details of the pressure space-time structure in the esophagus are not resolved with CM. This pilot study suggests that in a clinical setting conventional manometry may underdiagnose motility disturbances compared to high resolution manometry.
A132 AGA ABSTRACTS
801
803
INTRADUODENAL LIPID INHIBITS CENTRAL VAGAL STIMULATION OF GASTRIC ACID SECRETION THROUGH ACTIVATION OF CCK A RECEPTOR IN RATS. Hong Yang, Yvtte F. Tache, Ming-Luen Doong, John H. Walsh, Curel Ddrc., UCLA, Los Angeles, CA. Background: Intestinal lipids inhibit gastric acid secretion induced by meal in dogs and gastric emptying in rats via CCK and vagal capsaicin-sensitive afferent pathway (Lloyd et al: Gastroenterology, 102: 131,1992. Holzer et al: Am J Physiol267: G625, 1994). Intracisternal injection (ic) ofTRH is widely used to stimulate vagal efferent activity and mimics the cephalic phase of acid secretion. Aim: To investigate I) whether intraduodenal lipids inhibit central vagal gastric acid stimulation-induced by ic TRH analog; 2) whether CCK receptors are involved in these responses. Methods: Male SD rats (270-310 g) fasted for 24 h were anesthetized with urethane. Gastric acid secretion was induced by ic TRH analog, RX 77368 (5 ng) and measured by flushing the stomach through a gastric cannula. Intraduodenal (id) intralipid (0.5 ml) was administered through a duodenal fistula. Results: RX 77368 ic induced a net acid output of 56.8 ± 8.0 /Lmo1/90 min. CCK-8S (0.5 and 1 nmol/kg/h) iv infusion started 10 min before the ic RX 77368 inhibited the acid secretion by 23% and 82% respectively. The inhibitory action of CCK-8S was completely prevented by the CCK A receptor antagonist devazepide (l mg/kg) injected iv 10 min before the CCK-8S infusion. Intraduodenal intralipid (5%, 10% and 20%) administered 20 min before ic RX 77368 dose-dependently reduced by 24%, 83% and 100% the acid response and the inhibitory effect of intralipid was completely prevented by devazepide(l mg/kg). The CCK B receptor antagonist L-365260 (l mg/kg) had no effect on the inhibitory effect of intraduodenal lipid (Table). Conclusion: Intraduodenal lipid inhibits central TRH-induced gastric acid secretion through releasing endogenous CCK and the inhibitory action is mediated by CCK A receptors.
CONCURRENT EVALUATION OF INTRALUMINAL PRESSURES AND AXIAL ESOPHAGEAL MOVEMENT USING TOPOGRAPHIC METHODS IN THE OPOSSUM. Ray E. Clouse, Chandra Prakash, Robert A. Underwood, Annamaria Staiano, Laura R. Haroian, Nathaniel 1. Soper, Gastroenterology Div, Washington Univ, St. Louis, MO; Dept of Surg WUIMIS, Washington Univ, St. Louis, MO; astroenterology Div, Washington Univ, St. Louis, MO; Barnes-Jewish Hosp, St. Louis, MO; Dept of Surg - WUIMIS, Washington Univ, St. Louis, MO. Topographic methods consider spatial relationships of pressure data and are well suited for comparing intraluminal manometry with axial organ movement. These methods were used in 4 North American opossums (3.8-5.5 kg) to establish regional changes in esophageal length in relation to the topographically defined pressure segments comprising peristalsis. Using a transabdominal approach, up to 7 radiopaque clips were placed along the serosal esophageal surface in anesthetized animals. The clips began near the LES and extended into the proximal half of the esophagus. At least 4 weeks following surgery, manometry was performed using a 21-lumen system capable of creating 3-dimensional topographic plots and exporting data for additional topographic analysis (MMS, Enschede, Holland). Clip movement was extracted from digitized images obtained from concurrent videofluoroscopy that was synchronized with manometry. Clip locations were converted to percent esophageal length using topographically defined landmarks. All data from each swallow were analyzed and displayed using topographic methods. RESULTS: Three sequential pressure segments in the esophageal body that merged with a 4th segment at LES aftercontraction were found in each animal, as previously described. The entire esophagus shortened with the onset of swallowing to a maximum of 3.5 ±2.0% at 3.0s. In the proximal esophagus, shortening began with swallowing and progressively reached a maximum of 3.3 ± 1.6% of baseline at 1.8s after the swallow. This shortening occurred in concert with the 1st and early part of the 2nd topographic segments and was not appreciated in distal esophageal regions. With further development of the 2nd segment, shortening abruptly occurred simultaneously across more distal regions, compressing the distal esophageal half by 5.3 ±3.9%. Although this abrupt shortening preceded onset of distal contraction, shortening persisted until the topographic segment passed through each distal region. CONCLUSIONS: Regional axial esophageal movements can be identified that both precede and occur concurrently with the muscle contractions responsible for the peristaltic sequence. The most pronounced distal axial movement precedes peristalsis and coincides with development of the 2nd topographic segment, an effect that would improve bolus transit in response to pump action of this segment. Topographic methods are helpful in understanding the physiologic events involved in esophageal motility.
Effect of CCK receptor antagonists on the inhibition oficTRH analog induced gastric acid secretion by intraduodenal lipid iv id
acid
vehicle saline
vehicle lipid
vehicle lipid
vehicle lipid
13
5% 9
10% 8
20% 10
66+13
50+21
11±10
-2+3
devaze. saline
devaze. L·365260 L·365260 saline lipid lipid
20% 9 50+17
53+16
20% 5 57+19
-1+3
802 THE NOCICEPTIVE RESPONSE TO ACUTE PANCREATITIS: CHANGES IN BEHAVIOR, REFERRED HYPERALGESIA AND SPINAL C·FOS EXPRESSION. Lei Zou, John H. Winston, Mohan Shenoy, Pankaj Jay Pasricha, UTMB, Galveston, TX. Pain is the cardinal symptom of pancreatitis but little is known about its pathogenesis or its processing at the spinal or higher levels of the CNS. Methods: Pancreatitis was induced in rats by either intraperitoneal injection of L-arginine or intraductal taurocholate 5%. In order to assess global pain responsiveness in rats with pancreatitis we measured their activity in a caged environment, which was markedly decreased for the first 24 hours. We also studied the degree of referred hyperalgesia to the abdominal wall by stimulation with von Frey filaments. In other rats, spinal segments T6-Til were isolated and were processed for c-fos imrnunostaining. C-fos immunoreactive neurons were counted and were averaged for each segment. Results: Acute pancreatitis was associated with significant and measurable changes in home cage activity and response to abdominal stimulation with von Frey filaments. In addition, acute pancreatitis was associated with a significant increase in the number of c-fos staining nuclei per section per segment compared with controls: T6 (42 +1- 15 vs 29 +18; P <0.01 ), T7 (61 +1- 10 vs 39 +1- 7; P <.001), T8 (79 +1- 12 vs 52 +1- 14; P <0.001); T9 (72 +1- 12 vs 46 +1- 8; P
804 DOES HIGH RESOLUTION MANOMETRY DETECT ESOPHAGEAL MOTILITY DISORDERS MORE RELIABLE THAN CONVENTIONAL MANOMETRY? Patrick O. Janiak, Sudip K. Ghosh, Miriam Thumshim, James G. Brasseur, Michael Fried, Geoff S. Hebbard, Werner Schwizer, Univ Hosp Zurich, Zurich, Switzerland; Penn State Univ, University Park, PA; Repatriation Gen Hosp, Adelaide, Australia. Assessment of esophageal motility disorders by conventional manometry (CM) may be hampered by the lack of sufficient spatial resolution. High resolution manometry (HRM) provides greater detail of the space-time structure and may show motility patterns not detected with CM. Aim: To analyze quantitatively whether HRM gives sufficiently more information to improve assessment of motility compared to CM. Method: 10 normal volunteers and 9 patients with dysphagia (systemic scleroderma, n=5; reflux esophagitis, n=4) underwent HRM using a 21-channel catheter(l1.5 em spacing). A series of 5 lower resolution "catheters" were computer generated by different groupings of the sideholes of the HRM varying from 4 (spaced 6-8 cm) to 8 (spaced 3 em) sideholes. HRM contour plots of 95 swallows were compared to CM plots of a 6 sidehole catheter for motility disorders with blinded analysis by two clinicians. Using a computer based analysis we compared each lower resolution "catheter" to HRM by evaluating a) correlation coefficients in interpolated pressures, b)peristaltic wave speeds and c)space-time isocontours, Results: By clinical judgement 76% of swallows in dysphagic patients were classified as "disturbed" by CM compared to 92% by HRM. ROC analysis revealed for HRM at a sensitivity level of 90% a specificity of 100% whereas for CM a specificity of 89% was associated with a sensitivity of 70%. Computer analysis showed that the correlation in pressure decreased from 1.00 with HRM to 0.65 with the lowest resolution CM. Important details such as segmental and multiple contractions, abnormally displaced transition zone, variation of wave-speed, which were common motility features in patients, were resolved with HRM but not CM. Conclusion: Potentially important details of the pressure space-time structure in the esophagus are not resolved with CM. This pilot study suggests that in a clinical setting conventional manometry may underdiagnose motility disturbances compared to high resolution manometry.