Mechanism of action of cholecystokinin octapeptide on cat lower esophageal sphincter

In five cats we examined 1) the role of a cholinergic mechanism in cholecystokinin octapeptide (CCK-OP) excitation of the lower esophageal sphincter (LES) and 2) the interaction between CCK-OP-induced excitation and inhibition of the LES. Under ketamine anesthesia, LES pressure was monitored with a sleeve catheter. With CCK-OP, LES excitation was seen in four of five cats, and inhibition was seen in three of five cats. (4-Hydroxy-2-butynyl)trimethylammonium chloride (McNeil-A343) produced similar responses in the same cats but was less potent than CCK-OP. Atropine and/or hexamethonium reduced the response to CCK-OP. Pirenzepine had no effect on any CCK-OP response but reduced relaxation and enhanced excitation produced by McNeil-A343. Phentolamine increased CCK-OP-induced relaxation. In conclusion, CCK-OP can produce LES contraction through a preganglionic cholinergic mechanism involving a nicotinic synapse; however, induction of relaxation occurs predominantly at a postganglionic site involving adrenergic modulation. There is animal-to-animal variability in the balance of excitatory and inhibitory mechanisms to the LES, which determines the effect of a drug capable of activating both mechanisms.

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Lower esophageal sphincter function in the cat: role of central innervation assessed by transient vagal blockade

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1984.246.6.g666 ◽

1984 ◽

Vol 246 (6) ◽

pp. G666-G674 ◽

Cited By ~ 3

Author(s):

R. P. Reynolds ◽

T. Y. El-Sharkawy ◽

N. E. Diamant

Keyword(s):

Smooth Muscle ◽

Lower Esophageal Sphincter ◽

Vagal Nerve ◽

Sphincter Pressure ◽

Cholinergic Mechanism ◽

Nerve Blockade ◽

Vagal Blockade ◽

Balloon Distension ◽

Esophageal Sphincter

Studies were performed on four cats to assess the role of extrinsic vagal innervation in the control of lower esophageal sphincter (LES) function. Both cervical vagal nerves were blocked transiently by cooling. LES pressure was measured using a multilumen manometry tube. LES relaxation was assessed during intraesophageal balloon distension in both the striated and smooth muscle portions of the esophagus. Bilateral vagal nerve blockade lowered the mean LES pressure from 58 +/- 17 to 29 +/- 9 mmHg (P less than 0.01). During vagal blockade, balloon distension in the striated muscle esophagus further reduced sphincter pressure to 16 +/- 4 mmHg (P less than 0.01) and that in the smooth muscle esophagus to 15 +/- 3 mmHg (P less than 0.01). Swallow-induced LES relaxation was abolished during bilateral vagal nerve blockade. During vagal blockade, atropine reduced LES pressure to 10 +/- 1 mmHg, phentolamine to 13 +/- 6 mmHg, and hexamethonium to 10 +/- 4 mmHg (all P less than 0.01). We conclude that 1) normal LES tone in the cat is mediated primarily by two separate neural mechanisms: a vagal cholinergic mechanism and a nonvagal mechanism that utilizes both alpha-adrenergic and cholinergic receptors; 2) local, intramural mechanisms of high threshold are present in the striated and smooth muscle cat esophagus to allow distension-induced reflex inhibition of the LES; and 3) swallow-induced LES relaxation is dependent on vagally mediated central nervous system connections.

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Neural inhibition in the rat lower esophageal sphincter: Role of β3-adrenoceptor activation

General Pharmacology The Vascular System ◽

10.1016/s0306-3623(97)00094-3 ◽

1998 ◽

Vol 30 (1) ◽

pp. 37-41 ◽

Cited By ~ 11

Author(s):

M.A. Oriowo

Keyword(s):

Lower Esophageal Sphincter ◽

Neural Inhibition ◽

Esophageal Sphincter

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Triggering of transient LES relaxations in ferrets: role of sympathetic pathways and effects of baclofen

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.1.g157 ◽

2000 ◽

Vol 279 (1) ◽

pp. G157-G162 ◽

Cited By ~ 22

Author(s):

Esther Staunton ◽

Scott D. Smid ◽

John Dent ◽

L. Ashley Blackshaw

Keyword(s):

Gastroesophageal Reflux ◽

Lower Esophageal Sphincter ◽

Glucose Infusion ◽

Gastric Distention ◽

Low Level ◽

Before And After ◽

Esophageal Sphincter ◽

Splanchnic Mechanoreceptors ◽

High Level

Activation of gastric vagal mechanoreceptors by distention is thought to be the trigger for transient lower esophageal sphincter relaxations (TLESR), which lead to gastroesophageal reflux. The contribution of higher-threshold gastric splanchnic mechanoreceptors is uninvestigated. GABABreceptor agonists, including baclofen, potently reduce triggering of TLESR by low-level gastric distention. We aimed to determine first whether this effect of baclofen is maintained at high-level distention and second the role of splanchnic pathways in triggering TLESR. Micromanometric/pH studies in conscious ferrets showed that intragastric glucose infusion (25 ml) increased triggering of TLESR and reflux. Both were significantly reduced by baclofen (7 μmol/kg ip) ( P < 0.05). When 40 ml of air was added to the glucose infusion, more TLESR occurred than with glucose alone ( P < 0.01). These were also reduced by baclofen ( P < 0.001). TLESR after glucose/air infusion were assessed before and after splanchnectomy (2–4, 9–11, and 23–25 days), which revealed no change. Baclofen inhibits TLESR after both low- and high-level gastric distention. Splanchnic pathways do not contribute to increased triggering of TLESR by high-level gastric distention.

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Role of Ca2+ in genesis of lower esophageal sphincter tone and other active contractions.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.237.2.e163 ◽

1979 ◽

Vol 237 (2) ◽

pp. E163 ◽

Cited By ~ 4

Author(s):

J A Fox ◽

E E Daniel

Keyword(s):

Lower Esophageal Sphincter ◽

Muscle Stimulation ◽

Active Tension ◽

Sphincter Tone ◽

Esophageal Sphincter

The effects of absent or low Ca2+ (0.5 mM), verapamil, nifedipine, Na nitroprusside, theophylline, La2+, and ethanol on basal active tension (tone), "off" contractions, and carbachol contractions were studied in opossum lower esophageal sphincter strips. Incubation in Ca2+-free Ringer (0.1 mM EGTA) abolished tone and contractions. Low Ca2+, verapamil, nifedipine, and theophylline depressed tone more rapidly than "off" contractions. Only verapamil and nifedipine depressed carbachol contractions. Na nitroprusside rapidly depressed tone but left contractions unchanged. La3+ at 1 X 10(-3) M behaved like Ca2+-free incubation but produced sustained contractions with muscle stimulation. Ethanol depressed "off" contractions more than tone and did not affect carbachol-induced contractions. These results suggest that tone probably results from inward leak of Ca2+, whereas "off" contractions depend on release of Ca2+ sequestered in the cell by a mechanism not immediately dependent on increased Ca2+ influx. Carbachol may increase Ca2+ influx as well as utilize sequestered Ca2+. Nifedipine and verapamil may act to block both resting and stimulated Ca2+ influx. Na nitroprusside may act by increasing Ca2+ efflux. Ethanol may act by decreasing the availability of sequestered Ca2+ or by inhibiting the function of a mediator responsible for "off" contractions.

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The role of CA++ in the genesis of lower esophageal sphincter (LES) tone and contraction

Gastroenterology ◽

10.1016/0016-5085(78)93132-3 ◽

1978 ◽

Vol 74 (5) ◽

pp. 1035 ◽

Cited By ~ 8

Author(s):

J.E. Fox ◽

E.E. Daniel

Keyword(s):

Lower Esophageal Sphincter ◽

Esophageal Sphincter

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Pathophysiology of Barrett???s Esophagus: Role of the Stomach in Early Disease, Lower Esophageal Sphincter, and Esophageal Body Dysfunction With Advancing Disease

Problems in General Surgery ◽

10.1097/00013452-200106000-00003 ◽

2001 ◽

Vol 18 (2) ◽

pp. 12-17

Author(s):

Rodney J. Mason

Keyword(s):

Lower Esophageal Sphincter ◽

Early Disease ◽

Esophageal Body ◽

Esophageal Sphincter

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H. pylori and transient lower esophageal sphincter relaxations induced by gastric distension in healthy humans

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.2.g350 ◽

2001 ◽

Vol 281 (2) ◽

pp. G350-G356 ◽

Cited By ~ 17

Author(s):

Frank Zerbib ◽

Valérie Bicheler ◽

Véronique Leray ◽

Madeleine Joubert ◽

Stanislas Bruley des Varannes ◽

...

Keyword(s):

Helicobacter Pylori ◽

Lower Esophageal Sphincter ◽

Proinflammatory Cytokine ◽

Healthy Subjects ◽

Gastric Distension ◽

Healthy Humans ◽

Biopsy Specimens ◽

Esophageal Sphincter ◽

H Pylori

The role of Helicobacter pylori infection in the control of lower esophageal sphincter (LES) motility, especially the occurrence of transient LES relaxations (TLESRs), was studied in eight H. pylori-positive and eight H. pylori-negative healthy subjects. During endoscopy, biopsy specimens were taken from the cardia, fundus, and antrum for determinations of H. pyloristatus, gastritis, and proinflammatory cytokine mucosal concentrations. LES motility was monitored during three different 30-min periods: baseline, gastric distension (barostat), and gastric distension with CCK infusion. Gastric distension significantly increased the TLESR rate, whereas CCK increased the rate of distension-induced TLESRs further and reduced resting LES pressure without significant differences between infected and noninfected subjects. H. pylori status did not influence resting LES pressure or gastric compliance. Cytokine mucosal concentrations were increased in infected patients, but no correlation was found with the TLESR rate, which was also independent of inflammation at the cardia, fundus, and antrum. These results suggest that H. pylori-associated inflammation does not affect the motor events involved in the pathogenesis of gastroesophageal reflux.

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