Lower Esophageal Sphincter Contraction Research Articles

Electrical control activity of the lower esophageal sphincter in unanesthetized opossums.

We recorded lower esophageal sphincter (LES) pressure and myoelectrical activity concurrently from the esophagus, LES, stomach, and proximal small intestine in unanesthetized opossums. LES electrical activity was characterized by almost continuous, spikelike oscillations at 15-40/min, which were accompanied by minicontractions 5-15 mmHg in amplitude. Basal LES pressure, however, did not depend on electrical oscillations. The LES exhibited cyclic changes in pressure and electrical activity synchronous with gastric contractions associated with the migrating myoelectric complex (MMC). During phase I, the LES pressure was stable and its electrical activity showed continuous low-amplitude (less than 0.3 mV) oscillations at a rate of 20 +/- 2 per min. During phases II and III of MMC-related gastric activity, the LES developed strong phasic contractions, while the electrical oscillations grouped into clusters with an increased rate (32 +/- 1 per min) and amplitude (0.4-0.8 mV), each cluster corresponding to a phasic contraction. Feeding, pentobarbital, and cholinergic blockade abolished MMC-related LES activity and resulted in a steady rate of LES electrical oscillations. LES relaxation induced by swallows or esophageal balloon distention abolished the LES electrical oscillations. Increases in LES pressure induced by pharmacological and hormonal stimulation correlated with concurrent increases in the rate of electrical oscillations. We conclude that the opossum LES has a unique pattern of electrical activity that differs from the electrical activity recorded from smooth muscle elsewhere in the gastrointestinal tract. This electrical activity is a form of control wave associated with a minicontraction. Phasic LES contractions during the intestinal MMC cycle may result from an increase in the rate and amplitude of the LES electrical control waves and fusion of minicontractions.

Motilin: A mechanism incorporating the opossum lower esophageal sphincter into the migrating motor complex

The lower esophageal sphincter (LES) exhibits cyclical phasic contractile activity synchronous with phases II and III of the gastric migrating motor complex. Motilin has been implicated in this process, although the exact mechanism is unknown. The effect of motilin on LES pressure and on gastrointestinal myoelectric activity was examined in 8 unanesthetized opossums. Intraluminal pressure was recorded by a manometric assembly incorporating a sleeve device. Myoelectric activity was recorded from the stomach, duodenum, and jejunum via implanted electrodes. The opossum LES exhibited cyclical periods of phasic contractions synchronous with phases II and III of the gastric migrating motor complex cycle. Variations in the occurrence and magnitude of the phasic LES pressure waves paralleled the spontaneous cyclic fluctuations in the level of circulating plasma motilin. Pulse doses of exogenous motilin (25–400 ng/kg) elicited a contractile LES response that mimicked the spontaneous migrating motor complex-related phasic LES contractions. This effect was dose related with the maximal response occurring at a motilin dose of 100 ng/kg. The LES response to motilin was abolished by hexamethonium and significantly antagonized by atropine and 4-diphenylacetoxy-N-methylpiperidine methiodide, but was not affected by pirenzepine, phentolamine, or naloxone. The study findings support the hypothesis that cyclic increases in circulating endogenous motilin incorporate phasic LES as well as gastric contractile activity into the gastrointestinal migrating motor complex cycle. Motilin acts on the LES by the preganglionic stimulation of cholingeric nerves.

Variability of lower esophageal sphincter pressure in the fasted unanesthetized opossum.

The opossum has served as a useful animal model for in vivo studies of lower esophageal sphincter (LES) function. Previous investigations, however, have been confined to studies on anesthetized animals. In 10 opossums we investigated LES pressure during fasting cycles of the gastrointestinal migrating myoelectric complex (MMC) and examined the influences of anesthesia and feeding on LES pressure. Intraluminal pressure from the esophageal body, LES, and gastric antrum was recorded by a manometric assembly that incorporated a sleeve device. Myoelectric activity was recorded from the gastric antrum and duodenum via implanted electrodes. MMCs were readily recorded from all animals. MMC cycle length was 86 +/- 2.9 (SE) min. The LES exhibited cyclic changes in intraluminal pressure that occurred in synchrony with the gastric MMC cycle. During phase I of the gastric MMC cycle, LES pressure was essentially stable, although intermittent spontaneous oscillations at 3-4/min were sometimes noted. Forceful phasic LES contraction started during phase II of the gastric MMC, became maximal during phase III, and disappeared during phase I. The MMC-related phasic LES contraction occurred at a maximal rate of 1.4 +/- 0.05/min with amplitudes of 60-150 mmHg and were temporally associated with spike bursts and contractions in the gastric antrum. Pentobarbital sodium-induced anesthesia abolished MMC-related phasic LES activity and caused a transient rise in basal sphincter pressure. Phasic LES activity was also inhibited by atropine and feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Action of different agonists and antagonists of the cholinergic system on the rat lower esophageal sphincter

1. 1. Several compounds acting on the cholinergic system at different levels were tested for their stimulatory or inhibitory effects on the isolated lower esophageal sphincter (LES) of the rat. 2. 2. Results obtained with acetylcholine, bethanechol and compound McN-A343 on the one hand and atropine, pirenzepine, ganglion blocking agents and tetrodotoxin on the other, suggested that LES contraction was associated mainly with the stimulation of post-synaptic muscarinic receptors 3. 3. Nicotinic receptors (both ganglionic and muscular) seem to have a minor role, if any.

Effects of Nifedipine in Achalasia and in Patients With High-Amplitude Peristaltic Esophageal Contractions

We studied the esophageal effects of nifedipine in 20 patients with achalasia (20 mg sublingually) and nine patients with high-amplitude peristaltic esophageal contractions (nutcracker esophagus) (20 mg orally). In patients with achalasia, nifedipine decreased lower esophageal sphincter (LES) pressure by approximately 30%. In ten patients with achalasia, plasma nifedipine concentrations were 45.3 +/- 17.7 and 57.4 +/- 12.8 ng/mL (means +/- SEM) at 30 and 60 minutes, respectively, after drug administration. In patients with nutcracker esophagus, nifedipine decreased LES pressure by approximately 50% and contraction amplitude in the body of the esophagus by approximately 25%. After comparison was made with our previous results in normal subjects, we concluded that (1) nifedipine decreased LES pressure in patients with achalasia to a similar extent to that noted in normal subjects; (2) plasma concentrations measured after 20 mg of nifedipine given sublingually to achalasic patients were similar to those found under similar circumstances in normal subjects; and (3) nifedipine decreased LES pressure and contraction amplitude in patients with nutcracker esophagus to a greater extent than was found in normal subjects. These results suggest that double-blind, placebo-controlled clinical trials of nifedipine in the treatment of achalasia or nutcracker esophagus are indicated.

Afferent innervation of the lower esophageal sphincter of the cat. Pathways and functional characteristics

The sensory vagal and ‘sympathetic’ innervation of the lower esophageal sphincter (LES) has been investigated in cats using both electrophysiological and histochemical techniques. Histochemical studies produced evidence that ‘sympathetic’ afferents run in: (i) the splanchnic nerves; (ii) the sympathetic thoracic nerves; and (iii) the sympathetic cardiac branch. Electrophysiological studies allowed us to describe different kinds of LES receptors: (i) mucosal vagal receptors acting as rapidly adapting mechanoreceptors or as slowly adapting chemoreceptors; (ii) vagal and ‘sympathetic’ endings located in the muscular layers, adapting slowly and mainly activated by LES contractions; and (iii) vagal and ‘sympathetic’ endings located in the serous membrane behaving as rapidly adapting receptors sensitive to stretching.

Development of innervation in cat gastrointestinal sphincters during the postnatal period. (Functional studies)

o 1. 1. The development of function in the intramural nerves was investigated by evaluating the mechanical responses of the smooth muscle of cat gastrointestinal sphincters to transmural electrical stimulation (2–20 Hz, 0.5 msec, supramaximal intensity for 20 sec) between 1 and 60 days postnatal. 2. 2. The intramural nervous system of the gastrointestinal sphincters was found to develop functionally in a cranio-caudal sequence. 3. 3. The cholinergic innervation in the lower esophageal sphincter (LES) was well developed in the first postnatal days. The development of the non-cholinergic, non-adrenergic innervation, however, proceeded further. 4. 4. An age-determined increase in the amplitude of the adrenoblocker-resistant primary relaxation of LES evoked by switching on the electrical stimulation, was established. 5. 5. The cholinergic innervation in the pyloric sphincter (PS) and ileocecal sphincter (ICS) was developed in the first postnatal days. 6. 6. The non-cholinergic, non-adrenergic innervation appeared in PS between 10- and 15-days postnatal and in ICS between 15- and 60-days postnatal. 7. 7. Noradrenaline (1 μmol) elicited responses typical of adult cats as early as the first postnatal days: contraction in LES and relaxation in PS. 8. 8. In ICS it did not evoke the typical response, contraction, until 15 days after birth.

Paradoxical lower esophageal sphincter contraction induced by cholecystokinin-octapeptide in patients with achalasia

A recent study in cats suggests that cholecystokinin-octapeptide relaxes the feline lower esophageal sphincter (LES) by evoking an indirect neural inhibitory effect that overrides a direct excitatory myogenic effect. We reasoned that, if cholecystokinin-octapeptide has a dual effect on the human LES similar to that in the cat, cholecystokinin-octapeptide might increase LES pressure in patients with impaired inhibitory innervation. To test this hypothesis we determined the effect of intravenous bolus doses of cholecystokinin-octapeptide on LES pressure in three groups of subjects: 7 controls (group 1), 24 patients with untreated idiopathic achalasia (group 2), and 32 miscellaneous patients referred for esophageal manometry (group 3). Lower esophageal sphincter pressure was monitored by a perfused sleeve device. In 6 of 7 control subjects, cholecystokinin-octapeptide caused monophasic LES relaxation. The seventh subject demonstrated a biphasic response of LES relaxation followed by contraction. In 21 of 24 achalasia patients, cholecystokinin-octapeptide induced paradoxical monophasic LES contraction. In 2 achalasia patients, LES pressure did not change after cholecystokinin-octapeptide and in 1 achalasia patient LES pressure decreased, as in normal subjects. In the 32 miscellaneous patients, cholecystokinin-octapeptide induced LES relaxation in 25, a biphasic response in 4, no change in 2, and a paradoxical increase in 1. The patient demonstrating LES contraction to cholecystokinin-octapeptide had an unclassified esophageal motility disorder associated with incomplete LES relaxation after swallows. We conclude: (a) Cholecystokinin-octapeptide induces a paradoxical increase in LES pressure in most achalasia patients; (b) a presser LES response to cholecystokinin-octapeptide suggests post-ganglionic impairment of inhibitory nerves; and (c) achalasia patients demonstrating LES relaxation after cholecystokinin-octapeptide may have neural impairment limited to preganglionic fibers while the postganglionic inhibitory nerves remain at least partially intact.

Effect of cholecystokinin-octapeptide on opossum lower esophageal sphincter.

We evaluated the action of cholecystokini-octapeptide (CCK-OP) on lower esophageal sphincter (LES) pressure in the opossum. LES pressure was recorded by an infused sleeve device that straddled the sphincter, whereas intraluminal esophageal pressure and gastric pressure were recorded via conventional manometric catheters. Progressive intravenous pulse doses of CCK-OP caused 1) graded increases in LES pressure, 2) circular and longitudinal smooth muscle contraction in esophageal body, and 3) mild increases in intragastric pressure. Pressor effect of CCK-OP on the LES was weakly antagonized by tetrodotoxin (TTX), but not by atropine, phentolamine, or pyrilamine. TTX antagonism of CCK-OP appeared to be nonspecific because TTX also partially antagonized LES contractions induced by pentagastrin, substance P, and bethanechol. We conclude that CCK-OP at doses that cause LES relaxation in other species induces LES contraction in the opossum. This pressor effect appears to be elicited by a direct action of the hormone on LES smooth muscle.

Effect of Cholecystokinin-Octapeptide on Lower Esophageal Sphincter

The effect of cholecystokinin-octapeptide (CCK-OP) on the lower esophageal sphincter (LES) was studied in 50 cats in vivo. CCK-OP caused a dose-dependent fall in LES pressures in all but 4 animals. Maximal sphincter relaxation was obtained with 200 to 400 ng of CCK-OP per kg of body weight. Atropine sulfate and/or hexamethonium, or adrenergic blocking agents (phentolamine or propranolol), in doses that completely inhibit the action of maximal doses of their respective agonists, failed to block the CCK-OP effect. Tetrodotoxin, however, in doses that denervates the LES, antagonized the CCK-OP-induced sphincter relaxation. In these tetrodotoxin-treated animals, CCK-OP produced LES contraction similar to that observed after pentagastrin. These results suggest that CCK-OP stimulates the postganglionic nonadrenergic, noncholinergic inhibitory neurons responsible for sphincter relaxation. CCK-OP also stimulates the circular muscle by direct action causing LES contraction. The latter becomes apparent when the innervation of the LES is abolished by tetrodoxtin.

Neural control of the lower esophageal sphincter: influence of the vagus nerves.

We performed studies in the opossum to define the influence of the vagi in the control of lower esophageal sphincter (LES) function. Bilateral vagotomy caused transient sphincter hypertension which was prevented by phentolamine and by atropine. Stimulation of the peripheral end of vagus, after bilateral cervical vagotomy, caused relaxation of the LES over a wide range of frequency and intensity of electrical stimulation. The relaxation was less marked at the lower frequencies of stimulation, and atropine treatment did not enhance this relaxation. In other experiments, atropine treatment reversed the rise in gastric (fundic) pressure with the vagal stimulation, but atropine did not enhance the degree of LES relaxation. Stimulation of the central end of the vagus caused an increase in LES pressure due to a centrally mediated reflex; the efferents for this motor response were not present in the vagi, as the reflex contraction persisted after bilateral vagotomy. The LES contraction with the stimulation of the vagal afferents was antagonized by phentolamine as well as by atropine. These studies suggest that: (a) the vagi do not mediate any cholinergic excitatory influences to the LES and the vagal influence of the sphincter is entirely inhibitory; (b) the vagi carry afferent fibres for a centrally mediated neural reflex which contracts the LES, but the efferent path of this reflex arc does not lie in the vagi.