Somatostatin effects on lower esophageal sphincter function.

The effect of somatostatin (GH-RIH) infusion (2 microgram/min) on lower esophageal sphincter pressure (LESP) responses to various stimuli was evaluated in adult male baboons. GH-RIH infusion did not affect basal LESP, but did cause a significant suppression of mean immunoreactive insulin (IRI) to 5.8% of basal values (P less than 0.05). Pentagastrin IV caused dose-related increases in LESP that were unaffected by GH-RIH. Abdominal compression caused a threefold rise in LESP (P less than 0.005) both without and with GH-RIH. However, atropine (20 microgram/kg iv bolus) completely blocked this cholinergic LES pressure response. Intragastric alkali as well as intragastric glycine caused significant increases in LESP (P less than 0.05). These LESP responses to alkali and to glycine were totally abolished by GH-RIH. In conclusion, GH-RIH infusion in the baboon does not affect basal LESP, LES smooth muscle response to exogenous stimulation, nor a cholinergically mediated LES response. GH-RIH does inhibit the response of LESP both to intragastric alkali and to glycine by the apparent suppression of a hormonally mediated mechanism.     

Mechanism of cholecystokinin inhibition of lower esophageal sphincter pressure.

The purpose of this study were 1) to quantify the lower esophageal sphincter (LES) response to intravenous cholecystokinin (CCK) in both man and the opossum in vivo, 2) to characterize the interaction of CCK and gastrin on circular muscle of the LES, and 3) to determine the site of action of CCK on LES muscle. In both man and the opossum LES pressure was decreased significantly by either constant intravenous infusion or bolus injection of CCK. In vitro dose-response curves to gastrin I, CCK, and the octapeptide of CCK (OP) demonstrated that both CCK and OP were partial agonists on the LES muscle. Both CCK and OP contract LES muscle at lower threshold doses, but give smaller maximum responses than gastrin I. The maximum response of LES muscle to CCK was antagonized only by atropine and tetrodotoxin, but not by other antagonists, suggesting that CCK contracts LES muscle by acetylcholine release. In vitro studies on LES muscle showed that CCK selectively antagonized the effect of gastrin I, but not other agonists. These studied suggest that CCK reduces LES pressure in vivo by inhibition of the endogenous gastrin effect.     

Modulation of lower esophageal sphincter relaxation in the opossum.

The relationship of lower esophageal sphincter (LES) relaxation and sphincter pressure was studied in the basal state and after neurohumoral stimulation in the anesthetized opossum. LES relaxation was induced by electrical vagal stimulation, balloon distension, and swallowing, whereas LES pressure was increased by infusions of gastrin I, histamine, phenylephrine, or bethanechol. Each agent was selected to give an approximately twofold increase in LES pressure, at the highest dosage. The lower dosage gave a submaximal increase in LES pressure. Neither gastrin nor histamine modified sphincter relaxation as induced by vagal stimulation, esophageal distension, or swallowing. Phenylephrine or bethanechol made the LES less sensitive to vagal stimulation or esophageal distension without reducing maximal LES relaxation. Only bethanechol significantly decreased sphincter relaxation in response to swallowing (P less than 0.05). The results of this study suggest that LES relaxation is not a fixed response simply dependent on the inhibitory stimulus or the resting tonic level of LES pressure, but may be modulated by both alpha-adrenergic and cholinergic drugs.     

Prostaglandins and tetrodotoxin-insensitive relaxation of opossum lower esophageal sphincter.

Field stimulation with pulses of 0.5 or 5 ms relaxed isolated strips of lower esophageal sphincter (LES) of the opossum; only responses to 0.5-ms pulses were inhibited by tetrodotoxin. Black widow spider venom prevented relaxation to both stimuli; thus both stimuli may release nonadrenergic inhibitory mediator. Isoproterenol, but not PGEs or ATP, was a consistent relaxant of LES. PGF2alpha (approximately 1 microgram/ml) and stable endoperoxides (approximately 10 ng/ml) stimulated LES muscle. Doses of indomethacin (IDM) or 5,8,11,14-eicosatetraynoic acid (ETA), which inhibited contractions to arachidonic acid increased then abolished LES tone, inhibited relaxations to 5-ms pulses and less effectively to 0.5-ms pulses. Inhibition of relaxation preceded loss of tone. Tone could be restored by carbachol, PGEs, or PGF2alpha and relaxation after IDM but not ETA was also restored. Prostaglandins may participate in functioning of nonadrenergic inhibitory nerves and in maintaining sphincter tone. Cells that did not appear to be smooth muscle were in gap junction contact with smooth muscles and closely apposed to nerves with small agranular vesicles. A role for these structures, which are postulated to be interstitial cells, in tetrodotoxin-insensitive prostaglandin-related release of nonadrenergic inhibitory mediator was proposed.     

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.     

猫下食管括约肌对A型肉毒毒素的反应

目的： 应用A型肉毒毒素（BTA）局部注射于猫下食管括约肌（LES）,通过LES测压、局部乙酰胆碱（Ach）含量和乙酰胆碱酯酶（AchE）活性测定以及光镜、透射电镜观察,研究BTA对LES的作用机制,为临床BTA治疗贲门失弛缓症提供科学依据。方法：在胃镜下对BTA组（10只猫）LES分4点注射BTA,对照组（10只猫）注射生理盐水,分别于注射前、注射后1周测定LES的压力。处死猫后取LES,测定LES中Ach的含量和AchE活性;将LES作超薄切片,按Karnovsky-Roots法做AchE染色,在光镜和电镜下观察AchE阳性神经末梢和Ach囊泡的超微结构。结果：（1）BTA组LES压力（9.93±1.06） mmHg显著低于对照组（28.17±3.55) mmHg,P<0.01。（2）BTA组LES Ach含量(75.48±4.67) mg/g组织和AchE活性(38.20±2.17) 103 U/g组织均显著低于对照组,分别为(93.03±4.65) mg/g组织、(69.88±6.73) 103 U/g组织,均P<0.01。（3）在光镜下发现,运动终板色泽变淡,数目减少;在电镜下发现,神经末梢内含Ach的囊泡明显减少,末梢内AchE阳性反应物也明显减少。结论：猫LES局部注射BTA后,可引起LES压力明显下降,其机制可能为BTA破坏局部胆碱能神经末梢运动终板中的囊泡,导致局部Ach含量和AchE活性明显降低。     

Histamine receptors in the lower esophageal sphincter (LES)

The motor response of histamine on the lower esophageal sphincter and the receptors involved were investigated on isolated preparations from rats, guinea pigs and humans. Histamine exerted a spasmogenic effect through excitation of H₁-receptors. H₁-receptor selective agonists in the rat but not in the guinea pig seem to act through release of prostaglandin-like substances. Apparently H₂-receptors, whose stimulation causes relaxation of the sphincter, do not occur in the LES of rat and human whereas they are present in the guinea pig.H₂-receptor antagonists exerted different and some-times opposite effects and this suggests that their actions depend on the specific molecules and not on the H₂-receptor blockade. The significance and the importance of the above findings are discussed.     

Inhibition of lower esophageal sphincter circular muscle by female sex hormones

To determine the effect of estrogenic and progesteronic activity on lower esophageal sphincter (LES) circular muscle, studies were performed on 20 adult opossums. Does-response curves on circular smooth muscle strips from the LES were constructed for gastrin and acetylcholine alone, and with 17beta-estradiol and/or progesterone added. Each female hormone significantly decreased the maximal LES muscle responses to gastrin and acetylcholine. A combination of 17beta-estradiol and progesterone abolished the response to gastrin. In contrast, the male sex hormone, dihydrotestosterone, had no effect. In conclusion, administration of estrogen and progesteron, but not dihydrotestosterone, in vitro reduced LES muscle responses to gastrin and acetylcholine. These studies suggest that the female sex hormones can alter LES function and potentially may be of importance in the pathogenesis of heartburn of pregnancy.     

Generation of nitric oxide in the opossum lower esophageal sphincter during physiological experimentation

Lipopolysaccharide (LPS), given in vivo, modulates opossum esophageal motor functions by inducing the inducible nitric oxide synthase (iNOS), which increases nitric oxide (NO) production. Superoxide, a NO scavenger, is generated during this endotoxemia. Superoxide is cleared by superoxide dismutase (SOD) and catalase (CAT) to protect the physiological function of NO. This study examined whether lower esophageal sphincter (LES) motility, NO release, and iNOS and nitrotyrosine accumulation in the LES are affected by LPS in vitro. Muscle strips from the opossum LES were placed in tissue baths containing oxygenated Krebs buffer. NO release was measured with a chemiluminescence NOx analyzer, and Western blots were performed to analyze iNOS and nitrotyrosine production. The percent change in resting LES tone after a 6-hour exposure to LPS was significantly increased compared to pretreatment values. The percent LES relaxation upon electrical stimulation was significantly decreased in the control group at 6 hours, indicating that the LPS treatment had an effect. The NO concentration in the tissue bath of LPS- treated muscle without nerve stimulation was significantly less than that of LPS treatment combined with SOD/CAT or SOD/CAT alone. iNOS and nitrotyrosine were detectable and increased over time in the LES muscle of both the control and LPS-treated groups. Antioxidant enzymes may play a role in regulating NO-mediated neuromuscular functions in the LES.     

Factors influencing physiologic pressure variations of the lower esophageal sphincter in healthy probands

Manometric characteristics of lower esophageal sphincter (LES) in 59 healthy persons have been investigated. The aim of the investigation was to find out possible physiological changes of LES pressures considering posture, part of the day, maximal inspiration and expiration, empty or partially full stomach and abdominal compression. It has been proved that the minimal value of lower esophageal sphincter pressure in all the investigated patients was 1.77 kPA (13.3 mm Hg) while the maximal one was 4.53 kPa (34.0 mm Hg). The absolute difference between the lowest and the highest measured lower esophageal sphincter pressure was 1.43 kPa (10.77 mm Hg). The mean value of all pressures was 2.99 kPa (22.4 mm Hg). It seems that the posture during pressure measuring is irrelevant. The pressure does not vary more significantly considering neither the time of the day nor any exertion of the examinee.     

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

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.     

胃泌素和胃动素对人离体食管下括约肌张力的调节机制

目的探讨胃泌素和胃动素对人类食管下括约肌的套索纤维和钩状纤维的作用规律。方法制备人食管下括约肌的套索纤维、钩状纤维以及食管体部和胃底环行肌的肌条,运用离体组织张力测量技术,得出各肌条对胃泌素和胃动素的剂量-反应曲线和最大收缩效应值(Emax)。结果各类肌条对胃泌素和胃动素产生了规律及强度明显不同的浓度-依赖性收缩。套索纤维对胃泌素的Emax值[(4.91±0.95)mN/mm2]显著高于钩状纤维[(0.72±0.14)mN/mm2]。套索纤维和钩状纤维对胃动素均产生较强的收缩反应[(3.61±0.65)mN/mm2和(2.64±0.33)mN/mm2]。结论人类食管下括约肌的套索纤维和钩状纤维对胃泌素和胃动素具有明显不同的反应特性。     

Properties of inhibitory junctional transmission in smooth muscle of the guinea pig lower esophageal sphincter

Inhibitory neurotransmission in guinea pig lower esophageal sphincter (LES) muscles was investigated by using electrophysiological methods. Transmural nerve stimulation (TNS) initiated an inhibitory junction potential (i.j.p.); the amplitude increased 35% by atropine (10(-6) M) and converted to a muscarinic excitatory junction potential (e.j.p.) by apamin (10(-7) M) plus Nomega-nitro-L-arginine (L-NNA, 10(-5) M). In atropinized tissue, the i.j.p. amplitude was reduced 58% by guanethidine (5 x 10(-6) M), 41% by L-NNA (10(-5) M), 57% by suramin (10(-4) M), and it was abolished by apamin (10(-7) M), suggesting that this potential was produced by ATP and nitric oxide (NO) released from adrenergic and nitrergic nerves, respectively, through the activation of Ca2+-sensitive K+ channels.Hyperpolarizations produced by ATP and NO were inhibited by apamin. The i.j.p. amplitude was reduced after desensitizing the membrane with ATP. In atropinized tissue, TNS produced a relaxation that was reduced 15% by guanethidine (5 x 10(-6) M), 50% by L-NNA (10(-5) M), and 30% by apamin (10(-7) M). Thus the LES receives cholinergic excitatory and adrenergic and nitrergic inhibitory innervations; the latter two components contribute evenly to the i.j.p. generation. The relaxation is mainly produced by NO in a membrane potential-independent way.     

Regulation of the functional status of the lower esophageal sphincter with gastrointestinal hormones in cardiospasm and reflux esophagitis

A role of gastrointestinal hormones in the regulation of the lower esophageal sphincter was studied in 22 patients with cardiospasm and 21 with reflux esophagitis. The levels of gastrin, vasoactive intestinal polypeptide (VIP), glucagon, insulin, and c peptide were determined by radioactive assay before and after surgical treatment. In opposite abnormalities (cardiospasm and reflux esophagitis), there is a different degree of VIP secretion both at the beginning and after functional exercises. Before and after functional exercises, the level of VIP was higher than in those with cardiospasm. The value of VIP on fasting and after functional exercises may be an additional information to establish the diagnoses of cardiospasm and reflux esophagitis and to evaluate the efficiency of the treatment performed.