Yanfen Jiang

A Unique Esophageal Motor Pattern That Involves Longitudinal Muscles is Responsible for Emptying in Achalasia Esophagus

BACKGROUND & AIMS Achalasia esophagus is characterized by loss of peristalsis and incomplete esophagogastric junction (EGJ) relaxation. We studied mechanisms of esophageal emptying in patients with achalasia using simultaneous high-resolution manometry, multiple intraluminal impedance, and high-frequency intraluminal ultrasonography image recordings. METHODS Achalasia was categorized into 3 subtypes, based on the esophageal response to swallows: types 1 and 2 were defined by simultaneous pressure waves of <30 mm Hg and >30 mm Hg, respectively, and type 3 was defined by spastic simultaneous esophageal contractions. RESULTS Based on high-resolution manometry, the predominant achalasia pattern of type 2 was characterized by a unique motor pattern that consisted of upper esophageal sphincter contraction, simultaneous esophageal pressure (pan-esophageal pressurization), and EGJ contraction following swallows. High-frequency intraluminal ultrasonography identified longitudinal muscle contraction of the distal esophagus as the cause of pan-esophageal pressurization in type 2 achalasia. Multiple intraluminal impedance revealed that esophageal emptying occurred intermittently (36% swallows) during periods of pan-esophageal pressurization. Patients with achalasia of types 1 and 3 had no emptying or relatively normal emptying during most swallows, respectively. CONCLUSIONS In achalasia, esophageal emptying results from swallow-induced longitudinal muscle contraction of the distal esophagus, which increases esophageal pressure and allows flow across the nonrelaxed EGJ.

Comparison of the pharmacological properties of EDHF-mediated vasorelaxation in guinea-pig cerebral and mesenteric resistance vessels

In the presence of L‐NNA (100 μM), indomethacin (10 μM) and ODQ (10 μM), acetylcholine induced a concentration‐dependent vasorelaxation of guinea‐pig mesenteric and middle cerebral arteries precontracted with cirazoline or histamine, but not with high K+, indicating the contribution of an endothelium‐derived hyperpolarizing factor (EDHF). In cerebral arteries, charybdotoxin (ChTX; 0.1 μM) completely inhibited the indomethacin, L‐NNA and ODQ‐insensitive relaxation; iberiotoxin (IbTX, 0.1 μM), 4‐aminopyridine (4‐AP, 1 mM), or barium (30 μM) significantly reduced the response; in the mesenteric artery, ChTX and IbTX also reduced this relaxation. Glibenclamide (10 μM) had no affect in either the mesenteric or cerebral artery. Neither clotrimazole (1 μM) nor 7‐ethoxyresorufin (3 μM) affected EDHF‐mediated relaxation in the mesenteric artery, but abolished or attenuated EDHF‐mediated relaxations in the cerebral artery. AM404 (30 μM), a selective anandamide transport inhibitor, did not affect the vasorelaxation response to acetylcholine in the cerebral artery, but in the mesenteric artery potentiated the vasorelaxation response to acetylcholine in an IbTX, and apamin‐sensitive, but SR 141816A‐insensitive manner. Ouabain (100 μM) almost abolished EDHF‐mediated relaxation in the mesenteric artery, but enhanced the relaxation in the cerebral artery whereas the addition of K+ (5–20 mM) to precontracted guinea‐pig cerebral or mesenteric artery induced further vasoconstriction. These data suggest that in the guinea‐pig mesenteric and cerebral arteries different EDHFs mediate acetylcholine‐induced relaxation, however, EDHF is unlikely to be mediated by K+.

Vascular dysfunction in type 2 diabetic TallyHo mice: Role for an increase in the contribution of PGH2/TxA2 receptor activation and cytochrome p450 products

In this study, we tested the hypothesis that spontaneously diabetic TallyHo (TH) mice, a novel polygenic model for type 2 diabetes, will exhibit endothelial dysfunction associated with an increased contribution from endothelium-derived contractile factors (EDCF). The cellular mechanisms underlying the increased contribution of EDCF were explored in 16 and 30-week-old male TH and age-matched male C57BL/6J mice (n=4-9). Blood glucose and serum lipid profiles were markedly increased in the TH mice. Superoxide generation, assessed with a lucigenin chemiluminescence assay, was markedly increased in the aortae of TH mice. Endothelium-dependent vascular relaxations and contractions to acetylcholine (ACh), but not endothelium-independent relaxations to sodium nitroprusside, were impaired and vascular contractions to phenylephrine were significantly enhanced in aortae from TH mice. Nomega-nitro-L-arginine methyl ester markedly increased the ACh-induced contractions in TH mice, whereas SQ29548, a thromboxane receptor antagonist, and cytochrome P450 (CYP) inhibitors 17-octadecynoic acid and sulfaphenazole, the latter being specific for CYP2C6 and 2C9, decreased and (or) normalized the contractile response to ACh in TH mice. The present study indicates that enhanced contribution of prostaglandin H2/thromboxane A2 receptor and CYP, likely CYP2C6 and 2C9, play a critical role in the pathogenesis of increased EDCF in the aortae of type 2 diabetic TH mice.

Length-tension relationship of the external anal sphincter muscle: implications for the anal canal function

The length at which a muscle operates in vivo (operational length) and the length at which it generates maximal force (optimal length) may be quite different. We studied active and passive length-tension characteristics of external anal sphincter (EAS) in vivo and in vitro to determine the optimal and operational length of rabbit EAS. For the in vitro studies, rings of EAS (n = 4) were prepared and studied in a muscle bath under isometric conditions. For in vivo studies, female rabbits (n = 19) were anesthetized and anal canal pressure was recorded by use of a sleeve sensor placed in the custom-designed catheter holders of 4.5-, 6-, and 9-mm diameters. Measurements were obtained at rest and during EAS electrical stimulation. Sarcomere length of EAS muscle was measured by laser diffraction technique with no probe and three probes in the anal canal. In vitro studies revealed 2,054 mN/cm(2) active tension at optimal length. In vivo studies revealed a probe size-dependent increase in anal canal pressure and tension. Maximal increase in anal canal tension with stimulation was recorded with the 9-mm probe. Increases in anal canal tension with increase in probe size were completely abolished by pancuronium bromide. EAS muscle sarcomere length without and with 9-mm probe in the anal canal were 2.11 +/- 0.08 and 2.99 +/- 0.07 microm, respectively. Optimal sarcomere length, based on the thin filament length measured by thin filament analysis, is 2.44 +/- 0.10 microm. These data show that the operational length of EAS is significantly shorter than its optimal length. Our findings provide insight into EAS function and we propose the possibility of increasing anal canal pressure by surgical manipulation of the EAS sarcomere length.

Antireflux Action of Nissen Fundoplication and Stretch-Sensitive Mechanism of Lower Esophageal Sphincter Relaxation

BACKGROUND & AIMS Surgical fundoplication is an effective treatment for gastroesophageal reflux disease. One of the proposed mechanisms for its antireflux action is that it reduces lower esophageal sphincter (LES) relaxation. We investigated whether fundoplication works through a stretch-sensitive mechanism of LES relaxation. METHODS Studies were performed in rats. Intravenous and arterial lines were placed and tracheal intubation was performed. A midline laprotomy was performed to place sutures through the esophagus to exert axial stretch on the LES, and the vagus nerve was isolated in the neck for electrical stimulation. The LES pressure was monitored with a 2F solid-state pressure transducer placed through a gastrostomy. Cranial displacement of the LES was recorded using piezoelectric crystals. Data were recorded before and after 360-degree Nissen fundoplication. RESULTS Axial stretch and vagus nerve stimulation induced cranial displacement of the LES as well as LES relaxation in a dose-dependent manner. LES relaxation and axial stretch were each significantly reduced after fundoplication (P < .01). Nitric-oxide-induced LES relaxation was not affected by fundoplication. Removal of fundoplication restored axial stretch- and vagus nerve-stimulated LES relaxation as well as LES cranial displacement. CONCLUSIONS Fundoplication reduces LES relaxation by interfering with axial stretch on the LES. Based on this mechanism of the antireflux actions of fundoplication, it might be possible to design new surgical strategies to treat reflux disease and reduce complications of fundoplication surgery.

Effect of esophageal contraction on esophageal wall blood perfusion

Myocardial blood flow occurs during the diastolic phase of the cardiac cycle, because myocardial contraction during the systolic phase impedes myocardial perfusion. Using laser Doppler perfusion technique, we studied the effect of esophageal contraction on the esophageal wall perfusion. Studies were conducted in rats. A laser Doppler probe was anchored to the esophageal wall, and wall perfusion was studied under various experimental conditions. Increase and decrease in the systemic blood pressure induced by different pharmacological agents was associated with the increase and decrease in the esophageal wall perfusion, respectively. Esophageal contractions induced by electrical stimulation of the vagus nerve and electrical stimulation of the muscle directly resulted in a reduction in the esophageal wall perfusion, in a dose-dependent fashion. Esophageal wall perfusion could be monitored by placing the Doppler probe on the esophageal mucosa or on the outside of the esophageal wall. Esophageal contraction impedes entry of blood into the esophageal wall. Future studies may investigate if ischemia of the esophageal wall induced by sustained esophageal contractions/esophageal spasm is the cause of esophageal pain symptoms in humans.

Anatomical disruption and length-tension dysfunction of anal sphincter complex muscles in women with fecal incontinence.

BACKGROUND: Anal sphincter complex muscles, the internal anal sphincter, external anal sphincter, and puborectalis muscles, play an important role in the anal continence mechanism. Patients with symptoms of fecal incontinence have weak anal sphincter complex muscles; however, their length-tension properties and relationship to anatomical disruption have never been studied. OBJECTIVE: This study aimed to assess the anatomy of the anal sphincter complex muscles with the use of a 3-dimensional ultrasound imaging system and to determine the relationship between the anatomical defects and the length-tension property of external anal sphincter and puborectalis muscles in women with incontinence symptoms and in control subjects. DESIGN: Severity of anal sphincter muscle damage was determined by static and dynamic 3-dimensional ultrasound imaging. The length-tension property was determined by anal and vaginal pressure with the use of custom-designed probes. PATIENTS: Forty-four asymptomatic controls and 24 incontinent patients participated in this study. MAIN OUTCOME MEASURES: The anatomical defects and length-tension dysfunction of anal sphincter complex muscles in patients with fecal incontinence were evaluated. RESULTS: The prevalence of injury to sphincter muscles is significantly greater in the incontinent patients than in the controls. Eighty-five percent of patients but only 9% controls reveal damage to ≥2 of the 3 muscles of the anal sphincter complex. Anal and vaginal squeeze pressures increased with the increase in the probe size (length-tension curve) in the majority of controls. In patients, the increase in anal and vaginal squeeze pressures was either significantly smaller than in controls or it decreased with the increasing probe size (abnormal length-tension). LIMITATIONS: We studied patients with severe symptoms. Whether our findings are applicable to patients with mild to moderate symptoms remains to be determined. CONCLUSIONS: The length-tension property of the external anal sphincter and puborectalis muscles is significantly impaired in incontinent patients. Our findings have therapeutic implications for the treatment of anal incontinence.

Novel applications of external anal sphincter muscle sarcomere length to enhance the anal canal function

Background  Our recent studies show that the external anal sphincter muscle (EAS) operates at a sarcomere length range which is below optimal. In this study, we tested the hypothesis that by surgically increasing sarcomere length and bringing it close to the optimal length, EAS muscle function and anal canal pressure can be enhanced.

Inhibitory motor neurons of the esophageal myenteric plexus are mechanosensitive

Mechanosensitivity of enteric neurons has been reported in the small intestine and colon, but not in the esophagus. Our earlier in vivo studies show that mechanical stretch of the esophagus in the axial direction induces neurally mediated relaxation of the lower esophageal sphincter, possibly through mechanosensitive motor neurons. However, this novel notion that the motor neurons are mechanosensitive has not been examined in isolated esophageal myenteric motor neurons. The goal of our present study was to examine the mechanosensitivity of esophageal motor neurons in primary culture and elucidate the underlying molecular mechanisms. Immmunocytochemical analysis revealed that >95% cells were positive for the neuronal marker protein gene product 9.5 and that 66% of these cells costained with protein gene product 9.5 and neuronal nitric oxide (NO) synthase. Hypotonic solution induced an increase in the cytoplasm volume in all cells that was independent of extracellular Ca(2+). Hypotonic solution and mechanical stretch induced cytoplasmic free Ca(2+) signaling in ~65% of neurons in the presence, but not absence, of extracellular Ca(2+). Neurons grown on the elastic membrane responded to mechanical stretch by an increase in neuronal size and Ca(2+) signaling simultaneously. Hypotonic stretch-induced cytoplasmic free Ca(2+) signaling was not affected by extracellular Mg(2+), 5-nitro-2-(3-phenylpropylamino)benzoic acid, and nifedipine but was attenuated by 2-aminoethoxydiphenyl borate, Gd(3+), and Grammostola mechanotoxin 4, blockers of the stretch-activated ion channels. In ~57% of the neurons, hypotonic stretch also induced Ca(2+)-dependent cytoplasmic NO production, which was abolished by Grammostola mechanotoxin 4. These results prove that the esophageal inhibitory motor neurons possess a mechanosensitive property and also provide novel insights into the stretch-activated ion channel-Ca(2+)-NO signaling pathway in these neurons.

Esophageal wall blood perfusion during contraction and transient lower esophageal sphincter relaxation in humans

We recently reported that esophageal contraction reduces esophageal wall perfusion in an animal study. Our aim was to determine esophageal wall blood perfusion (EWBP) during esophageal contraction and transient lower esophageal sphincter relaxations (TLESRs) in humans. We studied 12 healthy volunteers. A custom-designed laser Doppler probe was anchored to the esophageal wall, 4-6 cm above the LES, by use of the Bravo pH system so that the laser light beam stay directed toward the esophageal mucosa. A high-resolution manometry equipped with impedance electrodes recorded esophageal pressures and reflux events. Synchronized pressure, impedance, pH, and EWBP recordings were obtained during dry and wet swallows and following a meal. Stable recordings of laser Doppler EWBP were only recorded when the laser Doppler probe was firmly anchored to the esophageal wall. Esophageal contractions induced by dry and wet swallows resulted in 46 ± 9% and 60 ± 10% reduction in the EWBP, respectively (compared to baseline). Reduction in EWBP was directly related to the amplitude (curvilinear fit) and duration of esophageal contraction. Atropine reduced the esophageal contraction amplitude and decreased the EWBP reduction associated with esophageal contraction. TLESRs were also associated with reduction in the EWBP, albeit of smaller amplitude (29 ± 3%) but longer duration (19 ± 2 s) compared with swallow-induced esophageal contractions. We report 1) an innovative technique to record EWBP for extended time periods in humans and 2) contraction of circular and longitudinal muscle during peristalsis and selective longitudinal muscle contraction during TLESR causes reduction in the EWBP; 3) using our innovative technique, future studies may determine whether esophageal wall ischemia is the cause of esophageal pain/heartburn.