Rectal Prolapse: Age-Related Differences in Clinical Presentation and What Bothers Women Most.
Diseases of the colon and rectum
Regional Gastrointestinal Transit and Contractility Patterns Vary in Postural Orthostatic Tachycardia Syndrome (POTS).
Digestive diseases and sciences
BACKGROUND: Rectal prolapse has a diverse symptom profile that affects patients of all ages.OBJECTIVE: We sought to identify bothersome symptoms and clinical presentation that motivated rectal prolapse patients to seek care, characterize differences in symptom severity with age, and determine factors associated with bothersome symptoms.DESIGN: Retrospective analysis of a prospectively maintained registry.SETTINGS: Tertiary referral academic center.PATIENTS: 129 consecutive women with full thickness rectal prolapse.MAIN OUTCOME MEASURES: Primary bothersome symptoms, 5-item Cleveland Clinic/Wexner Fecal Incontinence questionnaire, 5-item Obstructed Defecation Syndrome questionnaire. Patients were categorized by age<65 vs. age?65 years.RESULTS: Cleveland Clinic/Wexner Fecal Incontinence score>9 was more common in older patients (87% vs 60%, p=.002). Obstructed Defecation Syndrome score>8 was more common in younger patients (57% vs 28%, p<.001). Older patients were more likely than younger patients to report bothersome symptoms of pain (38% vs 19%, p=.021) and bleeding (12% vs 2%, p=.046). Mucus discharge was reported by most patients (older, 72% vs younger, 66%, p=.54) but was bothersome for only 18%, regardless of age. Older patients had more severe prolapse expression than younger patients (at rest, 33% vs 11%; during activity, 26% vs 19%; only with defecation, 40% vs 64%, p=.006). Older patients were more likely to seek care within 6 months of prolapse onset (29% vs 11%, p=.056). Upon multivariable regression, increasing age, narcotic use and non-protracting prolapse at rest were associated with reporting pain as a primary complaint.LIMITATIONS: Single center; small sample size.CONCLUSIONS: Rectal prolapse-related bothersome symptoms and healthcare utilization differ by age. Although rectal pain is often not commonly associated with prolapse, it bothers many women and motivates older women to undergo evaluation. Patient-reported functional questionnaires may not reflect patients' primary concerns regarding specific symptoms and could benefit from supplementation with questionnaires to elicit individualized symptom priorities. See Video Abstract at http://links.lww.com/DCR/B492 .
View details for DOI 10.1097/DCR.0000000000001843
View details for PubMedID 33496475
Postoperative complications and recurrence rates after rectal prolapse surgery versus combined rectal prolapse and pelvic organ prolapse surgery.
International urogynecology journal
BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is an autonomic disorder that affects multiple organs, including the gastrointestinal system. These patients often have multiple GI complaints with a severe impact on their quality of life. GI dysmotility patterns in POTS remains poorly understood and difficult to manage.AIMS: The aim of this study was to investigate the diagnostic yield of wireless motility capsule in patients with gastrointestinal symptoms and POTS, with use of a symptomatic control group without POTS as a reference.METHODS: We retrospectively reviewed the charts of patients who had both autonomic testing and wireless motility capsule between 2016 and 2020. The two groups were divided into those with POTS and those without POTS (controls) as diagnosed through autonomic testing. We compared the regional transit times and motility patterns between the two groups using the data collected from wireless motility capsule.RESULTS: A total of 25% of POTS patients had delayed small bowel transit compared to 0% of non-POTS patients (p=0.047). POTS patients exhibited hypo-contractility patterns within the small bowel, including decreased contractions/min (2.95 vs. 4.22, p=0.011) and decreased motility index (101.36 vs. 182.11, p=0.021). In multivariable linear regression analysis, migraine predicted faster small bowel transit (p=0.007) and presence of POTS predicted slower small bowel transit (p=0.044).CONCLUSIONS: Motility abnormalities among POTS patients seem to affect mostly the small bowel and exhibit a general hypo-contractility pattern. Wireless motility capsule can be a helpful tool in patients with POTS and GI symptoms as it can potentially help guide treatment.
View details for DOI 10.1007/s10620-020-06808-z
View details for PubMedID 33428036
Coronavirus Testing Before Motility Laboratory Procedures: An Update.
The American journal of gastroenterology
American Neurogastroenterology and Motility Society Task Force Recommendations for Resumption of Motility Laboratory Operations During the COVID-19 Pandemic.
The American journal of gastroenterology
Our primary objectives were to compare < 30-day postoperative complications and RP recurrence rates after RP-only surgery and combined surgery. Our secondary objectives were to determine preoperative predictors of < 30-day complications and RP recurrence.A prospective IRB-approved cohort study was performed at a single tertiary care center from 2017 to 2020. Female patients with symptomatic RP underwent either RP-only surgery or combined surgery based on the discretion of the colorectal and FPMRS surgeons. Primary outcome measures were?< 30-day complications separated into Clavien-Dindo (CD) classes and rectal prolapse on physical examination.Seventy women had RP-only surgery and 45 had combined surgery with a mean follow-up time of 208 days. Sixty-eight percent underwent abdominal RP repair, and 32% underwent perineal RP repair. Twenty percent had one or more complications, 14% in the RP-only group and 29% in the combined surgery group (p?=?0.06). On multivariate analysis, combined surgery patients had a 30% increased risk of complications compared to RP-only surgery patients (RR?=?1.3). Most of these complications were minor (14/17, 82.4%) and categorized as CD I or II, including urinary retention and UTI. Twelve percent of this cohort had RP recurrence, 11% in the RP-only group and 13% in the combined surgery group (p?=?0.76). Preoperative risk factors for RP recurrence included a primary complaint of rectal bleeding (RR 5.5) and reporting stools consistent with Bristol Stool Scale of 1 (RR 2.1).Patients undergoing combined RP?+?POP surgery had a higher risk of complications and equivalent RP recurrence rates compared to patients undergoing RP-only surgery.
View details for DOI 10.1007/s00192-021-04778-y
View details for PubMedID 33864476
Abnormal Balloon Expulsion Test in Patients with Fecal Incontinence.
Journal of gastrointestinal and liver diseases : JGLD
The American Neurogastroenterology and Motility Society Task Force recommends that gastrointestinal motility procedures should be performed in motility laboratories adhering to the strict recommendations and personal protective equipment (PPE) measures to protect patients, ancillary staff, and motility allied health professionals. When available and within constraints of institutional guidelines, it is preferable for patients scheduled for motility procedures to complete a coronavirus disease 2019 (COVID-19) test within 48 hours before their procedure, similar to the recommendations before endoscopy made by gastroenterology societies. COVID-19 test results must be documented before performing procedures. If procedures are to be performed without a COVID-19 test, full PPE use is recommended, along with all social distancing and infection control measures. Because patients with suspected motility disorders may require multiple procedures, sequential scheduling of procedures should be considered to minimize need for repeat COVID-19 testing. The strategies for and timing of procedure(s) should be adapted, taking into consideration local institutional standards, with the provision for screening without testing in low prevalence areas. If tested positive for COVID-19, subsequent negative testing may be required before scheduling a motility procedure (timing is variable). Specific recommendations for each motility procedure including triaging, indications, PPE use, and alternatives to motility procedures are detailed in the document. These recommendations may evolve as understanding of virus transmission and prevalence of COVID-19 infection in the community changes over the upcoming months.
View details for DOI 10.14309/ajg.0000000000000823
View details for PubMedID 32868631
Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea.
Digestive diseases and sciences
BACKGROUND AND AIMS: Functional defecatory dysfunction is attributed to the pathophysiology of fecal incontinence (FI) in some patients. We hypothesized that patients with FI and abnormal balloon expulsion test (BET) have distinct manometric characteristics as compared to the patients with FI and normal BET. We aimed to compare the anorectal pressure profile in patients with FI, with or without abnormal BET and to identify risk factors associated with abnormal BET in FI.METHODS: We performed a retrospective review of 77 consecutive patients with ROME IV FI. Wilcoxon rank sum test, t-test, and Fisher exact tests were performed for comparison. Multivariable logistic regression was performed to identify factors associated with abnormal BET.RESULTS: Thirty-two percent of patients had abnormal BET. Demographics and surgical history and clinical symptoms, except for sensation of incomplete evacuation (p=0.02) and abdominal pain (p=0.03), were comparable in both groups. Anorectal pressure profile except for the median rectal propulsive pressures were similar between groups. Rectal propulsive pressures at simulated defecation were significantly lower in patients with abnormal BET (p=0.02). Mean sensory threshold for first sensation was also significantly higher in patients who had abnormal BET (p=0.03). Rectal propulsive pressures (OR: 1.03, 95% CI: 1.00-1.06, p=0.032) and rectal sensory threshold for first sensation (OR:0.94, 95% CI: 0.90-0.99, p=0.02) were able to predict abnormal BET independently.CONCLUSIONS: In patients with FI and similar clinical and anal pressure profile, rectal sensory threshold and rectal propulsive pressures at simulated defecation can determine normal BET.
View details for DOI 10.15403/jgld-2273
View details for PubMedID 32830814
Pelvic Floor Disorders and Functional Anorectal Pain
DIAGNOSIS AND MANAGEMENT GUIDE FOR ANORECTAL DISEASE: A CLINICAL REFERENCE
Rectal Distension Increased the Rectoanal Gradient in Patients with Normal Rectal Sensory Function.
Digestive diseases and sciences
BACKGROUND: Many anti-nausea treatments are available for chronic gastrointestinal syndromes, but data on efficacy and comparative effectiveness are sparse.AIMS: To conduct a sectional survey study of patients with chronic nausea to assess comparative effectiveness of commonly used anti-nausea treatments.METHODS: Outpatients at a single center presenting for gastroenterology evaluation were asked to rate anti-nausea efficacy on a scale of 0 (no efficacy) to 5 (very effective) of 29 commonly used anti-nausea treatments and provide other information about their symptoms. Additional information was collected from the patients' chart. The primary outcome was to determine which treatments were better or worse than average using a t test. The secondary outcome was to assess differential response by individual patient characteristics using multiple linear regression.RESULTS: One hundred and fifty-three patients completed the survey. The mean efficacy score of all anti-nausea treatments evaluated was 1.73. After adjustment, three treatments had scores statically higher than the mean, including marijuana (2.75, p<0.0001), ondansetron (2.64, p<0.0001), and promethazine (2.46, p<0.0001). Several treatments, including many neuromodulators, complementary and alternative treatments, erythromycin, and diphenhydramine had scores statistically below average. Patients with more severe nausea responded better to marijuana (p=0.036) and diphenhydramine (p<0.001) and less so to metoclopramide (p=0.020). There was otherwise no significant differential response by age, gender, nausea localization, underlying gastrointestinal cause of nausea, and GCSI.CONCLUSIONS: When treating nausea in patients with chronic gastrointestinal syndromes, clinicians may consider trying higher performing treatments first, and forgoing lower performing treatments. Further prospective research is needed, particularly with respect to highly effective treatments.
View details for DOI 10.1007/s10620-020-06195-5
View details for PubMedID 32185665
High Prevalence of Slow Transit Constipation in Patients With Gastroparesis
JOURNAL OF NEUROGASTROENTEROLOGY AND MOTILITY
2019; 25 (2): 267?75
High Prevalence of Slow Transit Constipation in Patients With Gastroparesis.
Journal of neurogastroenterology and motility
Frequent observation of abnormal manometric patterns consistent with dyssynergia in healthy volunteers has warranted the need for reassessment of the current methods to enhance the diagnostic value of anorectal manometry in functional defecatory disorders. Whether rectal distention at simulated evacuation will affect anorectal pressure profile and increase rectoanal gradient is not known.One hundred and eight consecutive patients with chronic constipation, 93 females, median age 53 years (interquartile range: 40-65), were studied. Simulated evacuation was performed firstly with empty balloon and subsequently after balloon distention to 50 and 100 ml. Anorectal pressures were compared. We also performed subgroup analysis in relation to outcome of balloon expulsion test (BET). In addition, we studied the effect of rectal distension on the rectoanal pressure gradient with respect to rectal sensory function.Rectal balloon distension at simulated evacuation improved rectoanal gradient and decreased the rate of dyssynergia during high-resolution anorectal manometry. In subgroup analysis, the increase in rectoanal gradient and correction of dyssynergia with rectal distension was limited to the patients who had normal BET and normal rectal sensory function. Rate of anal relaxation, residual anal pressures, and rectoanal gradient were significantly different between patients with and without normal BET at 50 ml of rectal distension. Rectoanal gradient recorded only after rectal distension, along with BMI and maximum tolerable volumes, could predict BET results independently in patients with chronic constipation.Rectal distension during simulated evacuation will affect the anorectal pressure profile. Increase in rectoanal gradient and correction of dyssynergia was only significant in patients with normal rectal sensory function and normal BET.
View details for DOI 10.1007/s10620-020-06519-5
View details for PubMedID 32761289
Neural control properties of the external anal sphincter in young and elderly women.
Neurourology and urodynamics
Background/Aims: Current evidence suggests the presence of motility or functional abnormalities in one area of the gastrointestinal tract increases the likelihood of abnormalities in others. However, the relationship of gastroparesis to chronic constipation (slow transit constipation and dyssynergic defecation) has been incompletely evaluated.Methods: We retrospectively reviewed the records of all patients with chronic dyspeptic symptoms and constipation who underwent both a solid gastric emptying scintigraphy and a highresolution anorectal manometry at our institution since January 2012. When available, Xray defecography and radiopaque marker colonic transit studies were also reviewed. Based on the gastric emptying results, patients were classified as gastroparesis or dyspepsia with normal gastric emptying (control group). Differences in anorectal and colonic findings were then compared between groups.Results: Two hundred and six patients met the inclusion criteria. Patients with gastroparesis had higher prevalence of slow transit constipation by radiopaque marker study compared to those with normal emptying (64.7% vs 28.1%, P = 0.013). Additionally, patients with gastroparesis had higher rates of rectocele (88.9% vs 60.0%, P = 0.008) and intussusception (44.4% vs 12.0%, P = 0.001) compared to patients with normal emptying. There was no difference in the rate of dyssynergic defecation between those with gastroparesis vs normal emptying (41.1% vs 42.1%, P = 0.880), and no differences in anorectal manometry findings.Conclusions: Patients with gastroparesis had a higher rate of slow transit constipation, but equal rates of dyssynergic defecation compared to patients with normal gastric emptying. These findings argue for investigation of possible delayed colonic transit in patients with gastroparesis and vice versa.
View details for PubMedID 30870880
The assessment and management of defecatory dysfunction: a critical appraisal.
Current opinion in gastroenterology
The prevalence of fecal incontinence (FI) increases with age and affects more than 15% of the elderly population. Sarcopenia, skeletal muscle structural, and functional decline with aging, is known to be caused by neuromuscular dysfunction. However, age-related alterations of the neuromuscular function of the external anal sphincter (EAS) have not been studied. This study aims to quantitatively characterize the effect of aging on the EAS by assessing the firing patterns and size of motor unit action potential (MUAP) using high-density surface electromyography (HD-sEMG) recording and analysis techniques.Thirteen young (31.0?±?3.6 years) and 14 elderly (64.3?±?6.2 years) healthy women were recruited for this study. EMG activity of the EAS during maximal voluntary contraction was recorded by a 64-Channel, HD-sEMG intra-rectal probe. HD-sEMG signals were decomposed into MUAP spike trains to extract the firing rate and amplitudes thereof.HD-sEMG decomposition was successfully performed. For the young and elderly groups, mean motor unit (MU) firing rates of 11.4?±?2.1 pulses per second (PPS) and 9.6?±?2.3 PPS, and mean MUAP amplitudes of 45.2?±?14.3?µV and 61.9?±?21.2?µV were respectively obtained. Both the MU firing rate and MUAP amplitude were significantly different between two groups (P?.05). Moreover, the MUAP firing rate and amplitude correlated with age with a linear regression model (P?.05).This study represents the first effort to examine the effect of aging on the neuromuscular function of EAS. Results suggest an age-related impairment of lower motor neuron descending excitation to the EAS with a compensatory increase in mean MU size.
View details for DOI 10.1002/nau.24108
View details for PubMedID 31321803
Irritable bowel syndrome (IBS) patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity.
American journal of physiology. Gastrointestinal and liver physiology
To summarize the advances in diagnostic modalities and management options for defecatory dysfunction and highlight the areas in need of further research.The diagnostic utility of high-resolution anorectal manometry (ARM), which has emerged as a promising tool for the diagnosis of defecatory dysfunction, appears to be questionable in differentiating disease from normal physiology. There also seems to be discrepancy between results of various tests of anorectal function in the diagnosis of defecatory dysfunction. New revisions in diagnostic criteria for defecatory dysfunction by Rome IV consortium, may enhance its diagnostic yield. Biofeedback remains to be the most effective evidence-based treatment option for patients with defecatory dysfunction. Anorectal pressure profile cannot predict or mediate the success of biofeedback. Biofeedback may improve the symptoms through central effects.Despite the advances in the ARM and defecography techniques, no one test has been able to be considered as the 'gold standard' for diagnosis of defecatory dysfunction. The mechanism of action of biofeedback in defecatory dysfunction remains poorly understood.
View details for PubMedID 29064840
A rare cause of an upper gastrointestinal bleed.
Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection A Multicenter Experience
JOURNAL OF CLINICAL GASTROENTEROLOGY
2016; 50 (5): 398-402
The SCN5A-encoded voltage-gated mechanosensitive sodium (Na+) channel NaV1.5 is expressed in human GI smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominately Caucasian IBS patient cohorts, 2-3% have SCN5A missense mutations which alter NaV1.5 function and may contribute to IBS pathophysiology. In this study examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, and compared them to IBS negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and co-transfected with GFP into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 IBS patients (2.0%) had six rare SCN5A mutations, which were absent in 377 IBS-negative controls. All (6/6, 100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities: current density reduction (R225W, R433C, R986Q, F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, F1293S) and at least one kinetic parameter was altered in all mutations. Four IBS-associated SCN5A mutations (4/6, 67%) resulted in altered NaV1.5 mechanosensitivity (R225W, R433C, R986Q, F1293S). In this racially and ethnically diverse cohort of IBS patients we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function.
View details for DOI 10.1152/ajpgi.00016.2017
View details for PubMedID 29167113
Advancing treatment options for chronic idiopathic constipation
EXPERT OPINION ON PHARMACOTHERAPY
2016; 17 (4): 501-511
Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI).FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated.A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms.A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (?90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (?90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred.FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively.
View details for Web of Science ID 000375032900010
View details for PubMedID 26125460
Neurogenic Bowel Dysfunction in Patients with Neurogenic Bladder.
Current bladder dysfunction reports
2016; 11 (4): 334?40
Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating.The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation.Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge.
View details for DOI 10.1517/14656566.2016.1127356
View details for Web of Science ID 000370759000001
View details for PubMedID 26630260
Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2015; 309 (6): G506-G512
Patients with primary neurologic conditions often experience urinary and bowel dysfunction due to loss of sensory and/or motor control. Neurogenic bowel dysfunction is frequently characterized by both constipation and fecal incontinence. In general, the management of neurogenic bowel dysfunction has been less well studied than bladder dysfunction despite their close association.. It is widely accepted that establishment of a multifaceted bowel regimen is the cornerstone of conservative management. Continuing assessment is necessary to determine need for more invasive interventions. In the clinical setting, the Urologist may be the principle provider addressing bowel concerns in addition to bladder dysfunction, and furthermore, treatment of one often impacts the other. Future directions should include development of follow up and management guidelines that address the comprehensive care of this patient population.
View details for PubMedID 28717406
A Hidden Cause of Dysphagia. Primary Esophageal Lymphoma.
2015; 149 (3): 549-550
Abdominal Pain and Bloating in an Auto Mechanic
2014; 146 (7): 1610-1611
Distinct modulation of K-v1.2 channel gating by wild type, but not open form, of syntaxin-1A
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2007; 292 (5): G1233-G1242
Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel NaV1.5. NaV1.5 contributes to small bowel excitability, and NaV1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na(+) current in the human colon smooth muscle and to examine the effects of ranolazine on Na(+) current, mechanosensitivity, and smooth muscle contractility. Inward currents were recorded by whole cell voltage clamp from freshly dissociated human colon SMCs at rest and with shear stress. SCN5A mRNA and NaV1.5 protein were examined by RT-PCR and Western blots, respectively. Ascending human colon strip contractility was examined in a muscle bath preparation. SCN5A mRNA and NaV1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na(+) currents (-1.36 ± 0.36 pA/pF), shear stress increased Na(+) peaks by 17.8 ± 1.8% and accelerated the time to peak activation by 0.7 ± 0.3 ms. Ranolazine (50 ?M) blocked peak Na(+) current by 43.2 ± 9.3% and inhibited shear sensitivity by 25.2 ± 3.2%. In human ascending colon strips, ranolazine decreased resting tension (31%), reduced the frequency of spontaneous events (68%), and decreased the response to smooth muscle electrical field stimulation (61%). In conclusion, SCN5A-encoded NaV1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na(+) current in human colon SMCs and decreases contractility of human colon muscle strips. Our data provide a likely mechanistic explanation for constipation induced by ranolazine.
View details for DOI 10.1152/ajpgi.00051.2015
View details for Web of Science ID 000361817700011
View details for PubMedID 26185330
View details for PubMedCentralID PMC4572410
Calcium source diversity in feline lower esophageal sphincter circular and sling muscle
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2004; 286 (2): G271-G277
SNARE proteins, syntaxin-1A (Syn-1A) and SNAP-25, inhibit delayed rectifier K(+) channels, K(v)1.1 and K(v)2.1, in secretory cells. We showed previously that the mutant open conformation of Syn-1A (Syn-1A L165A/E166A) inhibits K(v)2.1 channels more optimally than wild-type Syn-1A. In this report we examined whether Syn-1A in its wild-type and open conformations would exhibit similar differential actions on the gating of K(v)1.2, a major delayed rectifier K(+) channel in nonsecretory smooth muscle cells and some neuronal tissues. In coexpression and acute dialysis studies, wild-type Syn-1A inhibited K(v)1.2 current magnitude. Of interest, wild-type Syn-1A caused a right shift in the activation curves of K(v)1.2 without affecting its steady-state availability, an inhibition profile opposite to its effects on K(v)2.1 (steady-state availability reduction without changes in voltage dependence of activation). Also, although both wild-type and open-form Syn-1A bound equally well to K(v)1.2 in an expression system, open-form Syn-1A failed to reduce K(v)1.2 current magnitude or affect its gating. This is in contrast to the reported more potent effect of open-form Syn-1A on K(v)2.1 channels in secretory cells. This finding together with the absence of Munc18 and/or 13-1 in smooth muscles suggested that a change to an open conformation Syn-1A, normally facilitated by Munc18/13-1, is not required in nonsecretory smooth muscle cells. Taken together with previous reports, our results demonstrate the multiplicity of gating inhibition of different K(v) channels by Syn-1A and is compatible with versatility of Syn-1A modulation of repolarization in various secretory and nonsecretory (smooth muscle) cell types.
View details for DOI 10.1152/ajpgi.00473.2006
View details for Web of Science ID 000247935800007
View details for PubMedID 17234891
Within muscular equivalents of cat lower esophageal sphincter (LES), the circular muscle develops greater spontaneous tone, whereas the sling muscle is more responsive to cholinergic stimulation. Smooth muscle contraction involves a combination of calcium release from stores and of calcium entry via several pathways. We hypothesized that there are differences in the sources of Ca(2+) used for contraction in sling and circular muscles and that these differences could contribute to functional asymmetry observed within LES. Contraction of muscle strips from circular and sling regions of LES was assessed in the presence of TTX. In Ca(2+)-free Krebs, tone was inhibited to a greater degree in circular than sling muscle. L-type Ca(2+) channel blockade with nifedipine or verapamil inhibited tone in LES circular but not sling muscle. Sarcoplasmic reticulum (SR) Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) caused greater increase in tone in sling than in circular muscle. The phospholipase C inhibitor U-73122 and the SR inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptor blocker 2-aminoethoxydiphenyl borate (2-APB) inhibited tone in circular and sling muscles, demonstrating that continuous release of Ca(2+) from Ins(1,4,5)P(3)-sensitive stores is important in tone generation in both muscles. In Ca(2+)-free Krebs, ACh-induced contractions (AChC) were inhibited to a greater degree in sling than circular muscles. However, nifedipine and verapamil greatly inhibited AChC in the circular but not sling muscle. Depletion of SR Ca(2+) stores with CPA or inhibition of Ins(1,4,5)P(3)-mediated store release with either U-73122 or 2-APB inhibited AChC in both muscles. We demonstrate that LES circular and sling muscles 1) use intracellular and extracellular Ca(2+) sources to different degrees in the generation of spontaneous tone and AChC and 2) use different Ca(2+) entry pathways. These differences hold the potential for selective modulation of LES tone in health and disease.
View details for DOI 10.1152/ajpgi.00291.2003
View details for Web of Science ID 000188002500011
View details for PubMedID 14563670