H. Henry Lai

Loss of caveolin-1 expression is associated with disruption of muscarinic cholinergic activities in the urinary bladder

Caveolin-1 (Cav1), a structural protein of caveolae, plays cell- and context-dependent roles in signal transduction pathway regulation. We have generated a knockout mouse homozygous for a null mutation of the Cav1 gene. Cav1 knockout mice exhibited impaired urinary bladder contractions in vivo during cystometry. Contractions of male bladder strips were evoked with electric and pharmacologic stimulation (5-40 Hz, 1-10 microM carbachol, 10 mM alpha,beta-methylene ATP, 100 mM KCl). Acetylcholine (ACh) and norepinephrine (NE) release from bladder strips were measured with a radiochemical method by incubating the strips with 14C-choline and 3H-NE prior to electric stimulation, whereas ATP release was measured using the luciferin-luciferase assay with a luminometer. A 60-75% decline in contractility was observed when Cav1 knockout muscle strips were stimulated with electric current or carbachol, compared to wildtype muscle strips. No difference in contractility was noted when contractions were evoked either by the purinergic agonist alpha,beta-methylene ATP, or by extracellular potassium. To investigate the relative contribution of non-cholinergic activity to bladder contractility, the amplitude of the electric stimulation-evoked contractions was compared in the presence of the muscarinic antagonist atropine (1 microM). While the non-muscarinic (purinergic) response was unaltered, muscarinic cholinergic response was principally disrupted in Cav1 knockout mice. The loss of Cav1 gene expression was also associated with a 70% reduction in ACh release. NE and ATP release was not altered. It is concluded that the loss of caveolin-1 is associated with disruption of M3 muscarinic cholinergic activity in the bladder. Both pre-junctional (acetylcholine neurotransmitter release from neuromuscular junctions) and post-junctional (M3 receptor-mediated signal transduction in bladder smooth muscles) mechanisms are disrupted, resulting in impaired bladder contraction.

Activation of cholinergic receptors blocks non-adrenergic non-cholinergic contractions in the rat urinary bladder

In the present study, the plasticity of the non-adrenergic non-cholinergic (NANC) response was investigated. Isolated rat bladder strips were electrically stimulated and the evoked contractions were isometrically recorded. The NANC part of the contractions were unmasked by applying 500 nM 4-DAMP, a potent muscarinic antagonist. Treatment of the bladder strips with 10 microM carbachol (a cholinergic agonist) increased the muscle tone but did not alter the neurally evoked contractions. However, carbachol decreased: (1) the NANC response from 74.6% to 33.3% of control and (2) the purinergic contractile response to alpha,beta-methylene ATP (alpha,beta-mATP) (10 microM) from 97.0% to 43.4% (p<0.05). Treatment with the cholinesterase inhibitor eserine (10 microM) also significantly decreased the NANC response to 21.1% (p<0.0001). The purinergic receptor antagonist suramin (100 microM) did not affect the neurally evoked contractions, however; subsequent addition of 4-DAMP decreased the contractions to 31%. Activation of the smooth muscle cholinergic receptors (with carbachol or eserine) and purinergic receptors (with alpha,beta-mATP) decreased the NANC contractions and the direct contractile response to alpha,beta-mATP. When the electrically evoked contractions were facilitated by the L-type Ca2+ channel activator, Bay-K 8644 the subsequent application of 4-DAMP did not unmask inhibited NANC contractions. We conclude that activation of muscarinic receptors by cholinergic agonist, carbachol or by endogenous acetylcholine (ACh) induce a cascade of events that leads to diminished purinergic response and consequently an inhibition of the bladder NANC response.

Vasodepressor syncope due to subclinical myocardial ischemia.

Vasodepressor Syncope. Introduction: Vasodepressor syncope is a common cause of syncope, but the initiating event that triggers the vasodepressor response remains incompletely understood. Although ischemia due to acute right coronary occlusion may precipitate hypotension and bradycardia through the Bezold‐Jarisch reflex, an ischemic precipitant for the common vasodepressor faint has not been previously identified. In the present study, we present evidence for a causal relationship between myocardial ischemia and vasodepressor syncope.

Relationship between Chronic Non-Urological Associated Somatic Syndromes (NUAS) and Symptom Severity in Urological Chronic Pelvic Pain Syndromes: Baseline Evaluation of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study

PURPOSE We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria. MATERIALS AND METHODS Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors. RESULTS Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001). CONCLUSIONS Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes.

Pelvic radiotherapy does not increase the complication rates of artificial urinary sphincter implantation

Aims of Study Patients with pelvic radiotherapy (XRT) have impaired tissue healing capacity, small vessel occlusion and ischemia, and more complex etiology of incontinence secondary to detrusor hyperactivity and decreased compliance. It is unclear whether XRT increases the complication rates of artificial urinary sphincter (AUS) implantation for intrinsic sphincter deficiency (ISD) because of these adverse factors. Two recent publications revealed conflicting results (1, 2). We present the largest contemporary retrospective series to date to clarify the issue.

Relationship between Central Obesity, General Obesity, Overactive Bladder Syndrome and Urinary Incontinence Among Male and Female Patients Seeking Care for their Lower Urinary Tract Symptoms

OBJECTIVES To describe the relationship between metabolic factors and lower urinary tract symptoms, overactive bladder syndrome (OAB) and urinary incontinence (UI). METHODS Adult male and female patients who presented to a clinician from the symptoms of lower urinary tract dysfunction research network were recruited. Urinary symptoms (presence of OAB, any UI, stress UI (SUI), urgency UI (UUI), urgency, frequency, and nocturia) were assessed with the lower urinary tract symptoms tool. Metabolic factors assessed included central obesity (waist circumference, using the Adult Treatment Panel III, the International Diabetes Federation thresholds, and waist circumference as a continuous variable), general obesity (body mass index as dichotomous or continuous variables), diabetes mellitus, hypertension, and dyslipidemia. Multivariable logistic regression was used to test for associations. RESULTS 920 participants were studied. In multivariable analyses, central obesity (per 10 cm larger waist) was associated with higher odds of UI in both sexes (odds ratio [OR] = 1.16, P = .008), SUI in females (OR = 1.27, P = .008), UUI in both sexes (OR = 1.24, P = .001), OAB in females (OR = 1.248, P = .003), as well as frequency and nocturia. General obesity (5-unit increase in body mass index) was associated with UI, UUI, urgency and frequency in both sexes, and with SUI and OAB in females. We did not find associations between central or general obesity and OAB in males. Dyslipidemia was associated with nocturia ≥2. CONCLUSION In patients, central and general obesity were key metabolic factors associated with UI in both males and females, and with OAB in females but not in males. The association between dyslipidemia and nocturia ≥2 needs further research.

Correlates of Health Care Seeking Activities in Patients with Urological Chronic Pelvic Pain Syndromes: Findings from the MAPP Cohort

Purpose: We examined health care seeking activities during a 12‐month period in a cohort of men and women with urological chronic pelvic pain syndromes. Materials and Methods: A total of 191 men and 233 women with urological chronic pelvic pain syndrome were followed with biweekly, Internet based questionnaires about symptoms and health care seeking activities, including 1) health care provider contacts, 2) office visits, 3) emergency room/urgent care visits, 4) medication changes and 5) medical procedures. Multivariable modeling was used to determine the association of demographic and clinical variables with health care seeking. Super users were defined as individuals who reported health care seeking activity at least 11 times during the 23 biweekly assessments. Results: Health care seeking activities included a mean of 2.4 office contacts, 2.5 office visits, 1.9 medication changes, 0.9 medical procedures and 0.3 emergency room/urgent care visits. A total of 31 health care seeking super users accounted for 26% of health care seeking activities. Worse baseline pain severity and female gender were associated with a higher rate of all health care seeking activities except emergency room/urgent care visits. A nonurological chronic pain condition was associated with more provider contacts, office visits and medical procedures. Greater baseline depression symptoms were associated with more provider contacts, office visits and medication changes. Other examined variables, including patient age, symptom duration, catastrophizing, anxiety, urinary symptom severity and symptom variability, had a minimal association with health care seeking. Conclusions: Health care seeking activities were strongly influenced by the severity of pain in patients with urological chronic pelvic pain syndromes but not by urinary symptom severity. Women and patients with nonurological overlapping pain conditions were more likely to be seen and treated for symptoms.

MP82-05 PSYCHOSOCIAL FACTORS, SLEEP, AND PHYSICAL FUNCTION IN WOMEN WITH LOWER URINARY TRACT SYMPTOMS

INTRODUCTION AND OBJECTIVES: The role of brain-derived neurotrophic factor (BDNF) in lower urinary tract dysfunction induced by spinal cord injury (SCI) is still unclear. Previous data showed that the neutralization of BDNF in SCI mice increased voided volume and improved the voiding efficiency (2016 AUA). BDNF might involve in the voiding phase via Ad-fiber afferents, on which the receptor of BDNF (tropomyosin receptor kinase B) is mainly distributed. Acid-sensing ion channels (ASIC), which can function as mechanosensors, are identified as a target of BDNF signaling. We therefore investigated the changes of urethral function and ASIC expression in dorsal root ganglia (DRG) after the neutralization of BDNF in SCI mice. METHODS: Female C57 BL/6N mice underwent Th8-9 spinal cord transection. Three weeks later, an osmotic pump was placed subcutaneously to administer 10mg/kg/hr of anti-BDNF antibody for 1 week. Four weeks after spinal cord transection, SCI mice were evaluated using single-filling cystometry and external urethral sphincter (EUS)-electromyogram (EMG) under an awake condition. CMG-EMG recordings were used to detect intermittent voiding coincided with reductions in intravesical pressure in CMG traces, which occurred during periods of reduced EUS-EMG activity. We measured voiding contraction time (VT), reduced EMG activity duration (RED) and the ratio of RED to VT. Bladder BDNF was measured and the transcripts of TRPV1 and ASIC1, 2, and 3 of L6/S1 DRG were also evaluated. RESULTS: Compared to vehicle-treated SCI mice, voided volume was significantly increased and voiding efficiency was significantly better in anti-BDNF antibody-treated SCI mice. In CMG-EMG recordings, the RED was significantly prolonged, and the ratio of RED to VT was significantly greater in anti-BDNF antibody-treated SCI mice than those in vehicle-treated SCI mice. Bladder BDNF levels of SCI mice were significantly increased compared with spinal intact mice, but decreased after anti-BDNF antibody treatment. The transcripts of TRPV1, ASIC2 and 3 were increased in SCI mice compared to spinal intact mice, and anti-BDNF treatment significantly decreased expressions of ASIC2 and 3, but not TRPV1. CONCLUSIONS: BDNF upregulation in the bladder is likely to be involved in dyssynergic activity of the EUS during voiding in association with ASIC overexpression in L6/S1 DRG in SCI mice. Thus, BDNF targeting treatments could be effective for voiding problems such as DSD and inefficient voiding after SCI.

MP29-19 CHARACTERIZATION OF UROLOGIC AND NON-UROLOGIC FEATURES OF INTERSTITAIL CYSTITIS PATIENTS WITH HUNNER LESIONS

INTRODUCTION AND OBJECTIVES: It has been hypothesized that IC/BPS (Interstitial cystitis/bladder pain syndrome) patients with Hunner lesions inside the bladder represent a different phenotype than IC/BPS patients without Hunner lesions. Here we compared the urologic symptoms (urgency, frequency, nocturia, urologic pain, bladder hypersensitivity, sexual function) and non-urologic features (severity and distribution of systemic pain, co-morbid functional pain syndromes, anxiety, depression) between IC/BPS patients with and without Hunner lesions visible on regular cystoscopy without hydrodistention. METHODS: A battery of questionnaires were given to IC/BPS patients from our clinical practice to assess their urologic and nonurologic features (Interstitial Cystitis Symptom and Problem Indexes (ICSI, ICPI), Pelvic Pain and Urgency/Frequency (PFU) Questionnaire, numeric ratings of pain, urgency, frequency, RICE Questionnaire, AUA Symptom Index, Body Pain Map, Brief Pain Inventory (BPI), PolySymptomatic Poly-Syndromic Questionnaire (PSPS-Q), and history of co-morbid functional pain syndromes). Among them, 123 patients underwent cystoscopy. RESULTS: 23% (28 patients) had classic Hunner lesions visible inside the bladder on regular cystoscopy without hydrodistention. 77% (95 patients) did not have Hunner lesions. When the two IC/BPS sub-groups were compared (with versus without Hunner lesions), IC/BPS patients with Hunner lesions were about a decade older (mean age 53 17 versus 42 15, p1⁄40.002), more likely to report nocturia/night time frequency (p1⁄40.016), and less likely to report anxiety (22% versus 43%, p1⁄40.049) and irritable bowel syndrome (7% versus 34%, p1⁄40.007) compared to IC/BPS patients without Hunner lesions. There was no statistical difference in their composite scores (ICSI, ICPI, PFU, AUASI), severity and bother of urologic pain, bladder hypersensitivity features (eg, increase in pain with bladder filling, decrease in pain with bladder emptying), daytime frequency, urgency, sexual function, severity and distribution of systemic pain, fibromyalgia, chronic fatigue syndrome, migraine headache, vulvodynia, and depression. CONCLUSIONS: A significant percentage (23%) of IC/BPS patients demonstrate classic Hunner lesions inside the bladder during cystoscopy without hydrodistention. IC/BPS patients with Hunner lesions did not exhibit urologic and non-urologic features that would easily distinguish them from those without Hunner lesions. Cystoscopy is needed to identify these patients.

MP29-12 USE OF A BODY PAIN MAP TO CHARACTERIZE UROLOGIC CHRONIC PELVIC PAIN SYNDROME – A MAPP RESEARCH NETWORK STUDY

H. Henry Lai*, St Louis, MO; Thomas Jemielita, Philadelphia, PA; Catherine S. Bradley, Iowa City, IA; Bruce Naliboff, Los Angeles, CA; Robert Gereau IV, St Louis, MO; David A. Williams, Ann Arbor, MI; Karl Kreder, Iowa City, IA; J. Quentin Clemens, Ann Arbor, MI; Larissa V. Rodriguez, Los Angeles, CA; John N. Krieger, Seattle, WA; John T. Farrar, Nancy Robinson, J. Richard Landis, Philadelphia, PA