The Severity and Distribution of Nonurologic Pain and Urogenital Pain in Overactive Bladder are Intermediate Between Interstitial Cystitis and Controls.

OBJECTIVES: (1) To compare the severity and distribution of nonurologic and urogenital pain between overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS) and controls, and (2) To examine the relationships between the severity of urogenital pain and severity of urinary symptoms among patients with OAB. SUBJECTS AND METHODS: Fifty-one OAB patients, 27 IC/BPS patients, and 30 controls were recruited. Nonurologic pain was assessed using a whole body map and Brief Pain Inventory. Urologic pain was assessed using the Interstitial Cystitis Symptom and Problem indexes, Genitourinary Pain Index, and 0-10 pain scale. Urogenital pain was assessed using a genital map, and report of pain related to bladder filling and urination. RESULTS: Among OAB patients, 6% reported pelvic pain only while 28% reported pelvic pain and beyond. 18% reported widespread pain. The distribution of nonurologic pain and urogenital pain in OAB patients were intermediate between IC/BPS and controls (IC/BPS>OAB>controls, P all <.05). The intensity of pain reported by OAB patients was intermediate between controls and IC/BPS (average 2.3 vs 0.8 vs 4.3 out of 10, P <.001). Among OAB patients, the pain severity (GUPI-pain, ICSI-pain, ICPI-pain) was positively correlated with urinary severity (UDI-6, IIQ-7, OABq-SS, OABq-QOL, P all < .05). OAB patients with pelvic pain have worse urinary symptoms and psychosocial health (anxiety, depression) compared to OAB patients without pelvic pain. CONCLUSION: A subset of OAB patients has pain inside and/or outside the pelvis. The intensity and distribution of pain in OAB was intermediate between IC/BPS and controls. Systemic processes such as central sensitization should be examined in this population.

Clustering of Patients with Interstitial Cystitis/Bladder Pain Syndrome and Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

PURPOSE: We performed clustering analysis of patient symptoms to discover common patient subtypes in females and males with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: The clinical variables included in k-means clustering were urological pain severity, urinary urgency, frequency and nonurological pain, each on a 0 to 10 numerical rating scale, and a yes or no response to each of the 6 UPOINT (Urological Treatment Program for Chronic Prostatitis) domains, including the urinary, psychosocial, organ specific, infection, neurological/systemic and skeletal muscle tenderness domains. RESULTS: Included in study were 211 patients seeking care of interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome. The k-means clustering algorithm identified 3 clusters of patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, including 1) a mild pelvic symptom cluster in about 30% of patients, 2) a severe pelvic symptom cluster in about 40% and 3) a systemic symptom cluster in about 30%. Patients in the systemic cluster were younger by about 5 to 7 years and more likely to be female. They had the most severe urinary symptoms (urgency, frequency and painful bladder filling), and the most severe pelvic and nonpelvic pain. They were also more likely to have chronic overlapping pain conditions, psychosocial issues (depression, anxiety and somatic symptoms) and poorer quality of life than patients in the 2 other pelvic clusters. They were not less likely to have Hunner lesions in the bladder. CONCLUSIONS: Symptom based clustering identified 3 clusters of patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. These patient subtypes had different pelvic and systemic presentations. Patients in the systemic cluster may benefit from interdisciplinary therapies. Future studies are needed to elucidate differences in pathophysiology among these clusters.

Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle.

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCß1 expression, BAY 60-2770 did increase sGCß1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.

cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle.

Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.