title: Can the adrenergic system be implicated in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clinical and experimental study.
abstract: OBJECTIVE
  To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications.
  
  
  METHODS
  Clinical study--In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were measured in plasma and 24 hr urine samples. Experimental study--Phenylephrine was injected subcutaneously (14 days) to female Wistar rats. Pain behavior, spinal Fos expression, urinary spotting, number of fecal pellets expelled, frequency of reflex bladder contractions, and urothelial height were analyzed. Urothelium permeability was investigated by trypan blue staining. Immunoreactivity against caspase 3 and bax were studied in the urothelium and against alpha-1-adrenoreceptor and TRPV1 in suburothelial nerves. Mast cell number was determined in the sub-urothelium. In rats with lipopolysaccharide-induced cystitis, urinary catecholamines, and Vesicular Monoamine Transporter 2 (VMAT2) expression in bladder nerves were analyzed.
  
  
  RESULTS
  The TILT test showed an increase of sympathetic activity. Noradrenaline levels in blood at resting conditions and in 24-hr urine samples were higher in BPS/IC patients. Phenylephrine administration increased visceral pain, spinal Fos expression, bladder reflex activity, urinary spotting and the number of expelled fecal pellets. The mucosa showed urothelial thinning and increased immunoreactivity for caspase 3 and bax. Trypan blue staining was only observed in phenylephrine treated animals. Suburothelial nerves co-expressed alpha1 and TRPV1. Mastocytosis was present in the suburothelium. Cystitis increased sympathetic nerve density and urinary noradrenaline levels.
  
  
  CONCLUSIONS
  Excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC.
authors.affiliation: Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal.|IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.|Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Urology, S. João Hospital, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Charrua
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.|Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Urology, S. João Hospital, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Canelas
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal.|IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.
authors.forename: Célia D
authors.initials: CD
authors.lastname: Cruz
authors.affiliation: Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lori Ann
authors.initials: LA
authors.lastname: Birder
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.|Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Urology, S. João Hospital, Porto, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruz
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000344:Afferent Pathways; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D018856:Cystitis, Interstitial / Q000378:metabolism* / Q000503:physiopathology; D003672:Defecation / Q000187:drug effects; D005260:Female; D006801:Humans; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D009929:Organ Size; D010525:Peripheral Nerves / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000378:metabolism; D018667:Tilt-Table Test; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D059265:Visceral Pain; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; C494828:Bax protein, rat; D016760:Proto-Oncogene Proteins c-fos; D018340:Receptors, Adrenergic, alpha-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D051028:bcl-2-Associated X Protein; D010656:Phenylephrine; C505410:Casp3 protein, rat; D053148:Caspase 3; D009638:Norepinephrine
keywords: bladder pain syndrome/interstitial cystitis; primary afferents; sympathetic system; urothelium