Substance P via NK1 receptor facilitates hyperactive bladder afferent signaling via action of ROS.
We explored whether substance P (SP) via neurokinin (NK) receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder in association with neurogenic inflammation. We evaluated ROS activity and cystometrograms as well as pelvic nervous activity in anesthetized rat bladder with SP stimulation. Our results showed that endogenous SP via NK(1), not NK(2), receptor mediated a micturition reflex. An increase in SP by electrical stimulation of the pelvic nerve or an increase in exogenous SP by intra-arterial or intrathecal administration can facilitate myogenic and neurogenic bladder contractions. Furthermore, exaggerated SP release increased ROS in the bladder and whole blood via increased mast cell degranulation, intercellular adhesion molecule expression, and leukocyte adhesion, a primary source of ROS in the inflamed bladder. Treatment with NK(1)-receptor antagonists or ROS scavengers reduced bladder intercellular adhesion molecule expression and ROS and ameliorated the hyperactive bladder response. Our study indicates that the mechanism by which SP participates in the neurogenic bladder may be complicated by its proinflammatory activity and its ability to stimulate ROS generation.
Chien
Chiang-Ting
CT
Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10022. ctchien@ha.ntu.edu.tw
Yu
Hong-Jeng
HJ
Lin
Tser-Bin
TB
Lai
Ming-Kuen
MK
Hsu
Su-Ming
SM
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004558:Electric Stimulation; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010388:Pelvis / Q000294:innervation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012021:Reflex, Abnormal / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride / Q000008:administration & dosage; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation; D001750:Urinary Bladder, Neurogenic / Q000503:physiopathology*; D014554:Urination / Q000187:drug effects; D017833:Visceral Afferents / Q000503:physiopathology
D001549:Benzamides; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D016166:Free Radical Scavengers; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D013373:Substance P; D012965:Sodium Chloride; C073839:SR 48968; D013482:Superoxide Dismutase; C066892:CP 96345