Pharmacological and genetic analysis of mechanisms underlying detrusor overactivity in rats.
OBJECTIVE
Suprapontine lesions, such as those resulting from cerebrovascular disease, cause bladder storage dysfunction. Detrusor overactivity (DO) following cerebral infarction may be explained by impairment of the suprapontine regulatory system. However, precise mechanisms underlying DO is not clear. The following studies were undertaken to examine pharmacological and genetic mechanisms of DO in rats.


CONCLUSIONS
Mechanisms of long-lasting DO in rats with cerebral infarction require signal transfer, which begins with the opening of glutamate receptors at the dorsal pontine tegmentum. DO induced by cerebral infarction has been proven to be accompanied by an increase in c-fos and zif268 expression in the dorsal pontine tegmentum and periaqueductal gray and mediated by the activation of N-methyl-D-aspartate (NMDA) receptors, cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PGES). Therefore, the arachidonic acid cascade is dynamically activated in the brain after brain ischemia. Bladder sensory pathways are potential targets for drugs used to treat various bladder dysfunctions because of their role in storage symptoms (i.e., urgency, frequency) and in triggering reflex bladder activity. Antimuscarinic drugs and alpha(1)-blockers are the main treatments for overactive bladder, a condition caused by neurologic lesions, aging, bladder outlet obstruction, and other pathologies. These drugs affect sensory bladder storage symptoms, suggesting an action on bladder and urethral afferent pathways. Using animal models of DO, we demonstrated that these drugs improved bladder storage function via suppression of C-fiber afferent nerves from the lower urinary tract.
Yokoyama
Osamu
O
Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan. oyoko@u-fukui.ac.jp
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003408:Cresols / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D010665:Phenylpropanolamine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D013997:Time Factors; D000068737:Tolterodine Tartrate; D014158:Transcription, Genetic / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001559:Benzhydryl Compounds; D003408:Cresols; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D016760:Proto-Oncogene Proteins c-fos; C545637:Ptger1 protein, rat; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000077409:Tamsulosin; D015232:Dinoprostone