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Am J Physiol Regul Integr Comp Physiol (December 1, 2005). doi:10.1152/ajpregu.00734.2005
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Submitted on October 14, 2005
Accepted on November 22, 2005

Role for Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) in Cystitis-induced Plasticity of Micturition Reflexes

Karen M Braas1, Victor May2, Peter Zvara3, Bernhard Nausch4, Jan Kliment3, J. Dana Dunleavy5, Mark T Nelson4, and Margaret A Vizzard6*

1 Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT, USA
2 Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT, USA; Pharmacology, University of Vermont College of Medicine, Burlington, VT, USA
3 Surgery, University of Vermont College of Medicine, Burlington, VT, USA
4 Pharmacology, University of Vermont College of Medicine, Burlington, VT, USA
5 Neurology, University of Vermont College of Medicine, Burlington, VT, USA
6 Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT, USA; Neurology, University of Vermont College of Medicine, Burlington, VT, USA

* To whom correspondence should be addressed. E-mail: margaret.vizzard{at}uvm.edu.

PACAP peptides are expressed and regulated in sensory afferents of the micturition pathway. Although these studies have implicated PACAP in bladder control, the physiological significance of these observations has not been firmly established. To clarify these issues, the roles of PACAP and PACAP signaling in micturition and cystitis were examined in receptor characterization and physiological assays. PACAP receptors were identified in various tissues of the micturition pathway including bladder detrusor smooth muscle and urothelium. Bladder smooth muscle expressed heterogeneously PAC1null, PAC1HOP1 and VPAC2 receptors; the urothelium was more restricted in expressing preferentially the PAC1 receptor subtype only. Immunocytochemical studies for PAC1 receptors were consistent with these tissue distributions. Furthermore, the addition of 50 - 100 nM PACAP27 or PACAP38 to isolated bladder strips elicited transient contractions and sustained increases in the amplitude of spontaneous phasic contractions. Treatment of the bladder strips with tetrodotoxin (1 µM) did not alter the spontaneous phasic contractions suggesting direct PACAP effects on bladder smooth muscle. PACAP also increased the amplitude of nerve-evoked contractions. By contrast, VIP had no direct effects on bladder smooth muscle. In a rat cyclophosphamide (CYP)-induced cystitis paradigm, intrathecal or intravesical administration of PAC1 receptor antagonist, PACAP6-38, reduced cystitis-induced bladder overactivity. In sum, these studies support roles for PACAP in micturition and suggest that inflammation-induced plasticity in PACAP expression in peripheral and central micturition pathways contribute to bladder dysfunction with cystitis.




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