Neuronal and smooth muscle receptors involved in the PACAP‐ and VIP‐induced relaxations of the pig urinary bladder neck

Abstract

Background and purpose: As pituitary adenylate cyclase-activating polypeptide 38 (PACAP 38)-and vasoactive intestinal peptide (VIP) are widely distributed in the urinary tract, the current study investigated the receptors and mechanisms involved in relaxations induced by these peptides in the pig bladder neck. Experimental approach: Urothelium-denuded strips were suspended in organ baths for isometric force recordings and the relaxations to VIP and PACAP analogues were investigated. Key results: VIP, PACAP 38, PACAP 27 and [Ala 11,22,28 ]-VIP produced similar relaxations. Inhibition of neuronal voltage-gated Ca 2 þ channels reduced relaxations to PACAP 38 and increased those induced by VIP. Blockade of capsaicin-sensitive primary afferents (CSPA), nitric oxide (NO)-synthase or guanylate cyclase reduced the PACAP 38 relaxations but failed to modify the VIP responses. Inhibition of VIP/PACAP receptors and of voltage-gated K þ channels reduced PACAP 38 and VIP relaxations, which were not modified by the K þ channel blockers iberiotoxin, charybdotoxin, apamin or glibenclamide. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin produced potent relaxations. Blockade of protein kinase A (PKA) reduced PACAP 38-and VIP-induced relaxations. Conclusions and implications: PACAP 38 and VIP relax the pig urinary bladder neck through muscle VPAC 2 receptors linked to the cAMP-PKA pathway and involve activation of voltage-gated K þ channels. Facilitatory PAC 1 receptors located at CSPA and coupled to NO release, and inhibitory VPAC receptors at motor endings are also involved in the relaxations to PACAP 38 and VIP, respectively. VIP/PACAP receptor antagonists could be useful in the therapy of urinary incontinence produced by intrinsic sphincter deficiency.

Urinary Bladder Function and Somatic Sensitivity in Vasoactive Intestinal Polypeptide (VIP)−/− Mice

“…VIP has been shown to relax urinary bladder from human (Uckert et al, 2002) or pig (Hernandez et al, 2006), and contract or produce no effects on urinary bladder from the rat (Erol et al, 1992;Igawa et al, 1993). These contradictory findings might be attributable to species differences (Uckert et al, 2002) and differential VIP receptor distribution.…”

“…VIP is a member of the glucagon/secretin superfamily of hormones (Dickinson et al, 1999) and acts through two high affinity receptors, the VPAC 1 and VPAC 2 receptors (Harmar et al, 1998). VIP exerts, species-specific, excitatory or inhibitory actions in neural pathways controlling micturition and these functions may be altered with neural injury, disease or inflammation (Erol et al, 1992;Igawa et al, 1993;Uckert et al, 2002;Hernandez et al, 2006). VIP-immunoreactivity has been demonstrated throughout the neural pathways of the lower urinary tract de Groat, 1989, 1992;Wanigasekara et al, 2003).…”

Expression of Phosphorylated cAMP Response Element Binding Protein (p-CREB) in Bladder Afferent Pathways in VIP−/− Mice with Cyclophosphamide (CYP)-Induced Cystitis

“…VIP has been shown to relax urinary bladder from human (Uckert et al, 2002) or pig (Hernandez et al, 2006), and contract or produce no effects on urinary bladder from the rat (Igawa et al, 1993;Erol et al, 1992). These contradictory findings might be attributable to species differences (Uckert et al, 2002).…”

“…Greater basal activity in the primary bladder afferents in the DRG or in the target organ itself (i.e., urinary bladder) could result in increased pCREB expression in the absence of inflammation by increasing Ca ++ and/or cAMP in VIP −/− mice. Primary afferent cells in the DRG express VIP (Morgan et al, 1999;Hernandez et al, 2006) and VIP receptors (Yashpal et al, 1991;Braas et al, 2006). Thus, absence of VIP in the VIP −/− mice could produce a direct effect on primary afferent cells.…”

The influence of resiniferatoxin on the chemical coding of neurons in dorsal root ganglia supplying the urinary bladder in the female pig

“…In addition, two supplementary functions have been postulated for PACAP in the micturition reflex pathways, including modulation of nociceptive transmission through interaction with NMDA receptors (Oshawa et al 2002) and/or modulation of inflammatory responses (Kim et al 2000) by downregulation of inflammatory cytokines including tumor necrosis factor-alpha. It has also been shown in pigs that PACAP produces relaxation in the urinary tract (Hernandez et al 2006). In the present study, RTX led to a distinct increase in the number of PACAP-IR bladder-projecting sensory neurons in the lumbar as well as sacro-coccygeal DRGs studied.…”