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


METHODS
Urothelium-denuded strips were suspended in organ baths for isometric force recordings and the relaxations to VIP and PACAP analogues were investigated.


RESULTS
VIP, PACAP 38, PACAP 27 and [Ala(11,22,28)]-VIP produced similar relaxations. Inhibition of neuronal voltage-gated Ca(2+) 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(+) channels reduced PACAP 38 and VIP relaxations, which were not modified by the K(+) 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
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(+) 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.
Hernández
M
M
Departamento de Fisiología, Fisiología Animal, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain. medardo@farm.ucm.es
Barahona
M V
MV
Recio
P
P
Benedito
S
S
Martínez
A C
AC
Rivera
L
L
García-Sacristán
A
A
Prieto
D
D
Orensanz
L M
LM
D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D019459:Urothelium / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015221:Potassium Channels; D014665:Vasodilator Agents; D014660:Vasoactive Intestinal Peptide; D000262:Adenylyl Cyclases; D020889:Rolipram