Heterogeneity of neuronal and smooth muscle receptors involved in the VIP- and PACAP-induced relaxations of the pig intravesical ureter.
1. The mechanisms and receptors involved in the vasoactive intestinal peptide (VIP)- and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced relaxations of the pig intravesical ureter were investigated. 2. VIP, PACAP 38 and PACAP 27 concentration-dependently relaxed U46619-contracted ureteral strips with a similar potency. [Ala(11,22,28)]-VIP, a VPAC(1) agonist, showed inconsistent relaxations. 3. The neuronal voltage-gated Ca(2+) channel inhibitor, omega-conotoxin GVIA (omega-CgTX, 1 microm), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin-sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 microm), N(G)-nitro-l-arginine (l-NOARG, 100 microm) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 microm), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by omega-CgTX, capsaicin, l-NOARG and ODQ. 4. The VIP and VIP/PACAP receptor antagonists, [Lys(1), Pro(2,5), Arg(3,4), Tyr(6)]-VIP (1 microm) and PACAP (6-38) (0.4 microm), inhibited VIP and VIP and PACAP 38, respectively, relaxations. 5. The nonselective and large-conductance Ca(2)-activated K(+) channel blockers, tetraethylammonium (3 mm) and charybdotoxin (0.1 microm), respectively, and neuropeptide Y (0.1 microm) did not modify the VIP relaxations. The small-conductance Ca(2)-activated K(+) channel blocker apamin (1 microm) did not change the PACAP 27 relaxations. 6. The cAMP-dependent protein kinase A (PKA) blocker, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS, 100 microm), reduced VIP relaxations. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin relaxed ureteral preparations. The rolipram relaxations were reduced by Rp-8-CPT-cAMPS. Forskolin (30 nm) evoked a potentiation of VIP relaxations. 7. These results suggest that VIP and PACAP relax the pig ureter through smooth muscle receptors, probably of the VPAC(2) subtype, linked to a cAMP-PKA pathway. Neuronal VPAC receptors localized at motor nerves and PAC(1) receptors placed at sensory nerves and coupled to NO release, seem also to be involved in the VIP and PACAP 38 relaxations.
Hernández
Medardo
M
Departamento de Fisiología, Facultad de Farmacia, UCM, 28040-Madrid, Spain. medardo@vet.ucm.es
Barahona
María Victoria
MV
Recio
Paz
P
Rivera
Luis
L
Benedito
Sara
S
Martínez
Ana Cristina
AC
García-Sacristán
Albino
A
Orensanz
Luis M
LM
Prieto
Dolores
D
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D018999:Charybdotoxin / Q000008:administration & dosage; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006162:Guanylate Cyclase / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000187:drug effects; D018005:Receptors, Vasoactive Intestinal Peptide / Q000502:physiology*; D020889:Rolipram / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000502:physiology*; D013552:Swine; D019789:Tetraethylammonium / Q000008:administration & dosage; D014513:Ureter / Q000166:cytology / Q000187:drug effects* / Q000293:injuries; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D009478:Neuropeptide Y; D009479:Neuropeptides; D010069:Oxadiazoles; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D024681:Potassium Channels, Calcium-Activated; D011810:Quinoxalines; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide; D018005:Receptors, Vasoactive Intestinal Peptide; C106317:pituitary adenylate-cyclase-activating peptide (6-27); C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D018999:Charybdotoxin; C071686:vasoactive intestinal contractor receptor; D005576:Colforsin; D001030:Apamin; D014660:Vasoactive Intestinal Peptide; D019789:Tetraethylammonium; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D020866:omega-Conotoxin GVIA; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D020889:Rolipram; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester