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Heterogeneity of neuronal and smooth muscle receptors involved in the VIP‐ and PACAP‐induced relaxations of the pig intravesical ureter
Author(s) -
Hernández Medardo,
Barahona María Victoria,
Recio Paz,
Rivera Luis,
Benedito Sara,
Martínez Ana Cristina,
GarcíaSacristán Albino,
Orensanz Luis M,
Prieto Dolores
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705582
Subject(s) - vasoactive intestinal peptide , apamin , endocrinology , medicine , pituitary adenylate cyclase activating peptide , chemistry , charybdotoxin , channel blocker , potassium channel blocker , adenosine , tetraethylammonium , agonist , neuropeptide , receptor , potassium channel , biology , calcium , potassium , organic chemistry
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. 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. The neuronal voltage‐gated Ca 2+ channel inhibitor, ω ‐conotoxin GVIA ( ω ‐CgTX, 1 μ M ), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin‐sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 μ M ), N G ‐nitro‐ L ‐arginine ( L ‐NOARG, 100 μ M ) and 1H‐[1,2,4]‐oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 5 μ M ), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by ω ‐CgTX, capsaicin, L ‐NOARG and ODQ. The VIP and VIP/PACAP receptor antagonists, [Lys 1 , Pro 2,5 , Arg 3,4 , Tyr 6 ]‐VIP (1 μ M ) and PACAP (6–38) (0.4 μ M ), inhibited VIP and VIP and PACAP 38, respectively, relaxations. The nonselective and large‐conductance Ca 2 ‐activated K + channel blockers, tetraethylammonium (3 m M ) and charybdotoxin (0.1 μ M ), respectively, and neuropeptide Y (0.1 μ M ) did not modify the VIP relaxations. The small‐conductance Ca 2 ‐activated K + channel blocker apamin (1 μ M ) did not change the PACAP 27 relaxations. The cAMP‐dependent protein kinase A (PKA) blocker, 8‐(4‐chlorophenylthio)adenosine‐3′,5′‐cyclic monophosphorothioate (Rp‐8‐CPT‐cAMPS, 100 μ M ), 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 n M ) evoked a potentiation of VIP relaxations. 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.British Journal of Pharmacology (2004) 141 , 123–131. doi: 10.1038/sj.bjp.0705582