Inhibitory effect of PACAP(6-38) on relaxations induced by PACAP, VIP and non-adrenergic, non-cholinergic nerve stimulation in the guinea-pig taenia caeci

L. Lénárd, Z. Lázár, R. Benkó, R. Szigeti, Z. Báthori, G. Tóth, B. Penke, L. Barthó

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Abstract

The effect of the pituitary adenylate cyclase activating polypeptide (PACAP) receptor antagonist PACAP(6-38) on the relaxant response to exogenous PACAP, vasoactive intestinal polypeptide (VIP) and nonadrenergic, non- cholinergic (NANC) nerve stimulation was tested in the guinea-pig taenia caeci, in the presence of atropine (10-6 M) and guanethidine (3x10-6 M). PACAP(6-38) (3x10-6 M) strongly inhibited sub-maximal relaxations evoked by exogenous PACAP (1-3x 10-8 M) or VIP (10-8 M), but not those due to isoprenaline (4-8x10-8 M) or ATP (10-6 M). PACAP(6-38) caused a small but significant (approximately 20%) inhibition of the NANC relaxation due to electrical field stimulation (1 Hz or 10 Hz for 20 s). At these frequencies PACAP(6-38) caused no inhibition of the NANC relaxation in the presence of the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'- disulphonic acid (PPADS; 5x10-5 M), or PPADS plus the NO-synthase blocker N(G)-nitro-L-arginine (L-NOARG; 10-4 M); in preparations pretreated with L- NOARG (10-4 M) alone PACAP(6-38) retained its inhibitory effect. The PPADS- and L-NOARG-resistant NANC relaxation with 10 Hz electrical stimulation was blocked by apamin (10-7 M); it was not significantly modified by the tachykinin receptor antagonist spantide (10-5 M). Tachyphylaxis to PACAP(1- 27) (10-7 M for 10 min) strongly inhibited the relaxation due to PACAP(1- 38) (1-3x10-8 M) and reduced electrical stimulation-evoked relaxations by half. The putative VIP antagonist VIP(10-28) (10-5 M) failed to significantly reduce the relaxant action of exogenous VIP (1-3x10-8 M). Relaxation induced by PACAP(1-38) (1-2x10-8 M) was not influenced by a mixture of PPADS (5x10-5 M) and L-NOARG (10-4 M). It is concluded that: (a) PACAP(6-38) is a VIP/PACAP antagonist in the guinea-pig taenia caeci; (b) a release of a VIP/PACAP-like substance from enteric nerves is involved in the NANC relaxation in this preparation, but its contribution is relatively small and seems to depend on the functional integrity of the PPADS-sensitive inhibitory mechanism; (c) the PPADS- plus L-NOARG-resistant NANC relaxation probably involves apamin-sensitive K+ channels.

Original languageEnglish
Pages (from-to)492-497
Number of pages6
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume361
Issue number5
DOIs
Publication statusPublished - 2000

Fingerprint

Pituitary Adenylate Cyclase-Activating Polypeptide
Taenia
Vasoactive Intestinal Peptide
Guinea Pigs
Nitroarginine
Cholinergic Agents
Electric Stimulation
Apamin
Purinergic P2 Receptor Antagonists
Pituitary Adenylate Cyclase-Activating Polypeptide Receptors
Tachykinin Receptors
Tachyphylaxis
Guanethidine
Atropine
Isoproterenol
Nitric Oxide Synthase
Arginine

Keywords

  • Non-adrenergic non-cholinergic (NANC) relaxation
  • PACAP antagonist
  • Pituitary adenylate cyclase activating polypeptide (PACAP)
  • Taenia caeci (guinea pig)
  • Vasoactive intestinal polypeptide (VIP)
  • VIP antagonist

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{0180966d4ab34aaead9b2bddafc9434f,
title = "Inhibitory effect of PACAP(6-38) on relaxations induced by PACAP, VIP and non-adrenergic, non-cholinergic nerve stimulation in the guinea-pig taenia caeci",
abstract = "The effect of the pituitary adenylate cyclase activating polypeptide (PACAP) receptor antagonist PACAP(6-38) on the relaxant response to exogenous PACAP, vasoactive intestinal polypeptide (VIP) and nonadrenergic, non- cholinergic (NANC) nerve stimulation was tested in the guinea-pig taenia caeci, in the presence of atropine (10-6 M) and guanethidine (3x10-6 M). PACAP(6-38) (3x10-6 M) strongly inhibited sub-maximal relaxations evoked by exogenous PACAP (1-3x 10-8 M) or VIP (10-8 M), but not those due to isoprenaline (4-8x10-8 M) or ATP (10-6 M). PACAP(6-38) caused a small but significant (approximately 20{\%}) inhibition of the NANC relaxation due to electrical field stimulation (1 Hz or 10 Hz for 20 s). At these frequencies PACAP(6-38) caused no inhibition of the NANC relaxation in the presence of the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'- disulphonic acid (PPADS; 5x10-5 M), or PPADS plus the NO-synthase blocker N(G)-nitro-L-arginine (L-NOARG; 10-4 M); in preparations pretreated with L- NOARG (10-4 M) alone PACAP(6-38) retained its inhibitory effect. The PPADS- and L-NOARG-resistant NANC relaxation with 10 Hz electrical stimulation was blocked by apamin (10-7 M); it was not significantly modified by the tachykinin receptor antagonist spantide (10-5 M). Tachyphylaxis to PACAP(1- 27) (10-7 M for 10 min) strongly inhibited the relaxation due to PACAP(1- 38) (1-3x10-8 M) and reduced electrical stimulation-evoked relaxations by half. The putative VIP antagonist VIP(10-28) (10-5 M) failed to significantly reduce the relaxant action of exogenous VIP (1-3x10-8 M). Relaxation induced by PACAP(1-38) (1-2x10-8 M) was not influenced by a mixture of PPADS (5x10-5 M) and L-NOARG (10-4 M). It is concluded that: (a) PACAP(6-38) is a VIP/PACAP antagonist in the guinea-pig taenia caeci; (b) a release of a VIP/PACAP-like substance from enteric nerves is involved in the NANC relaxation in this preparation, but its contribution is relatively small and seems to depend on the functional integrity of the PPADS-sensitive inhibitory mechanism; (c) the PPADS- plus L-NOARG-resistant NANC relaxation probably involves apamin-sensitive K+ channels.",
keywords = "Non-adrenergic non-cholinergic (NANC) relaxation, PACAP antagonist, Pituitary adenylate cyclase activating polypeptide (PACAP), Taenia caeci (guinea pig), Vasoactive intestinal polypeptide (VIP), VIP antagonist",
author = "L. L{\'e}n{\'a}rd and Z. L{\'a}z{\'a}r and R. Benk{\'o} and R. Szigeti and Z. B{\'a}thori and G. T{\'o}th and B. Penke and L. Barth{\'o}",
year = "2000",
doi = "10.1007/s002100000225",
language = "English",
volume = "361",
pages = "492--497",
journal = "Naunyn-Schmiedeberg's Archives of Pharmacology",
issn = "0028-1298",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Inhibitory effect of PACAP(6-38) on relaxations induced by PACAP, VIP and non-adrenergic, non-cholinergic nerve stimulation in the guinea-pig taenia caeci

AU - Lénárd, L.

AU - Lázár, Z.

AU - Benkó, R.

AU - Szigeti, R.

AU - Báthori, Z.

AU - Tóth, G.

AU - Penke, B.

AU - Barthó, L.

PY - 2000

Y1 - 2000

N2 - The effect of the pituitary adenylate cyclase activating polypeptide (PACAP) receptor antagonist PACAP(6-38) on the relaxant response to exogenous PACAP, vasoactive intestinal polypeptide (VIP) and nonadrenergic, non- cholinergic (NANC) nerve stimulation was tested in the guinea-pig taenia caeci, in the presence of atropine (10-6 M) and guanethidine (3x10-6 M). PACAP(6-38) (3x10-6 M) strongly inhibited sub-maximal relaxations evoked by exogenous PACAP (1-3x 10-8 M) or VIP (10-8 M), but not those due to isoprenaline (4-8x10-8 M) or ATP (10-6 M). PACAP(6-38) caused a small but significant (approximately 20%) inhibition of the NANC relaxation due to electrical field stimulation (1 Hz or 10 Hz for 20 s). At these frequencies PACAP(6-38) caused no inhibition of the NANC relaxation in the presence of the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'- disulphonic acid (PPADS; 5x10-5 M), or PPADS plus the NO-synthase blocker N(G)-nitro-L-arginine (L-NOARG; 10-4 M); in preparations pretreated with L- NOARG (10-4 M) alone PACAP(6-38) retained its inhibitory effect. The PPADS- and L-NOARG-resistant NANC relaxation with 10 Hz electrical stimulation was blocked by apamin (10-7 M); it was not significantly modified by the tachykinin receptor antagonist spantide (10-5 M). Tachyphylaxis to PACAP(1- 27) (10-7 M for 10 min) strongly inhibited the relaxation due to PACAP(1- 38) (1-3x10-8 M) and reduced electrical stimulation-evoked relaxations by half. The putative VIP antagonist VIP(10-28) (10-5 M) failed to significantly reduce the relaxant action of exogenous VIP (1-3x10-8 M). Relaxation induced by PACAP(1-38) (1-2x10-8 M) was not influenced by a mixture of PPADS (5x10-5 M) and L-NOARG (10-4 M). It is concluded that: (a) PACAP(6-38) is a VIP/PACAP antagonist in the guinea-pig taenia caeci; (b) a release of a VIP/PACAP-like substance from enteric nerves is involved in the NANC relaxation in this preparation, but its contribution is relatively small and seems to depend on the functional integrity of the PPADS-sensitive inhibitory mechanism; (c) the PPADS- plus L-NOARG-resistant NANC relaxation probably involves apamin-sensitive K+ channels.

AB - The effect of the pituitary adenylate cyclase activating polypeptide (PACAP) receptor antagonist PACAP(6-38) on the relaxant response to exogenous PACAP, vasoactive intestinal polypeptide (VIP) and nonadrenergic, non- cholinergic (NANC) nerve stimulation was tested in the guinea-pig taenia caeci, in the presence of atropine (10-6 M) and guanethidine (3x10-6 M). PACAP(6-38) (3x10-6 M) strongly inhibited sub-maximal relaxations evoked by exogenous PACAP (1-3x 10-8 M) or VIP (10-8 M), but not those due to isoprenaline (4-8x10-8 M) or ATP (10-6 M). PACAP(6-38) caused a small but significant (approximately 20%) inhibition of the NANC relaxation due to electrical field stimulation (1 Hz or 10 Hz for 20 s). At these frequencies PACAP(6-38) caused no inhibition of the NANC relaxation in the presence of the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'- disulphonic acid (PPADS; 5x10-5 M), or PPADS plus the NO-synthase blocker N(G)-nitro-L-arginine (L-NOARG; 10-4 M); in preparations pretreated with L- NOARG (10-4 M) alone PACAP(6-38) retained its inhibitory effect. The PPADS- and L-NOARG-resistant NANC relaxation with 10 Hz electrical stimulation was blocked by apamin (10-7 M); it was not significantly modified by the tachykinin receptor antagonist spantide (10-5 M). Tachyphylaxis to PACAP(1- 27) (10-7 M for 10 min) strongly inhibited the relaxation due to PACAP(1- 38) (1-3x10-8 M) and reduced electrical stimulation-evoked relaxations by half. The putative VIP antagonist VIP(10-28) (10-5 M) failed to significantly reduce the relaxant action of exogenous VIP (1-3x10-8 M). Relaxation induced by PACAP(1-38) (1-2x10-8 M) was not influenced by a mixture of PPADS (5x10-5 M) and L-NOARG (10-4 M). It is concluded that: (a) PACAP(6-38) is a VIP/PACAP antagonist in the guinea-pig taenia caeci; (b) a release of a VIP/PACAP-like substance from enteric nerves is involved in the NANC relaxation in this preparation, but its contribution is relatively small and seems to depend on the functional integrity of the PPADS-sensitive inhibitory mechanism; (c) the PPADS- plus L-NOARG-resistant NANC relaxation probably involves apamin-sensitive K+ channels.

KW - Non-adrenergic non-cholinergic (NANC) relaxation

KW - PACAP antagonist

KW - Pituitary adenylate cyclase activating polypeptide (PACAP)

KW - Taenia caeci (guinea pig)

KW - Vasoactive intestinal polypeptide (VIP)

KW - VIP antagonist

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U2 - 10.1007/s002100000225

DO - 10.1007/s002100000225

M3 - Article

VL - 361

SP - 492

EP - 497

JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

SN - 0028-1298

IS - 5

ER -