Pharmacological evidence for both neuronal and smooth muscular PAC1 receptors and a VIP-specific receptor in rat colon.
The receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) were characterised in vitro on rat colon longitudinal smooth muscle with adherent myenteric ganglia. VIP, PACAP-38 and PACAP-27 all caused concentration-dependent relaxations. PACAP-27 and PACAP-38 were equipotent, while VIP was less potent. Tetrodotoxin (10(-6) M), L-NAME (10(-4) M), 7-NINA (10(-5) M) and ODQ (3 x 10(-6) M) reduced the amplitude of the relaxatory responses to PACAP-38 but did not affect relaxations induced by VIP or PACAP-27. Apamin (10(-6) M) almost totally abolished the PACAP-27- and PACAP-38-induced relaxations, while VIP-induced relaxations were only slightly reduced. Tetraethylammonium (TEA) reduced VIP- but not PACAP-27-induced relaxations, while charybdotoxin was ineffective. Cross-desensitisation between PACAP-27, PACAP-38 and VIP could be revealed to some extent.


CONCLUSIONS
VIP, PACAP-27 and PACAP-38 are effective relaxants in rat colon longitudinal muscle. The receptors involved are classified as: (1) a neuronal PAC1 receptor localised on NO-synthesising neurones, the preferred ligand being PACAP-38. Activation of this receptor leads to an increased NO production. (2) A smooth muscle PAC1 receptor, the preferred ligand being PACAP-27. However, also PACAP-38 and, to a less extent, VIP activate this receptor. The relaxatory responses elicited by both PACAP-27 and PACAP-38 are abolished by apamin and thus mediated through small conductance Ca2+-activated K+ channels. (3) A VIP-specific receptor localised on smooth muscle cells. The mechanisms whereby this receptor elicits a relaxatory response involve, at least to some extent, TEA-sensitive K+ channels.
Ekblad
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Department of Physiological Sciences, Lund University Hospital, Sweden. eva.ekblad@mphy.lu.se
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D005260:Female; D007191:Indazoles / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D010069:Oxadiazoles / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000187:drug effects / Q000502:physiology*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C495403:Adcyap1 protein, rat; C495505:Adcyap1r1 protein, rat; D007191:Indazoles; D009479:Neuropeptides; D010069:Oxadiazoles; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011810:Quinoxalines; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; D001030:Apamin; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D013779:Tetrodotoxin; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester