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Characterization of the contraction to 5‐HT in the canine colon longitudinal muscle
Author(s) -
Prins Nicolaas H.,
Briejer Michel R.,
Schuurkes Jan A.J.
Publication year - 1997
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.0700954
Subject(s) - methysergide , 5 ht receptor , serotonin , medicine , endocrinology , receptor antagonist , receptor , muscle contraction , antagonist , chemistry , tetrodotoxin , serotonin antagonists , contraction (grammar) , biology
1 Although conscious dogs have often been used for colonic motility studies with 5‐hydroxytryptamine (5‐HT), the effects of 5‐HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5‐HT of the canine isolated colon longitudinal muscle. 2 Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5‐HT induced contractions from 3 nM onwards, which were not affected by selective inhibition of 5‐HT re‐uptake, monoamine oxidase or blockade of α‐adrenoceptors. Tetrodotoxin (0.3 μm) did not affect the responses to 5‐HT, suggesting that smooth muscle 5‐HT receptors are involved. The selective 5‐HT 4 receptor antagonist SB 204070 (10 nM) slightly enhanced contractions to 5‐HT and therefore it was included in the organ bath solution in all further experiments. The 5‐HT 1 and 5‐HT 2 receptor antagonist methysergide (0.1 μm) depressed the curve to 5‐HT, but the selective 5‐HT 3 receptor antagonist granisetron (0.3 μm) had no effect. 3 Besides 5‐HT, α‐methyl‐5‐HT (α‐Me‐5‐HT), 5‐methoxytryptamine (5‐MeOT), 2‐methyl‐5‐HT (2‐Me‐5‐HT) and 5‐carboxamidotryptamine (5‐CT) also induced contractions, with the following rank order of potency (pEC 50 values in parentheses): 5‐HT (6.9) = α‐methyl‐5‐HT (6.9) >2‐Me‐5‐HT (5.8) = 5‐MeOT (5.7) = 5‐CT (5.6), indicative of 5‐HT 2 receptor involvement. α‐Me‐5‐HT produced a bell‐shaped curve, which was not affected by α‐adrenoceptor blockade. 5‐HT, 5‐MeOT, 2‐Me‐5‐HT and 5‐CT produced a monophasic concentration‐response curve, consistent with an interaction with a single receptor site. 8‐Hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and tryptamine only induced contractions at a concentration exceeding 1 μM. 4 The selective 5‐HT 2B receptor antagonist SB 204741 (0.3 μM) did not affect the curve to 5‐HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with p K b values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1 μm) shifted the curve to 5‐MeOT rightward yielding an apparent pA 2 of 7.1. Other antagonists at 5‐HT 2A receptors also surmountably inhibited the contractions to 5‐HT (apparent pA 2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of ‘pseudo‐irreversible’ antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5‐HT 2A receptors. 5 It was concluded that 5‐HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5‐HT 2A receptors. The presence of inhibitory 5‐HT 4 receptors cannot be ruled out.