1 We aimed to characterize 5-HT receptors mediating contraction and relaxation to 5-HT in dog proximal stomach longitudinal muscle (LM) strips.2 Of the tryptamine analogues tested, 5-HT was the most potent contractile agent at basal length, while 5-CT was the most potent relaxant of PGF 2a -induced contraction. Neither the contractions to 5-HT, nor the relaxations to 5-CT were in¯uenced by tetrodotoxin, illustrating that action potential propagation is not involved. 3 The 5-HT-induced contraction was antagonized by mesulergine (0.03 to 0.3 mM) and ketanserin (2 ± 20 nM), but the antagonism was not of a simple competitive nature, indicating multiple receptor involvement. Ketanserin (3 to 30 nM) and mesulergine (30 nM) competitively antagonized the a-Me-5-HT-induced contraction (pK B : 8.83+0.09 and pA 2 : 8.25+0.06 respectively). These a nity values are in line with literature a nities of ketanserin and mesulergine at 5-HT 2A receptors in various bioassays. 4 The 5-CT-induced inhibition of PGF 2a -induced contraction was competitively antagonized by mesulergine (pK B estimate: 8.52+0.12) and by the selective 5-HT 7 receptor antagonist SB-269970 (pK B estimate: 9.36+0.14). Both pK B estimates are in line with literature a nities of these compounds for 5-HT 7 receptors. Mesulergine (30 nM) and SB-269970 (10 nM) shifted the relaxant curve to 5-HT parallel to the right in the presence of ketanserin (0.3 mM) (pA 2 estimates of 8.08+0.10 and 8.75+0.14 respectively), indicative of 5-HT 7 receptor involvement. 5 It is concluded that 5-HT induces dog proximal stomach (LM) contraction via smooth muscle 5-HT 2A receptors and relaxation via smooth muscle 5-HT 7 receptors.
1 Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT 1A receptors mediating relaxation of the proximal stomach in conscious dogs. 2 Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean7s.e.m.). All drugs were injected intravenously. 3 The 5-HT 1A receptor agonist flesinoxan (10, 50, 100 and 150 mg kg À1 ) induced a dose-dependent relaxation of the canine proximal stomach (50710, 230751, 290738 and 275733 ml, respectively; n ¼ 9 -11). The selective 5-HT 1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. N G -nitro-L-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. 4 After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317750 vs 142728 ml, respectively; n ¼ 5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. 5 It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT 1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.
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