Pharmacological characterization of the 5‐HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle

We aimed to characterize 5‐HT receptors mediating contraction and relaxation to 5‐HT in dog proximal stomach longitudinal muscle (LM) strips. 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 2α ‐induced contraction. Neither the contractions to 5‐HT, nor the relaxations to 5‐CT were influenced by tetrodotoxin, illustrating that action potential propagation is not involved. The 5‐HT‐induced contraction was antagonized by mesulergine (0.03 to 0.3 μ M ) and ketanserin (2–20 n M ), but the antagonism was not of a simple competitive nature, indicating multiple receptor involvement. Ketanserin (3 to 30 n M ) and mesulergine (30 n M ) competitively antagonized the α‐Me‐5‐HT‐induced contraction (pK B : 8.83±0.09 and pA 2 : 8.25±0.06 respectively). These affinity values are in line with literature affinities of ketanserin and mesulergine at 5‐HT 2A receptors in various bioassays. The 5‐CT‐induced inhibition of PGF 2α ‐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 affinities of these compounds for 5‐HT 7 receptors. Mesulergine (30 n M ) and SB‐269970 (10 n M ) shifted the relaxant curve to 5‐HT parallel to the right in the presence of ketanserin (0.3 μ M ) (pA 2 estimates of 8.08±0.10 and 8.75±0.14 respectively), indicative of 5‐HT 7 receptor involvement. 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.British Journal of Pharmacology (2002) 136 , 321–329; doi: 10.1038/sj.bjp.0704716