5-HT1B receptor-mediated contractions in human temporal artery:: evidence from selective antagonists and 5-HT receptor mRNA expression

1 In the human temporal artery both 5-HT1-like and 5-HT2A receptors mediate the contractile effects of 5-hydroxytryptamine (5-HT) and we have suggested that the 5-HT1-like receptors resemble more closely recombinant 5-HT1B than 5-HT1D receptors. To investigate further which subtype is involved, we investigated the blockade of 5-HT-induced contractions by the 5-HT1B-selective antagonist SE-224289 (2,3,6,7-tetrahydro-1'-methyl-5-{2-methyl-4'[(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] carbonyl) furo[2,3-f]indole-3-spiro-4'-piperidine oxalate) and the 5-HT1D-selective antagonist BRL-15572 (1-phenyl-3[4-3-chlorophenyl piperazin-1-yl] phenylpropan-2-ol). We also used RT-PCR to search for the mRNA of 5-HT1B, 5-HT1D and other 5-HT receptors. 2 The contractile effects of 5-HT in temporal artery rings were partially antagonized by SB-224289 (20, 200 nM) (apparent K-B = 1 nM) and ketanserin (1 mu M) but not by BRL-15572 (500 nM). 3 Sumatriptan evoked contractions (EC50, 170 nM) that were resistant to blockade by BRL-15572 (500 nM) but antagonized by SE-224289 (20, 200 nhl). 4 The potency of 5-HT (EC50) was estimated to be 94 nM for the ketanserin-sensitive receptor and 34 nM for the SB-224289-sensitive receptor. The fraction of maximal 5-HT response mediated through SB-224289-sensitive receptors was 0.20 - 0.67, the remainder being media ted through ketanserin-sensitive receptors. 5 We detected arterial receptor mRNA for the following receptors (incidence): 5-HT1B (8/8)t 5-HT1D (2/8), 5-HT1F (0/4), 5-HT2A (0/8), 5-HT2B (0/8), 5-HT2C (0/8), 5-HT4 (4/8) and 5-HT7 (4/8). 6 We conclude that the ketanserin-resistant fraction of the 5-HT effects and the effects of sumatriptan are mediated by 5-HT1B receptors. The lack of antagonism by BRL-15572 rules out 5-HT1D receptors as mediators of the contractile effects of 5-HT and sumatriptan.