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 SB-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 KB = 1 nM) and ketanserin (1 microM) 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 SB-224289 (20, 200 nM). 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 mediated through ketanserin-sensitive receptors. 5. We detected arterial receptor mRNA for the following receptors (incidence): 5-HT1B (8/8), 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.
Verheggen
R
R
Department of Neurosurgery, University of Göttingen, Germany.
Hundeshagen
A G
AG
Brown
A M
AM
Schindler
M
M
Kaumann
A J
AJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D001713:Biphenyl Compounds / Q000494:pharmacology; D017931:DNA Primers; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D013699:Temporal Arteries / Q000187:drug effects* / Q000502:physiology
D001713:Biphenyl Compounds; D017931:DNA Primers; C470302:HTR1B protein, human; D010879:Piperazines; D010881:Piperidones; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; C108518:SB 22489G; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D018170:Sumatriptan; C108532:BRL 15572