Vasoconstriction in Human Isolated Middle Meningeal Arteries: Determining the Contribution of 5-HT1B- And 5-HT1F-receptor Activation

Br J Clin Pharmacol. 1999 Jan;47(1):75-82. doi: 10.1046/j.1365-2125.1999.00851.x.

Abstract

Aims: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction.

Methods: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines.

Results: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively).

Conclusions: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Binding, Competitive
  • CHO Cells
  • Cell Line
  • Cloning, Molecular
  • Cricetinae
  • Humans
  • In Vitro Techniques
  • Meningeal Arteries / drug effects*
  • Oxadiazoles / pharmacology*
  • Piperazines / pharmacology*
  • Pyridines / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, Serotonin / classification
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Sumatriptan / pharmacology
  • Vasoconstriction / drug effects*

Substances

  • Benzamides
  • N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-3-methyl-4-(4-pyridyl)benzamide
  • Oxadiazoles
  • Piperazines
  • Pyridines
  • RNA, Messenger
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • GR 127935
  • Sumatriptan