BIBN4096BS and CGRP(8-37) antagonize the relaxant effects of alpha-CGRP more than those of beta-CGRP in human extracranial arteries

Naunyn Schmiedebergs Arch Pharmacol. 2005 May;371(5):383-92. doi: 10.1007/s00210-005-1064-4. Epub 2005 Jun 28.

Abstract

We hypothesize that dilatation of extracranial arteries during migraine could be caused by CGRP. We compared the relaxant effects of alpha-calcitonin gene-related peptide (alpha-CGRP) and beta-calcitonin gene-related peptide (beta-CGRP) and the antagonism by BIBN4096BS and CGRP(8-37) on rings of human temporal and occipital arteries precontracted with KCl. beta-CGRP relaxed temporal (-logEC50M = 8.1) and occipital arteries (-logEC50M = 7.6) with 19-fold and 29-fold lower potencies respectively than alpha-CGRP. Nearly maximal effective concentrations of alpha-CGRP (4 nM) and beta-CGRP (50 nM) caused stable relaxations of the temporal artery for 4 h without fading. BIBN4094BS antagonized the effects of alpha-CGRP (pK(B) = 10.1 and 9.9, respectively) more than beta-CGRP (pK(B) = 9.3 and 9.2 respectively) on both temporal and occipital arteries. CGRP(8-37) antagonized the effects of alpha-CGRP (pK(B) = 6.6 and 6.4 respectively) more than beta-CGRP (pK(B) = 5.7 and 5.5 respectively) on both temporal and occipital arteries. Antagonism of the relaxant effects of alpha-CGRP (4 nM) and beta-CGRP (50 nM) by BIBN4096BS (10 and 100 nM) was reversible for beta-CGRP, but irreversible for alpha-CGRP, 1 h after BIBN4096BS washout. We conclude that alpha-CGRP and beta-CGRP interact either at different binding sites of the same CGRP receptor system or all together with different receptor systems in human extracranial arteries. BIBN4096BS binds more firmly to the receptor activated by alpha-CGRP than to the receptor activated by beta-CGRP.

MeSH terms

  • Adult
  • Aged
  • Calcitonin Gene-Related Peptide / antagonists & inhibitors*
  • Calcitonin Gene-Related Peptide / pharmacology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Miotics / pharmacology*
  • Muscle, Smooth, Vascular / drug effects*
  • Peptide Fragments / pharmacology*
  • Piperazines / pharmacology*
  • Quinazolines / pharmacology*
  • Temporal Arteries / drug effects
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects*
  • Vasodilator Agents / antagonists & inhibitors*

Substances

  • Miotics
  • Peptide Fragments
  • Piperazines
  • Quinazolines
  • Vasodilator Agents
  • calcitonin gene-related peptide (8-37)
  • Calcitonin Gene-Related Peptide
  • olcegepant