Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat.
Calcitonin gene-related peptide (CGRP) is believed to play a pivotal role in the pathogenesis of migraine via activation of CGRP receptors in the trigeminovascular system. The CGRP receptor antagonist, BIBN4096BS, has proven efficacy in the acute treatment of migraine attacks and represents a new therapeutic principle. We used an improved closed cranial window model to measure changes of the middle meningeal artery (MMA) and cortical pial artery/arteriole diameter (PA) and changes in local cortical cerebral blood flow (LCBF(Flux)) in anaesthetised artificially ventilated rats. The ability of BIBN4096BS (i.v.) to prevent the vasodilatatory actions of rat-alphaCGRP, betaCGRP and endogenously released CGRP following transcranial electrical stimulation (TES) was investigated. BIBN4096BS was per se without vasoactive effect on any of the measured variables and significantly inhibited the hypotension induced by both types of CGRP (P < 0.001). The alphaCGRP induced MMA dilatation was reduced from 97.4 +/- 14 to 2.1 +/- 1.3% (P < 0.001) and the betaCGRP induced dilatation was fully blocked by BIBN4096BS. ID(50) was 5.4 +/- 1.6 microg kg(-1) for alphaCGRP and 16.3 +/- 1.6 microg kg(-1) for betaCGRP. Transcranial electrical stimulation induced a 119.1 +/- 6.9% increase in MMA diameter. BIBN4096BS (333 microg kg(-1)) attenuated this increase (19.8 +/- 2.1%) (P < 0.001). Systemic CGRP and TES induced an increase in PA diameter that was not significantly inhibited by BIBN4096BS. The CGRP induced increase in LCBF(Flux) was similar not prevented by the antagonist. We suggest that systemic BIBN4096BS exerts its inhibitory action mainly on large dural blood vessels (MMA).
Petersen
Kenneth A
KA
Danish Headache Center, University of Copenhagen and Department of Neurology, Glostrup University Hospital, Ndr. Ringvej 57, DK-2600 Glostrup, Denmark. kapetersen@dadlnet.dk
Birk
Steffen
S
Doods
Henri
H
Edvinsson
Lars
L
Olesen
Jes
J
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012886:Skull / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D010879:Piperazines; D011799:Quinazolines; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant