Improvement of the closed cranial window model in rats by intracarotid infusion of signalling molecules implicated in migraine.
Intravital microscopy on a closed cranial window allows one to measure change in the diameter of cranial blood vessels after intravenous (i.v.) administration of pharmacodynamic substances. Putative targets being pursued in migraine are large vasodilating peptide molecules such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase polypeptide (PACAP)-38. High i.v. doses are required to study their craniovascular pharmacology. Unfortunately, this leads to a drop in blood pressure (BP) that subsequently causes blood vessels to dilate by autoregulation. Hence it is difficult to decipher what effect is caused by direct receptor agonist interaction or contributed by autoregulation. In the present study we infused substances with an ingenious indwelling catheter in the common carotid artery in rats. Intracarotidly seven-, 12- and 17-fold lower doses of CGRP, PACAP-38 and capsaicin were required, respectively, compared with i.v. infusion to induce the same dilation in dural artery. Dilating intracarotid (i.c.) doses caused no or a minimal fall in BP, whereas equi-responsive i.v. doses caused a marked BP reduction. The CGRP blocking potential of olcegepant was amplified by > 20 times on i.c. infusion. Pial artery responses to CGRP did not change with i.c. infusion, demonstrating that dilations after i.v. CGRP are mediated by autoregulation rather than through specific receptors. We applied CGRP topically, which induced concentration-dependent dural vasodilation, but no effect on pial artery or on BP. In conclusion, this new approach offers an improvement of the existing model by allowing more accurate assessment of effects of pharmaca on the cranial vasculature without inducing significant systemic effects.
Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Science, University of Copenhagen, Glostrup, Denmark. saugup01@glo.regionh.dk
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S
Gupta
D K
DK
Bhatt
L J
LJ
Boni
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Olesen
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D002339:Carotid Arteries; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008297:Male; D008853:Microscopy / Q000379:methods; D008881:Migraine Disorders / Q000139:chemically induced* / Q000378:metabolism; D010879:Piperazines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004151:Dipeptides; D010879:Piperazines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011799:Quinazolines; D014665:Vasodilator Agents; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C406305:olcegepant