• Udayasankar Arulmani, Martin P Schuijt, Jan P C Heiligers, Edwin W Willems, Carlos M Villalón, and Pramod R Saxena.
• Department of Pharmacology, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
• Basic Clin. Pharmacol. Toxicol. 2004 Jun 1; 94 (6): 291-7.

AbstractSeveral studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel selective CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl] carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [[R-(R,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed to investigate the effects of intravenous BIBN4096BS on alpha-CGRP-induced systemic and regional haemodynamic changes in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of alpha-CGRP (0.25, 0.5 and 1 microg kg(-1) min.(-1)) dose-dependently decreased mean arterial blood pressure with an accompanying increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. Alpha-CGRP also increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodynamic responses to alpha-CGRP were clearly attenuated in BIBN4096BS (3 mg kg(-1) intravenously)-pretreated animals. These results indicate that exogenously administered alpha-CGRP dilates regional vascular beds via CGRP receptors on the basis of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional haemodynamics under resting conditions.

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