Effects of the Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist BIBN4096BS on alpha-CGRP-Induced Regional Haemodynamic Changes in Anaesthetised Rats

Department of Pharmacology, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Basic & Clinical Pharmacology & Toxicology (Impact Factor: 2.38). 07/2004; 94(6):291-7. DOI: 10.1111/j.1742-7843.2004.pto940606.x
Source: PubMed


Several 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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Available from: Pramod R Saxena, Oct 06, 2014
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    • "In contrast to studies in vitro, preclinical in vivo studies in multiple species with CGRP 8 –37 and olcegepant have reported no intrinsic hemodynamic effects. Specifically regarding coronary function, in vivo hemodynamic studies in normal dogs have reported no effect of CGRP 8 –37 on coronary or myocardial regional blood flow (Shen et al., 2001), and no effect of the small-molecule CGRP receptor antagonist olcegepant on myocardial vascular conductance has been reported in normal rat and pig (Kapoor et al., 2003;Arulmani et al., 2004). In addition, in vivo ischemia/reperfusion studies in rat and pig reported that CGRP 8 –37 and olcegepant had no effect on infarct size (Kä llner et al., 1998Kä llner et al., , Wu et al., 2001). "
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