Effects of BIBN4096BS on cardiac output distribution and on CGRP-induced carotid haemodynamic responses in the pig.
Calcitonin gene related peptide (CGRP) seems to be involved in the pathogenesis of migraine, since plasma CGRP levels increase during the headache phase. In the present study, we investigated the effects of a novel 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*,S*)]-), on the regional cardiac output distribution and on the carotid haemodynamic changes induced by alpha-CGRP in anaesthetised pigs. Treatment with BIBN4096BS (100, 300 and 1000 microg kg(-1), i.v.) did not affect the heart rate, mean arterial blood pressure or systemic vascular conductance, but a small decrease in cardiac output was noticed; the latter was, however, not significantly different from that in vehicle-treated animals. The highest dose of BIBN4096BS moderately decreased vascular conductance in the lungs, kidneys, spleen and adrenals. Vascular conductance in other tissues including the brain, heart, gastrointestinal system, skin and skeletal muscles remained unchanged. Intracarotid artery infusions of alpha-CGRP (10, 30 and 100 pmol kg(-1) min(-1) during 3 min) increased the total carotid blood flow and conductance, but decreased the arterial blood pressure. These responses were dose-dependently blocked by BIBN4096BS. The above results show that BIBN4096BS is a CGRP receptor antagonist in the porcine carotid and systemic circulations, but the endogenous CGRP does not seem to play an important physiological role in regulating basal vascular tone. These findings suggest that BIBN4096BS may have therapeutic usefulness in migraine.
Kapoor
Kapil
K
Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Arulmani
Udayasankar
U
Heiligers
Jan P C
JP
Willems
Edwin W
EW
Doods
Henri
H
Villalón
Carlos M
CM
Saxena
Pramod R
PR
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002302:Cardiac Output / Q000187:drug effects* / Q000502:physiology; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D013552:Swine
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010879:Piperazines; D011799:Quinazolines; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant