Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteries
(2004) In British Journal of Pharmacology 143(8). p.1066-1073- Abstract
- 1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-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) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no... (More)
- 1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-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) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E-max. 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller ( lumen diameter similar to200 mum) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K-A, for CGRP(1) receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP1-like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration ( 10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca2+](i)) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations ( 0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP1 receptors in human subcutaneous arteries. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/259038
- author
- Sheykhzade, M ; Lind, H and Edvinsson, Lars LU
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- calcitonin gene-related peptide, subcutaneous artery, human, BIBN4096BS, affinity
- in
- British Journal of Pharmacology
- volume
- 143
- issue
- 8
- pages
- 1066 - 1073
- publisher
- Wiley
- external identifiers
-
- pmid:15477223
- wos:000225967300019
- scopus:11244302448
- ISSN
- 1476-5381
- DOI
- 10.1038/sj.bjp.0705967
- language
- English
- LU publication?
- yes
- id
- f1209176-6edc-4653-8f2d-cf398e1562e8 (old id 259038)
- date added to LUP
- 2016-04-01 16:48:10
- date last changed
- 2024-02-27 00:15:31
@article{f1209176-6edc-4653-8f2d-cf398e1562e8,
abstract = {{1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-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) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E-max. 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller ( lumen diameter similar to200 mum) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K-A, for CGRP(1) receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP1-like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration ( 10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca2+](i)) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations ( 0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP1 receptors in human subcutaneous arteries.}},
author = {{Sheykhzade, M and Lind, H and Edvinsson, Lars}},
issn = {{1476-5381}},
keywords = {{calcitonin gene-related peptide; subcutaneous artery; human; BIBN4096BS; affinity}},
language = {{eng}},
number = {{8}},
pages = {{1066--1073}},
publisher = {{Wiley}},
series = {{British Journal of Pharmacology}},
title = {{Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteries}},
url = {{http://dx.doi.org/10.1038/sj.bjp.0705967}},
doi = {{10.1038/sj.bjp.0705967}},
volume = {{143}},
year = {{2004}},
}