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Characterization of...
Characterization of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Arteries
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Chan, K. Y. (author)
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- Edvinsson, Lars (author)
- Lund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Eftekhari, Sajedeh (author)
- Lund University,Lunds universitet,Medicin, Lund,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medicine, Lund,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Kimblad, Per Ola (author)
- Lund University,Lunds universitet,Thoraxkirurgi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Thoracic Surgery,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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Kane, S. A. (author)
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Lynch, J. (author)
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Hargreaves, R. J. (author)
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de Vries, R. (author)
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Garrelds, I. M. (author)
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van den Bogaerdt, A. J. (author)
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Danser, A. H. J. (author)
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MaassenVanDenBrink, A. (author)
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(creator_code:org_t)
- 2010-06-23
- 2010
- English.
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 334:3, s. 746-752
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Abstract
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- The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan- 3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-c arboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alpha CGRP were greater in distal coronary arteries (i.d. 600-1000 mu m; E-max = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E-max = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E-max = 11 +/- 3%), and coronary arterioles (i.d. 200-300 mu m; E-max = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 mu M) antagonized alpha CGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 mu M telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alpha CGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Annan klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Other Clinical Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kirurgi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Surgery (hsv//eng)
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Chan, K. Y.
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Edvinsson, Lars
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Eftekhari, Sajed ...
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Kimblad, Per Ola
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Kane, S. A.
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Lynch, J.
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show more...
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Hargreaves, R. J ...
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de Vries, R.
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Garrelds, I. M.
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van den Bogaerdt ...
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Danser, A. H. J.
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MaassenVanDenBri ...
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Lund University