Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX
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Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX. / Sheykhzade, Majid; Abdolalizadeh, Bahareh; Koole, Cassandra; Pickering, Darryl S; Dreisig, Karin; Johansson, Sara Ellinor; Abboud, Balsam Kadri; Dreier, Rasmus; Berg, Jais Oliver; Jeppesen, Jørgen Lykke; Sexton, Patrick; Edvinsson, Lars; Wootten, Denise; Sams, Anette.
In: European Journal of Pharmacology, Vol. 829, 2018, p. 85-92.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX
AU - Sheykhzade, Majid
AU - Abdolalizadeh, Bahareh
AU - Koole, Cassandra
AU - Pickering, Darryl S
AU - Dreisig, Karin
AU - Johansson, Sara Ellinor
AU - Abboud, Balsam Kadri
AU - Dreier, Rasmus
AU - Berg, Jais Oliver
AU - Jeppesen, Jørgen Lykke
AU - Sexton, Patrick
AU - Edvinsson, Lars
AU - Wootten, Denise
AU - Sams, Anette
PY - 2018
Y1 - 2018
N2 - The purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and SAX, a metabolically stable CGRP analog, in isolated rat and human artery segments (vasoactivity), in recombinant human CGRP receptors (cAMP accumulation), and in native rat receptors (receptor binding).Vasodilatory potencies (pEC50) of SAX and CGRP in isolated rat mesenteric artery were 8.2 ± 0.12 and 9.0 ± 0.11 and the CGRP receptor antagonist BIBN4096BS competitively inhibited the vasodilatory effects of SAX and CGRP with potencies (pA2) of 7.6 ± 0.13 and 8.0 ± 0.16. mRNAs encoding CGRP receptors (CLR and RAMP1) were expressed in the artery. In rat cerebral membranes, binding affinities (pKi) of SAX and CGRP were 8.3 ± 0.19 and 9.3 ± 0.14.In human subcutaneous artery, SAX and CGRP induced vasodilation (pEC50 8.8 ± 0.18 and 9.5 ± 0.13), while pEC50s for cAMP production by human recombinant receptors were 9.1 ± 0.16 and 10.2 ± 0.19. Here, pA2 values of BIBN4096BS were 10.5 ± 0.24 and 11.1 ± 0.32. The presence of albumin caused a selective 10-fold reduction in potency and binding affinity of SAX.In conclusion, SAX and CGRP act on a uniform BIBN4096BS sensitive receptor population in our experiments and the potency of SAX is 5-10 fold lower than that of CGRP.
AB - The purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and SAX, a metabolically stable CGRP analog, in isolated rat and human artery segments (vasoactivity), in recombinant human CGRP receptors (cAMP accumulation), and in native rat receptors (receptor binding).Vasodilatory potencies (pEC50) of SAX and CGRP in isolated rat mesenteric artery were 8.2 ± 0.12 and 9.0 ± 0.11 and the CGRP receptor antagonist BIBN4096BS competitively inhibited the vasodilatory effects of SAX and CGRP with potencies (pA2) of 7.6 ± 0.13 and 8.0 ± 0.16. mRNAs encoding CGRP receptors (CLR and RAMP1) were expressed in the artery. In rat cerebral membranes, binding affinities (pKi) of SAX and CGRP were 8.3 ± 0.19 and 9.3 ± 0.14.In human subcutaneous artery, SAX and CGRP induced vasodilation (pEC50 8.8 ± 0.18 and 9.5 ± 0.13), while pEC50s for cAMP production by human recombinant receptors were 9.1 ± 0.16 and 10.2 ± 0.19. Here, pA2 values of BIBN4096BS were 10.5 ± 0.24 and 11.1 ± 0.32. The presence of albumin caused a selective 10-fold reduction in potency and binding affinity of SAX.In conclusion, SAX and CGRP act on a uniform BIBN4096BS sensitive receptor population in our experiments and the potency of SAX is 5-10 fold lower than that of CGRP.
U2 - 10.1016/j.ejphar.2018.04.007
DO - 10.1016/j.ejphar.2018.04.007
M3 - Journal article
C2 - 29653090
VL - 829
SP - 85
EP - 92
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
ER -
ID: 193173387