Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, DK-2600 Glostrup, Denmark.
Eur J Pharmacol. 2018 Jun 15;829:85-92. doi: 10.1016/j.ejphar.2018.04.007. Epub 2018 Apr 10.
The main purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and a recently discovered metabolically stable CGRP analogue, SAX, in isolated rat and human artery segments. In rat, CGRP and SAX induced similar vasodilatory responses in isolated mesenteric artery with the potency of SAX being lower than that of CGRP (vasodilatory pEC 8.2 ± 0.12 and 9.0 ± 0.11, respectively). A corresponding difference in receptor binding affinity of SAX and CGRP was determined in rat cerebral membranes (pKi 8.3 ± 0.19 and 9.3 ± 0.14, respectively). CGRP and SAX-induced vasodilation was antagonised with similar potencies by the CGRP receptor antagonist BIBN4096BS supporting a uniform receptor population for the agonists. In human tissue, SAX and CGRP induced similar pharmacological responses with different potencies in subcutaneous artery (vasodilatory pEC 8.8 ± 0.18 and 9.5 ± 0.13, respectively) and human recombinant receptors (cAMP signalling pEC 9.1 ± 0.16 and 10.2 ± 0.19). Like in the rat mesenteric artery, both SAX and CGRP-responses were inhibited by the CGRP receptor antagonist BIBN4096BS with similar antagonistic potencies. In conclusion, all pharmacological characteristics of SAX and CGRP in human and rat sources points towards action via a uniform BIBN4096BS sensitive receptor population with the potency of SAX being 5-10 fold lower than that of CGRP.
本研究的主要目的是比较人 αCGRP（CGRP）和最近发现的代谢稳定的 CGRP 类似物 SAX 在离体大鼠和人动脉段中的体外药理学特性。在大鼠中，CGRP 和 SAX 在离体肠系膜动脉中引起相似的血管舒张反应，SAX 的效力低于 CGRP（血管舒张 pEC8.2±0.12 和 9.0±0.11，分别）。在大鼠脑膜中确定了 SAX 和 CGRP 的相应受体结合亲和力差异（pKi8.3±0.19 和 9.3±0.14，分别）。CGRP 受体拮抗剂 BIBN4096BS 以相似的效力拮抗 CGRP 和 SAX 诱导的血管舒张，支持激动剂的均匀受体群体。在人组织中，SAX 和 CGRP 以不同的效力在皮下动脉（血管舒张 pEC8.8±0.18 和 9.5±0.13，分别）和人重组受体（cAMP 信号传导 pEC9.1±0.16 和 10.2±0.19）中诱导相似的药理反应。与大鼠肠系膜动脉一样，SAX 和 CGRP 反应均被 CGRP 受体拮抗剂 BIBN4096BS 抑制，具有相似的拮抗效力。总之，SAX 和 CGRP 在人和大鼠来源中的所有药理特性都表明通过统一的 BIBN4096BS 敏感受体群体起作用，SAX 的效力比 CGRP 低 5-10 倍。
