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 (pK_i) 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.