Characterisation of CGRP receptors in human and porcine isolated coronary arteries: Evidence for CGRP receptor heterogeneity

This study sets out to characterise calcitonin gene-related peptide (CGRP) receptors in human and porcine isolated proximal and distal coronary arteries using BIBN4096BS. Human (h)-αCGRP induced relaxations that were blocked by BIBN4096BS in all arteries studied. In contrast to the other vessels, the Schild plot slope in the human distal coronary artery segments (0.68 ± 0.07) was significantly less than unity and BIBN4096BS potently blocked these responses (pKb (10 nM): 9.29 ± 0.34, n = 5). In the same preparation, h-αCGRP8-37 behaved as a weak antagonist of h-αCGRP-induced relaxations (pKb (3 μM): 6.28 ± 0.17, n = 4), with also a Schild plot slope smaller than unity. The linear agonists, [ethylamide-Cys2,7]-h-αCGRP ([Cys(Et)2,7]-h- αCGRP) and [acetimidomethyl-Cys2,7]-h-αCGRP ([Cys(Acm)2,7]-h-αCGRP), had a high potency (pEC50: 8.21 ± 0.25 and 7.25 ± 0.14, respectively), suggesting the presence of CGRP2 receptors, while the potent blockade by BIBN4096BS (pKb (10 nM): 10.13 ± 0.29 and 9.95 ± 0.11, respectively) points to the presence of CGRP1 receptors. Using RT-PCR, mRNAs encoding for the essential components for functional CGRP 1 receptors were demonstrated in both human proximal and distal coronary artery. Further, h-αCGRP (100 nM) increased cAMP levels, and this was attenuated by BIBN4096BS (1 μM). The above results demonstrate the presence of CGRP1 receptors in all coronary artery segments investigated, but the human distal coronary artery segments seem to have an additional population of CGRP receptors not complying with the currently classified CGRP1 or CGRP2 receptors.

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