Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteries

1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1 -[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]4-(1,4- dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E-max. 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller ( lumen diameter similar to200 mum) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K-A, for CGRP(1) receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP1-like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration ( 10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca2+](i)) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations ( 0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP1 receptors in human subcutaneous arteries.