Homologous desensitization of calcitonin gene-related peptide-induced relaxation in rat intramural coronary arteries.

We investigated the type of desensitization of calcitonin gene-related peptide (CGRP)-induced responses in rat isolated intramural coronary arteries using isometric myograph and FURA-2 technique. In coronary arteries precontracted with 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha (U46619), development of tachyphylaxis to CGRP is characterized by significant attenuation of CGRP-induced maximal reduction in the tension and Ca2+ during the second CGRP concentration-response curve; however, there was no further reduction in the CGRP-induced maximum relaxation during the third CGRP concentration-response curve. There was no sign of tachyphylaxis to CGRP when CGRP concentration-response curves were recorded in 36 mM K+-depolarized coronary arteries contrary to the results obtained in 300 nM U46619-precontracted coronary arteries. Preincubation with colchicine did not prevent the development of tachyphylaxis to CGRP in U46619-precontracted coronary arteries, indicating no role for endocytosis. Development of tachyphylaxis to CGRP was completely abolished by preincubating the coronary arteries with 1 microM RO 31-8220, indicating a role for protein kinases. Pre-exposure of the coronary arteries to isoprenaline or forskolin did not attenuate the CGRP-induced relaxation in these vessels, indicating that the cAMP-protein kinase A (PKA) pathway is not involved. Like CGRP, the coronary arteries developed tachyphylaxis toward isoprenaline during the second exposure. However, there was no sign of tachyphylaxis to either forskolin or dibutyryl cAMP (dbcAMP) during the second exposure. In conclusion, these results suggest that development of tachyphylaxis to CGRP in U46619-precontracted coronary is related to CGRP receptor-mediated activation of protein kinase.