TY - JOUR
T1 - Long-lasting physiological antagonism of calcitonin gene-related peptide towards endothelin-1 in rat mesenteric arteries and human coronary arteries
AU - Labruijere, Sieneke
AU - Compeer, Matthijs G.
AU - van den Bogaerdt, Antoon J.
AU - van den Brink, Antoinette Maassen
AU - De Mey, Jo G. R.
AU - Danser, A. H. Jan
AU - Batenburg, Wendy W.
PY - 2013/11/15
Y1 - 2013/11/15
N2 - Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding calcitonin-gene related peptide (CGRP), most likely because CGRP causes ET-/ETAR dissociation. Here we investigated this phenomenon in human coronary microarteries (HCMA). We simultaneously verified the effects of CGRP in RMA and HCMA towards other vasoconstrictors, i.e., the alpha(1)-adrenoceptor agonist phenylephrine, the thromboxane A(2) analog U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F-2 alpha) and KG. Long-lasting contraction (remaining after washing away the agonist) was observed for ET-1 in RMA, but not HCMA. Constrictions to phenylephrine, U46619 or KCl did not last upon washing. When added on Lop of ET-1-initiatecl contraction in RMA, CGRP effectively counteracted vasoconstriction, i.e., it caused full relaxation. Inhibitory effects of CGRP were also observed when briefly exposing RMA and HCMA to CGRP 1 h before the addition of ET 1, Similar inhibitory effects of transient CGRP pre-incubation were seen towards phenylephrine. U46619 or KCl in RMA and HCMA. In conclusion, our data imply that CGRP, like ET-1, causes long-lasting effects that remain apparent up to 1 h after its removal horn the organ bath. Thus, in addition to the reported dissociation of ET-1/ETAR complexes, CGRP causes long-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs.
AB - Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding calcitonin-gene related peptide (CGRP), most likely because CGRP causes ET-/ETAR dissociation. Here we investigated this phenomenon in human coronary microarteries (HCMA). We simultaneously verified the effects of CGRP in RMA and HCMA towards other vasoconstrictors, i.e., the alpha(1)-adrenoceptor agonist phenylephrine, the thromboxane A(2) analog U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F-2 alpha) and KG. Long-lasting contraction (remaining after washing away the agonist) was observed for ET-1 in RMA, but not HCMA. Constrictions to phenylephrine, U46619 or KCl did not last upon washing. When added on Lop of ET-1-initiatecl contraction in RMA, CGRP effectively counteracted vasoconstriction, i.e., it caused full relaxation. Inhibitory effects of CGRP were also observed when briefly exposing RMA and HCMA to CGRP 1 h before the addition of ET 1, Similar inhibitory effects of transient CGRP pre-incubation were seen towards phenylephrine. U46619 or KCl in RMA and HCMA. In conclusion, our data imply that CGRP, like ET-1, causes long-lasting effects that remain apparent up to 1 h after its removal horn the organ bath. Thus, in addition to the reported dissociation of ET-1/ETAR complexes, CGRP causes long-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs.
KW - Endothelin-1
KW - Calcitonin-gene related peptide
KW - BQ123
KW - Rat mesenteric artery
KW - Human coronary artery
U2 - 10.1016/j.ejphar.2013.10.012
DO - 10.1016/j.ejphar.2013.10.012
M3 - Article
C2 - 24140435
SN - 0014-2999
VL - 720
SP - 303
EP - 309
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -