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TRP channel activation promotes dissociation of ET‐1/ET A ‐complexes and terminates vasoconstriction in rat resistance arteries.
Author(s) -
Meens Merlijn JPMT,
Compeer Matthijs G,
Zandvoort Marc A,
Hackeng Tilman M,
De Mey Jo GR
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.961.7
Subject(s) - chemistry , mesenteric arteries , vasoconstriction , allosteric regulation , vasodilation , agonist , receptor , calcitonin gene related peptide , endocrinology , medicine , biophysics , biochemistry , biology , neuropeptide , artery
Objectives We tested whether TRP channel activation promotes dissociation of ET‐1/ET A ‐complexes. Methods 2 nd order rat mesenteric arteries were investigated by two‐photon laser scanning microscopy and wire‐myography. Results ET‐1 (1–16nM) and rhodamine‐labeled ET‐1 (Rh‐ET‐1; 1–16nM) cause ET A ‐mediated contractions that fade slowly after agonist removal and are insensitive to ET B ‐antagonism. Contractions remaining after ET‐1 exposure are transiently reversed by several vasodilators, but persistently inhibited by i) TRP‐channel activators such as rutaecarpine (10 μM), allyl isothiocyanate (10 μM) and capsaicin (1 μM) or ii) CGRP (0.1 μM). CGRP‐receptor antagonists reduce the effects of TRP channel activators and CGRP. ET‐1 causes contractions with its original potency after reversal of ET‐1‐induced contractions by CGRP. Rh‐ET‐1 (16nM) binds to the tunica media of intact arteries. This persists after label removal but is abolished by CGRP (0.1 μM). Conclusion In arterial smooth muscle, ET‐1 binds “irreversibly” to ET A ‐receptors; this causes prolonged signaling of the ET‐1/ET A ‐complex. ET‐1/ET A ‐complexes are a) insensitive to vasodilators or removal of free ligand and b) susceptible to allosteric inhibition by endogenous CGRP released by TRP channel activation. This research was performed within the framework of project T2‐108 of the Dutch Top Institute Pharma.