title: Differential localization and characterization of functional calcitonin gene-related peptide receptors in human subcutaneous arteries.
abstract: OBJECTIVE
  Calcitonin gene-related peptide (CGRP) and its receptor are widely distributed within the circulation and the mechanism behind its vasodilation not only differs from one animal species to another but is also dependent on the type and size of vessel. The present study examines the nature of CGRP-induced vasodilation, characteristics of the CGRP receptor antagonist telcagepant and localization of the key components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) of the CGRP receptor in human subcutaneous arteries.
  
  
  METHODS
  CGRP-induced vasodilation and receptor localization in human subcutaneous arteries were studied by wire myograph in the presence and absence of the CGRP receptor antagonist telcagepant and immunohistochemistry respectively.
  
  
  RESULTS
  At concentrations of 1, 3, 5, 10 and 30 nm, telcagepant had a competitive antagonist-like behaviour characterized by a parallel rightwards shift in the log CGRP concentration-tension/calcium curve with no depression of the maximal relaxation. CGRP-induced vasodilation was not affected by mechanical removal of the endothelium or addition of L-NG-nitroarginine methyl ester and indomethacin, antagonists for synthesis of nitric oxide and prostaglandins, respectively. CLR and RAMP1 were localized in the vascular smooth muscle and endothelial cells.
  
  
  CONCLUSIONS
  The present results indicate that CGRP exerts its vasodilatory effect in human subcutaneous arteries by binding to its receptors located on the smooth muscle cells and is suggested to be endothelium-independent. In conclusion, these results underline the dynamic distribution of CGRP receptor components in the human circulation reflecting the important role of CGRP in fine tuning of the blood flow in resistance arteries.
authors: Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
authors: L
authors: L
authors: Edvinsson
authors: H
authors: H
authors: Ahnstedt
authors: R
authors: R
authors: Larsen
authors: M
authors: M
authors: Sheykhzade
mesh_terms: D000328:Adult; D000368:Aged; D001158:Arteries / Q000187:drug effects* / Q000502:physiology*; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D015237:Dinoprost; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000098:blood supply*; D055815:Young Adult
chemical_list: D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D018015:Receptors, Calcitonin Gene-Related Peptide; D015237:Dinoprost; C525458:telcagepant
keywords: MK-0974; affinity; calcitonin gene-related peptide; human subcutaneous artery; telcagepant