title: Functional and molecular characterization of the endothelin system in retinal arterioles.
abstract: OBJECTIVE
  Activation of the endothelin (ET) system has been implicated in the pathogenesis of retinal ischemic disease. Although ET-1, the predominant endogenous isoform of ET, has been shown to cause constriction of retinal vessels, the expression and functional significance of its synthesis and the involved specific ET receptors in retinal arterioles remain unknown. The authors examined the roles of ET(A) and ET(B) receptors and of endothelin-converting enzyme (ECE)-1 in ET-1-induced vasomotor responses of single retinal arterioles.
  
  
  METHODS
  To exclude systemic confounding effects, porcine retinal arterioles were isolated for vasoreactivity and molecular studies.
  
  
  RESULTS
  Isolated and pressurized retinal arterioles developed basal tone and constricted in a manner dependent on concentration to ET-1. ET-1 precursor big ET-1 elicited time-dependent vasoconstriction over 20 minutes, which was blocked by the ECE-1 inhibitor phosphoramidon. ET(A) receptor antagonist BQ123 inhibited most (approximately 90%) of vasoconstrictions to ET-1 and big ET-1. ET(B) receptor agonist sarafotoxin also elicited concentration-dependent constriction of retinal arterioles but with significantly less potency than ET-1. ET(B) receptor antagonist BQ788 abolished vasoconstriction to sarafotoxin but only slightly reduced responses to ET-1 and big ET-1. Protein and mRNA expressions of ET(A), ET(B), and ECE-1 were detected in retinal arterioles. Immunohistochemistry revealed ET(A) and ET(B) receptors predominantly in smooth muscle and ECE-1 predominantly in endothelium and smooth muscle.
  
  
  CONCLUSIONS
  ET-1 elicits constriction of retinal arterioles predominantly through the activation of smooth muscle ET(A) receptors. Endogenous production of ET-1 from vascular ECE-1 is sufficient to evoke ET(A) receptor-dependent constriction in retinal arterioles.
authors.affiliation: Department of Ophthalmology, Scott and White Eye Institute, Temple, Texas 76504, USA. thein@tamu.edu
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Zhaoxu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xu
authors.forename: Sonal
authors.initials: S
authors.lastname: Somvanshi
authors.forename: Taiji
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Yoshida
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000502:physiology*; D012161:Retinal Artery / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014661:Vasoconstriction / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon