title: Effects of an endothelin receptor antagonist on a model of hypertensive retinopathy.
abstract: Hypertensive retinopathy manifests itself as progressive retinal microvascular pathology in response to aberrant blood flow. The current study sought to evaluate whether dysfunction of the vasoactive endothelin-1 (ET-1) system is involved in the pathogenesis of hypertension-induced retinopathy in an animal model of systemic hypertension. The endothelin receptor antagonist, bosentan, was administered to spontaneously hypertensive rats (SHRs) and comparisons were made with untreated SHRs and normotensive Wistar Kyoto (WKY) rats. The retinal mRNA expression of ET-1, ET-converting enzyme-1, ET(A) and ET(B) receptors and the basement membrane proteins, laminin beta1, collagen IV and fibronectin was quantified using real-time RT-PCR. In addition, retinal arteriole and/or capillary bed damage was assessed by qualitative and quantitative microscopy. mRNA for the ET(A) receptor was increased in SHRs, when compared to WKY control animals (p < 0.001). Treatment with bosentan in SHRs significantly reduced the expression of ET-1 (p < 0.05), and both the ET(A) (p < 0.0001) and ET(B) (p < 0.05) receptor subtypes. The laminin beta1, collagen IV and fibronectin mRNA expression was significantly higher in SHRs when compared to WKY control animals (p < 0.001). Treatment with bosentan abolished these responses and also the appearance of various microvascular lesions. ET-mediated vasoregulation abnormalities in the retinal microvasculature could play an associative role in lesion formation during hypertensive retinopathy.
authors.affiliation: Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Louise
authors.initials: L
authors.lastname: McDonald
authors.forename: Graham R
authors.initials: GR
authors.lastname: Lee
authors.forename: Tanyth E
authors.initials: TE
authors.lastname: Degooyer
authors.forename: Denise
authors.initials: D
authors.lastname: McDonald
authors.forename: Paul
authors.initials: P
authors.lastname: Canning
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kelso
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McDermott
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001485:Basement Membrane; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics; D012164:Retinal Diseases / Q000378:metabolism / Q000503:physiopathology*; D012171:Retinal Vessels / Q000378:metabolism / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008565:Membrane Proteins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000077300:Bosentan