title: Protection of protease-activated receptor 2 mediated vasodilatation against angiotensin II-induced vascular dysfunction in mice.
abstract: BACKGROUND
  Under conditions of cardiovascular dysfunction, protease-activated receptor 2 (PAR2) agonists maintain vasodilatation activity, which has been attributed to increased cyclooxygenase-2, nitric oxide synthase and calcium-activated potassium channel (SK3.1) activities. Protease-activated receptor 2 agonist mediated vasodilatation is unknown under conditions of dysfunction caused by angiotensin II. The main purpose of our study was to determine whether PAR2-induced vasodilatation of resistance arteries was attenuated by prolonged angiotensin II treatment in mice. We compared the vasodilatation of resistance-type arteries (mesenteric) from angiotensin II-treated PAR2 wild-type mice (WT) induced by PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) to the responses obtained in controls (saline treatment). We also investigated arterial vasodilatation in angiotensin II-treated PAR2 deficient (PAR2-/-) mice.
  
  
  RESULTS
  2fly-induced relaxations of untreated arteries from angiotensin II-treated WT were not different than saline-treated WT. Treatment of arteries with nitric oxide synthase inhibitor and SK3.1 inhibitor (L-NAME + TRAM-34) blocked 2fly in angiotensin II-treated WT. Protein and mRNA expression of cyclooxygenase-1 and -2 were increased, and cyclooxygenase activity increased the sensitivity of arteries to 2fly in only angiotensin II-treated WT. These protective vasodilatation mechanisms were selective for 2fly compared with acetylcholine- and nitroprusside-induced relaxations which were attenuated by angiotensin II; PAR2-/- were protected against this attenuation of nitroprusside.
  
  
  CONCLUSIONS
  PAR2-mediated vasodilatation of resistance type arteries is protected against the negative effects of angiotensin II-induced vascular dysfunction in mice. In conditions of endothelial dysfunction, angiotensin II induction of cyclooxygenases increases sensitivity to PAR2 agonist and the preserved vasodilatation mechanism involves activation of SK3.1.
authors.affiliation: Memorial University, St, John's, Newfoundland and Labrador, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chia
authors.forename: Satomi
authors.initials: S
authors.lastname: Kagota
authors.forename: Enoka P
authors.initials: EP
authors.lastname: Wijekoon
authors.forename: John J
authors.initials: JJ
authors.lastname: McGuire
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C487404:2-furoyl-LIGRLO-amide; C496900:Kcnn3 protein, mouse; D009842:Oligopeptides; D011720:Pyrazoles; D044464:Receptor, PAR-2; D051640:Small-Conductance Calcium-Activated Potassium Channels; C411671:TRAM 34; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester