title: Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin.
abstract: This study investigated the effect of peroxynitrite (OONO(-))-induced nitrosylation of filamentous (F)-actin on myogenic tone in isolated and pressurized posterior cerebral arteries (PCAs). Immunohistochemical staining was used to determine 3-nitrotyrosine (NT) and F-actin content in vascular smooth muscle after exposure to 10(-7) M or 10(-4) M OONO(-) for 5 or 60 min in isolated third-order PCAs (n = 37) from male Wistar rats pressurized to 75 mmHg in an arteriograph chamber, quantified with confocal microscopy. Additionally, the role of K(+) channels in OONO(-)-induced dilation was investigated with 3 microM glibenclamide or 10 mM tetraethylammonium chloride before OONO(-) exposure. OONO(-) (10(-4) M) induced a 40% dilation of tone (P < 0.05) while diminishing F-actin content by half (P < 0.05) and causing a 60-fold increase in NT (P < 0.05) in the vascular smooth muscle of PCAs. Additionally, F-actin was inversely correlated with both diameter and NT content (P < 0.05) and was significantly colocalized in the vascular smooth muscle with NT (overlap coefficient = 0.8). The dilation to ONOO(-) was independent of K(+) channel activity and thiol oxidation as glibenclamide, tetraethylammonium chloride, and dithiothreitol had no effect on OONO(-)-induced dilation or F-actin or NT content in PCAs. Because NT was colocalized with F-actin, we hypothesize that OONO(-) induces nitrosylation of F-actin in vascular smooth muscle leading to depolymerization and the subsequent loss of myogenic tone, which may promote vascular damage during oxidative stress such as in ischemia and reperfusion injury.
authors.affiliation: Department of Neurology, University of Vermont, 89 Beaumont Ave., Given C454, Burlington, VT 05405, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maneen
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D020769:Posterior Cerebral Artery / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000199:Actins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013438:Sulfhydryl Compounds; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D019789:Tetraethylammonium; D005905:Glyburide; D004229:Dithiothreitol