title: Mechanisms of enhanced basal tone of brain parenchymal arterioles during early postischemic reperfusion: role of ET-1-induced peroxynitrite generation.
abstract: The contributions of vasoconstrictors (endothelin-1 (ET-1), peroxynitrite) and endothelium-dependent vasodilatory mechanisms to basal tone were investigated in parenchymal arterioles (PAs) after early postischemic reperfusion. Transient middle cerebral artery occlusion (tMCAO) was induced for 2 hours with 30 minutes reperfusion in male Wistar rats and compared with ischemia alone (permanent MCAO (pMCAO); 2.5 hours) or sham controls. Changes in lumen diameter of isolated and pressurized PAs were compared. Quantitative PCR was used to measure endothelin type B (ETB) receptors. Constriction to intravascular pressure ('basal tone') was not affected by tMCAO or pMCAO. However, constriction to inhibitors of endothelial cell, small- (SK) and intermediate- (IK) conductance, Ca(2+)-sensitive K(+) channels (apamin and TRAM-34, respectively) were significantly enhanced in PAs from tMCAO compared with pMCAO or sham. Addition of the ETB agonist sarafotoxin caused constriction in PAs from tMCAO but not from sham animals (21 ± 4% versus 3 ± 3% at 1 nmol/L; P<0.01) that was inhibited by the peroxynitrite scavenger FeTMPyP (5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride) (100 μmol/L). Expression of ETB receptors was not found on PA smooth muscle, suggesting that constriction to sarafotoxin after tMCAO was due to peroxynitrite and not ETB receptor expression. The maintenance of basal tone in PAs after tMCAO may restrict flow to the ischemic region and contribute to infarct expansion.
authors.affiliation: 1] Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA [3] Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont, USA.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
authors.forename: Julie G
authors.initials: JG
authors.lastname: Sweet
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Gokina
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: White
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009129:Muscle Tonus / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D044023:Receptor, Endothelin B / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D014664:Vasodilation / Q000502:physiology
chemical_list: D019332:Endothelin-1; D044023:Receptor, Endothelin B; D030421:Peroxynitrous Acid