title: Vascular dysfunction in sepsis: effects of the peroxynitrite decomposition catalyst MnTMPyP.
abstract: The mechanisms contributing to sepsis vascular dysfunction are not well known. We tested the hypothesis that peroxynitrite scavenging ameliorates sepsis-induced macrovascular and microvascular dysfunction. Male Sprague-Dawley rats were killed 48 h after cecal ligation (n = 15) and puncture or sham procedure (n = 15). Their aortas and mesenteric vessels were mounted in organ baths for isometric tension recording. We studied contraction in resting vessels (norepinephrine 1 nM-10 μM and 10 nM-10 μM) and endothelium-dependent relaxation (acetylcholine, 10 nM-10 μM and 1 nM-10 μM) for aortas and microvessels, respectively. Vascular rings were preincubated for 30 min with the superoxide scavenger Cu-Zn-superoxide dismutase (SOD) (100 U/mL), the SOD mimetic and peroxynitrite scavenger tempol (10 M), the NO synthase inhibitor N-nitro-l-arginine methyl ester (10 M), or the peroxynitrite decomposition catalyst manganese tetrakis(4-N-methylpyridyl)porphyrin (MnTMPyP) (10 M). Fluorescence to 3-nitrotyrosine, oxidized dihydroethidium, and NOS2 was assessed in vascular tissue. Vascular NOS2, endothelial nitric oxide synthase (NOS1), NADPH-oxidase-1 (NOX-1), and SOD expression was analyzed by reverse transcription-polymerase chain reaction. Sepsis induced (i) in macrovessels, impairment of norepinephrine-induced contractions; (ii) in microvessels, impairment in norepinephrine-induced contractions and acetylcholine-induced relaxations; (iii) aortic and microvascular tissue increased reactivity to 3-nitrotyrosine, oxidized dihydroethidium, NOS2, and increased expression of NOS2, as well as increased expression of NOX-1 in microvascular tissue. Contractile responses in aortic and microvascular rings improved by ex vivo treatment with MnTMPyP and tempol, whereas vascular relaxation in microvessels improved only with MnTMPyP. Peroxynitrite scavenging protects from vascular dysfunction in sepsis.
authors.affiliation: Hospital Universitario de Getafe, CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Nin
authors.forename: Mariam
authors.initials: M
authors.lastname: El-Assar
authors.forename: Carolina
authors.initials: C
authors.lastname: Sánchez
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferruelo
authors.forename: Alberto
authors.initials: A
authors.lastname: Sánchez-Ferrer
authors.forename: Leticia
authors.initials: L
authors.lastname: Martínez-Caro
authors.forename: Yeny
authors.initials: Y
authors.lastname: Rojas
authors.forename: Marta de
authors.initials: Md
authors.lastname: Paula
authors.forename: Javier
authors.initials: J
authors.lastname: Hurtado
authors.forename: Andrés
authors.initials: A
authors.lastname: Esteban
authors.forename: José A
authors.initials: JA
authors.lastname: Lorente
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D055806:Microvessels / Q000187:drug effects; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D014665:Vasodilator Agents; D030421:Peroxynitrous Acid; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; D000109:Acetylcholine; D009638:Norepinephrine