title: Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase.
abstract: Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 microm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) (P<0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC(50) 200+/-56 nmol/L) compared with WT and iNOS-deficient shams (16+/-4 and 13+/-6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35+/-13 nmol/L, P<0.01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodilation in patients with septic shock.
authors.affiliation: Sections of Critical Care and Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. shollenb@rpslmc.edu
authors.forename: S M
authors.initials: SM
authors.lastname: Hollenberg
authors.forename: M
authors.initials: M
authors.lastname: Broussard
authors.forename: J
authors.initials: J
authors.lastname: Osman
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D003643:Death; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D018715:Microscopy, Video; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000494:pharmacology; D018805:Sepsis / Q000201:enzymology / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009638:Norepinephrine