ONO1714, a new inducible nitric oxide synthase inhibitor, attenuates sepsis-induced diaphragmatic dysfunction in hamsters.
Sepsis causes impairment of diaphragmatic contractility and endurance capacity. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in the pathogenesis. Peroxynitrite, a NO-derived powerful oxidant, may be responsible for infection-induced diaphragmatic muscle failure. Therefore, we examined whether ONO1714, a new selective iNOS inhibitor, prevents sepsis-induced diaphragmatic dysfunction. Fifty male Golden-Syrian hamsters were randomly divided into five groups: hamsters that underwent sham laparotomy alone and received saline injection (Group Sham), those that underwent cecal ligation with puncture (CLP) and received saline injection (Group Sepsis), those that underwent sham laparotomy and received injection of ONO1714 0.3 mg/kg (Group Sham-ONO1714high), those that underwent CLP and received ONO1714 0.1 mg/kg (Group Sepsis-ONO1714low), and those that underwent CLP and received ONO1714 0.3 mg/kg (Group Sepsis-ONO1714high). ONO1714 or saline was intraperitoneally injected 10 min before surgery. Diaphragmatic contractility was assessed in vitro using diaphragm muscle strips excised 24 h after operation. Diaphragm fatigability was assessed by time until tension decreased to 50% of the initial value (T50%) during fatigue trials. Twitch, tetanic tensions, and T50% during fatigue trials were reduced in Group Sepsis. Pretreatment with ONO1714 dose-dependently attenuated sepsis-induced diaphragmatic contractile profiles and endurance capacity. CLP increased plasma nitrite/nitrate (NOx; stable NO metabolites), and diaphragm malondialdehyde (MDA; a product of lipid peroxidation), positive immunostaining for nitrotyrosine (peroxynitrite footprint), and iNOS activity. ONO1714 attenuated the increase. This beneficial effect of ONO1714 may be attributable, in part, to inhibition of peroxynitrite-induced lipid peroxidation in the diaphragm.


CONCLUSIONS
Sepsis impairs diaphragmatic contractility and endurance capacity, which may be involved in acute respiratory failure. Pretreatment with ONO1714, a new selective inducible nitric oxide synthase inhibitor, attenuated sepsis-induced diaphragmatic dysfunction in hamsters.
Departments of Anaesthesiology and Intensive Care Unit, Kobe University School of Medicine, Kobe, Japan.
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Nishina
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Mikawa
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Kodama
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Obara
D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D006224:Cricetinae; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008315:Malondialdehyde / Q000378:metabolism; D008647:Mesocricetus; D009119:Muscle Contraction / Q000502:physiology; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000097:blood; D052247:Nitric Oxide Synthase Type II; D012120:Respiration Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018805:Sepsis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II