Inducible nitric oxide synthase inhibition potentiates multiple organ dysfunction induced by endotoxin in conscious rats.
This study was designed to investigate the effects of inducible nitric oxide synthase (iNOS) inhibition with S-methylisothiourea (SMT) and L-N-(1-iminoethyl)-lysine (L-Nil) on the endotoxemia induced by intravenous lipopolysaccharide (LPS, 10 mg/kg) in conscious rats. Arterial pressure (AP), heart rate (HR), WBC, platelets, plasma nitrite/nitrate, tumor necrosis factor alpha (TNF alpha), and biochemical factors were measured for 24 hours after LPS with or without iNOS inhibitors. RT-PCR was employed to determine the iNOS and endothelial NOS (eNOS) mRNA. Pathologic examinations of the liver and heart were performed. SMT and L-Nil improved the systemic hypotension and increased the HR after LPS. These agents attenuated the LPS-induced leukocytopenia and thrombocytopenia and the increase in nitrite/nitrate. However, iNOS inhibition aggravated the LPS-induced changes in TNF alpha, all biochemical factors, and the hepatic and cardiac tissue damage. The iNOS mRNA, but not the eNOS, was reduced. Our results in conscious rats indicate that iNOS inhibition enhances the organ dysfunction and tissue damage in sepsis. The discrepancy may be attributed to the method for evaluating the sepsis and the effects of anesthesia. Further investigation is required to ensure the effects of iNOS inhibition on sepsis before iNOS inhibitors can be applied in clinical cases with sepsis.
Lee
Chia-Chi
CC
Institute of Medical Science, Tzu Chi University, Hualien, Taiwan.
Lin
Nien-Tseng
NT
Hsu
Yung Hsing
YH
Chen
Hsing I
HI
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness / Q000502:physiology*; D004731:Endotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced* / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000503:physiopathology
D004731:Endotoxins; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C027744:S-methylisothiopseudouronium; D008239:Lysine