S-Methylisothiourea sulfate improves renal, but not hepatic dysfunction in canine endotoxic shock model.
OBJECTIVE
Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathophysiology of septic shock. This study was designed to see whether S-methylisothiourea sulfate (SMT), a selective inhibitor for iNOS, prevents cardiovascular changes and multiple organ damage in the canine endotoxic shock model.


METHODS
Prospective, comparable, experimental study.


METHODS
Laboratory at a university hospital.


METHODS
Twenty male mongrel dogs were studied under pentobarbital anesthesia.


METHODS
Dogs were divided into three groups: bacterial lipopolysaccharide (LPS) group (n = 7) receiving continuous infusion of LPS (2 mg/kg/h for 1 h); LPS plus SMT group (n = 7) receiving LPS and SMT (1 mg/kg, bolus i. v., followed by continuous infusion of 1 mg/kg/h for 1 h); and vehicle plus SMT group (n = 6).


RESULTS
Hemodynamics, blood gas parameters, and urine output were measured during 6 h observation periods. Serum levels of lactate, transaminases, and bilirubin were measured at baseline, 1 and 6 h. Creatinine and free water clearance, urine sodium excretion and fractional excretion of sodium were calculated. LPS caused a profound hypotension associated with decreases in cardiac output and oxygen delivery, lactic acidosis, renal and liver dysfunction, and thrombocytopenia. SMT prevented the LPS-induced hypotension and renal dysfunction, whereas it did not affect the LPS-induced decreases in cardiac output or oxygen delivery, hyperlactatemia, liver dysfunction, or thrombocytopenia. SMT alone had no appreciable effects on hemodynamics, blood gases, liver or renal functions.


CONCLUSIONS
These findings show that SMT improves renal, but not hepatic dysfunction, in dogs with endotoxic shock, suggesting that iNOS-derived NO plays differential roles in sepsis-associated multiple organ dysfunction.
Mitaka
C
C
Department of Emergency and Critical Care Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. c.mitaka.icu@med.tmd.ac.jp
Hirata
Y
Y
Masaki
Y
Y
Takei
T
T
Yokoyama
K
K
Imai
T
T
D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects*; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012772:Shock, Septic / Q000188:drug therapy*
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium