Effects of early neuronal and delayed inducible nitric oxide synthase blockade on cardiovascular, renal, and hepatic function in ovine sepsis.
BACKGROUND
Recent evidence suggests that nitric oxide produced via the neuronal nitric oxide synthase is involved mainly in the early response to sepsis, whereas nitric oxide derived from the inducible nitric oxide synthase is responsible during the later phase. We hypothesized that early neuronal and delayed inducible nitric oxide synthase blockade attenuates multiple organ dysfunctions during sepsis.


METHODS
Sheep were randomly allocated to sham-injured, nontreated animals (n = 6); injured (48 breaths of cotton smoke and instillation of Pseudomonas aeruginosa into the lungs), nontreated animals (n = 7); and injured animals treated with a neuronal nitric oxide synthase inhibitor from 1 to 12 h and an inducible nitric oxide synthase inhibitor from 12 to 24 h postinjury (n = 6).


RESULTS
The injury induced arterial hypotension, vascular leakage, myocardial depression, and signs of renal and hepatic dysfunctions. The treatment significantly attenuated, but did not fully prevent, the decreases in mean arterial pressure and left ventricular stroke work index. Although the elevation of creatinine levels was partially prevented, the decreases in urine output and creatinine clearance were not affected. The injury-related increases in bilirubin levels, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated. Although plasma nitrite/nitrate levels were significantly increased versus baseline from 12-24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals.


CONCLUSIONS
The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.
Department of Anesthesiology, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, Texas, USA. lanm@gmx.de
Matthias
M
Lange
Atsumori
A
Hamahata
Daniel L
DL
Traber
Yoshimitsu
Y
Nakano
Aimalohi
A
Esechie
Collette
C
Jonkam
Elbert B
EB
Whorton
Sanna
S
von Borzyskowski
Lillian D
LD
Traber
Perenlei
P
Enkhbaatar
D000818:Animals; D001774:Blood Chemical Analysis; D001831:Body Temperature; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D007677:Kidney Function Tests; D007958:Leukocyte Count; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D008111:Liver Function Tests; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000502:physiology; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D018805:Sepsis / Q000150:complications* / Q000503:physiopathology; D012756:Sheep
D004791:Enzyme Inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III