Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice.
Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l-N6-(1-iminoethyl)-lysine (L-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. L-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas L-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. L-NIL, but not L-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. L-NIL restored the sinusoidal perfusion, but L-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. L-NIL tended to minimize this infiltration, whereas L-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by L-NIL, whereas L-NAME further elevated it. L-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. L-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.
Ito
Yoshiya
Y
Deptartment of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724-5044, USA.
Abril
Edward R
ER
Bethea
Nancy W
NW
McCuskey
Robert S
RS
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D000082:Acetaminophen; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D000410:Alanine Transaminase; D005978:Glutathione; D019331:NG-Nitroarginine Methyl Ester