Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure.
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Administration of MCT to rats causes rapid sinusoidal endothelial cell (SEC) injury, hemorrhage, pooling of blood and fibrin deposition in centrilobular regions of liver. These events precede hepatic parenchymal cell (HPC) injury and produce marked changes in the microvasculature of the liver, which could interrupt blood flow and produce hypoxia in affected regions. To test the hypothesis that hypoxia occurs in liver after MCT exposure, rats were treated with 300mgMCT/kg, and hypoxia was detected immunohistochemically. MCT produced significant hypoxia in centrilobular regions of livers by 8h after treatment. Inasmuch as fibrin deposition can impair oxygen delivery by reducing blood flow, the effect of anticoagulant treatment on MCT-induced hypoxia was determined. Administration of warfarin to MCT-treated rats reduced hypoxia in the liver by approximately 70%, suggesting that fibrin deposition plays a causal role in the development of hypoxia in the liver. Conversely, administration of l-NAME, a nonspecific inhibitor of nitric oxide synthases (NOSs), enhanced MCT-induced hypoxia and HPC injury. l-NAME did not, however, affect SEC injury or coagulation system activation. Results from these studies show that hypoxia occurs in the liver after MCT exposure. Furthermore, hypoxia precedes HPC injury, and manipulations that modify hypoxia also modulate HPC injury.
Copple
Bryan L
BL
Department of Pharmacology and Toxicology, Center for Integrative Toxicology, and National Food Safety and Toxicology Center, 214 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824, USA.
Roth
Robert A
RA
Ganey
Patricia E
PE
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000032:analysis; D006820:Hyaluronic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000627:therapeutic use*
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D014859:Warfarin; D016686:Monocrotaline; D005340:Fibrinogen; D006820:Hyaluronic Acid; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester