title: Direct Inhibitory Effects of Carbon Monoxide on Six Venoms Containing Fibrinogenolytic Metalloproteinases.
abstract: Since the introduction of antivenom administration over a century ago to treat venomous snake bite, it has been the most effective therapy for saving life and limb. However, this treatment is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases (SVMP) by inhibiting these Zn+2-dependent enzymes directly with carbon monoxide (CO) exposure. Assessment of the fibrinogenolytic effects of venoms collected from the Arizona black rattlesnake, Northern Pacific rattlesnake, Western cottonmouth, Eastern cottonmouth, Broad-banded copperhead and Southern copperhead on human plasmatic coagulation kinetics was performed with thrombelastography in vitro. Isolated exposure of all but one venom (Southern copperhead) to CO significantly decreased the ability of the venoms to compromise coagulation. These results demonstrated that direct inhibition of transition metal-containing venom enzymes by yet to be elucidated mechanisms (e.g. CO, binding to Zn+2or displacing Zn+2from the catalytic site, CO binding to histidine residues) can in many instances significantly decrease fibrinogenolytic activity. This new paradigm of CO-based inhibition of the anticoagulant effects of SVMP could potentially diminish haemostatic compromise in envenomed patients until antivenom can be administered.
authors.affiliation: The Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Nielsen
authors.affiliation: The Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Losada
mesh_terms: D017836:Agkistrodon; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D003435:Crotalid Venoms / Q000201:enzymology*; D017839:Crotalus; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D030162:Reptilian Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012909:Snake Bites / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D013916:Thrombelastography; D015032:Zinc / Q000378:metabolism
chemical_list: D003435:Crotalid Venoms; D011480:Protease Inhibitors; D030162:Reptilian Proteins; D002248:Carbon Monoxide; D045726:Metalloproteases; D015032:Zinc