New model for in vivo studies of pharmacological interventions with endogenous fibrinolysis: effects of thrombin inhibitors.
A new rat model for investigation of the interactions of thrombin inhibitors with endogenous fibrinolysis in vivo is described. The method utilizes the thrombin-like snake enzyme batroxobin, which mainly cleaves the fibrinopeptide A from fibrinogen and activates factor XIII only to a slight degree. Compared to thrombin-formed fibrin, batroxobin-formed fibrin is more readily lysed by plasmin, since it only cross-links fibrin to a minor extent. Radiolabeled fibrinogen (125I) was given intravenously to monitor the effects of batroxobin on fibrinogen and the effects of plasmin on the fibrin formed. Batroxobin was given intravenously in a dose that converted most fibrinogen to fibrin. Five to 10 minutes after batroxobin administration, 125I-activity in the blood decreased, indicating the disappearance of fibrinogen from the circulating blood. At the same time, the 125I activity as measured with a gamma counter increased over the lungs. The fibrin formed in the microvasculature of the lungs started an endogenous fibrinolysis. This could be seen as reappearance of the 125I activity in the blood from fibrin degradation products accompanied by a decrease in the 125I activity over the lungs. When the rats were given tranexamic acid, the endogenous fibrinolysis was markedly decreased, measured as 125I activity in the blood, over the lungs and in lung parenchyma samples. The thrombin inhibitor DuP 714, which apparently inhibits not only thrombin but also plasmin and tissue plasminogen activator, completely prevented the fibrinolytic phase. The selective thrombin inhibitor argatroban, on the other hand, led to shortened lysis time. It is concluded that the present method provides a convenient and accurate means of studying pharmacological interventions with endogenous fibrinolysis. The differential effects of selective and nonselective thrombin inhibitors on endogenous fibrinolysis at comparable levels of thrombin inhibition are clearly demonstrated.
Lenfors
S
S
Cardiovascular Pharmacology, Preclinical R & D, Astra Hässle AB, Mölndal, Sweden.
Gustafsson
D
D
D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D012103:Batroxobin / Q000008:administration & dosage*; D001896:Boron Compounds / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage*; D010875:Pipecolic Acids / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors
D000991:Antithrombins; D001896:Boron Compounds; D009842:Oligopeptides; D010875:Pipecolic Acids; D013449:Sulfonamides; C066061:acetylphenylalanyl-prolyl-boroarginine; D001120:Arginine; D012103:Batroxobin; D013917:Thrombin; C031942:argatroban