Application of a laser-induced endothelial injury model in the screening of antithrombotic drugs.
A method of inducing microthrombi in small rat mesenteric vessels (approximately 20 to 30 micron) has been developed to study platelet reactions and to investigate antithrombotic drugs. For microscopy, a high-power water immersion system, based on a Leitz Orthoplan microscope, was used. In sodium pentabarbital anesthetized male Wistar rats and in fawn-hooded bleeder rats vascular lesions were produced with a Coherent CR-2 ion laser (argon laser). The laser induced vascular damage, without intravascular heat precipitates, which led to the adhesion, transformation, and aggregation of platelets at the damaged vessel wall. Fibrin threads were rarely formed in these early platelet thrombi. Thrombus formation was estimated by the number of laser injuries required to induce a defined thrombus. The first steps of thrombus formation, in particular the adhesion and reversible aggregation, were significantly reduced in this model in fawn-hooded bleeder rats. A number of different drugs modified thrombus formation in this model, for instance, ASA, defibrotide, unfractionated or low molecular heparins. It is unlikely that a single mechanism is responsible for the observed antithrombotic effects of each of these drugs. The inhibition of platelet adhesion by changes of membrane glycoproteins, interference with the early activation of plasma proteins, effects on prostaglandin metabolism, inhibition of activators stemming from damaged endothelial cells, and other effects have to be considered.
Weichert
W
W
Department of Internal Medicine, J.W. Goethe University, Frankfurt/Main, FRG.
Breddin
H K
HK
Staubesand
J
J
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000473:pathology* / Q000648:ultrastructure; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D007834:Lasers / Q000009:adverse effects*; D008297:Male; D008854:Microscopy, Electron; D008857:Microscopy, Interference; D010979:Platelet Function Tests; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D006493:Heparin; D001241:Aspirin