Thrombin inhibitors and anti-coagulants on thrombin-induced embolisation in rabbit cranial vasculature.
111Indium-labelled platelets were continuously monitored in the cranial vasculature of anaesthetised rabbits and thrombin inhibitors and anti-coagulants were tested on the sustained platelet accumulation induced by intracarotid injection of thrombin (90 U/kg). Pretreatment, commencing 30 min prior to thrombin, with a 1-h intracarotid infusion of D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK; 0.25-1.0 micrograms/kg per min), unfractionated heparin (Multiparin; 5-20 U/kg bolus + 0.75-3.0 U/kg per min infusion) or low molecular weight heparin (Fragmin; 2.4-9.6 U/kg per min) produced dose-related reductions in platelet accumulation. Continuous infusion of acetyl-D-phenylalanyl-prolyl-boroarginine (DuP-714 ester; 30 micrograms/kg per min) for 30 min induced marked accumulation of platelets in the pulmonary circulation in the absence of thrombin. Bolus intracarotid injection, 1 min before thrombin, of Hirulog (0.05-0.2 mg/kg), PPACK (10-30 micrograms/kg), Multiparin (25-100 U/kg), Fragmin (150 U/kg) or DuP-714 ester (15-30 micrograms/kg) caused significant reductions in platelet accumulation. When injected 1 min after thrombin, Hirulog (1 mg/kg), PPACK (100 micrograms/kg), Fragmin (150 U/kg) and DuP-714 ester (30 micrograms/kg) had no significant effect and Multiparin (100 U/kg) increased platelet accumulation. The results demonstrate that pretreatment with a range of thrombin inactivators, acting via different mechanisms, can inhibit thrombin-induced cerebral thromboembolism in the rabbit.
Department of Pharmacology, King's College, University of London, UK.
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D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D001896:Boron Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017985:Dalteparin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007204:Indium; D007261:Infusions, Intra-Arterial; D002542:Intracranial Embolism and Thrombosis / Q000139:chemically induced / Q000517:prevention & control*; D007553:Isotope Labeling; D008297:Male; D008970:Molecular Weight; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D000991:Antithrombins; D001896:Boron Compounds; D005343:Fibrinolytic Agents; D006629:Hirudins; D009842:Oligopeptides; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D007204:Indium; C066061:acetylphenylalanyl-prolyl-boroarginine; D006493:Heparin; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone; D017985:Dalteparin; C074619:bivalirudin