Prevention of intra-coronary thrombosis in the anaesthetised dog: the importance of thromboxane A2 and thrombin.
Vapiprost (GR32191, a TxA2 antagonist), r-hirudin, aspirin, ticlopidine and aspirin plus ticlopidine were examined for their ability to prevent electrically-induced thrombosis in an artificially stenosed coronary artery in the anaesthetised dog. Drugs or vehicle were administered prior to a 2 h period of electrical damage which was followed by a further 2 h observation period. In all vehicle-treated animals, blood flow markedly declined with onset of the damaging current; 80% completely occluded. All treatments reduced the incidence of complete occlusion to a similar extent. Vapiprost and r-hirudin also largely prevented the decline in blood flow both during and following the damage period whilst aspirin and ticlopidine, either alone or in combination were much less effective. With r-hirudin treatment, marked cyclic changes in flow occurred throughout the experiment; these were abolished by administration of vapiprost. In this dog model, TxA2 and thrombin appear to work in concert to produce coronary thrombosis, ADP being of minor importance. The superior effect of vapiprost over aspirin suggests a beneficial role for endogenous prostacyclin.
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research Ltd, Ware, Hertfordshire, UK.
B P
BP
White
A T
AT
Sullivan
P
P
Lumley
D000758:Anesthesia; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000009:adverse effects; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D001713:Biphenyl Compounds; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D006629:Hirudins; D011994:Recombinant Proteins; D013928:Thromboxane A2; D013917:Thrombin; C060013:vapiprost; D013988:Ticlopidine; D001241:Aspirin; C060225:desirudin