Thrombin is an important mediator of platelet aggregation in stenosed canine coronary arteries with endothelial injury.
Cyclic variations in coronary blood flow (CFVs) in dogs with experimental coronary artery stenosis and endothelial injury appear to result primarily from the aggregation of platelets at the site of stenosis followed by dislodgement and distal embolization. Using this canine model, we tested the hypotheses: (a) that thrombin is an important mediator of CFVs in dogs with coronary stenoses and endothelial injury; (b) that inhibition of thrombin with heparin, or MCI-9038, a selective thrombin inhibitor, abolishes CFVs in this model; and (c) that abolition of CFVs by thrombin inhibition is time dependent. CFVs, produced in open-chest dogs by placing a flow-reducing plastic constrictor around the left anterior coronary artery, were monitored for either 30 min (group I) or 3 h (group II) before treatment with either heparin or 4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl (MCI-9038). In group I, cyclic flow variations were abolished by heparin in 12 of 18 dogs and by MCI-9038 in 5 of 7 dogs. In group II, cyclic flow variations were not abolished by heparin in any of seven dogs and were abolished by MCI-9038 in only one of seven dogs. Thus, (a) thrombin appears to be an important mediator of cyclic flow variations in dogs with coronary artery stenosis and endothelial injury and (b) inhibition of thrombin abolishes CFVs after short but not prolonged periods of CFVs.
Eidt
J F
JF
Department of Medicine (Cardiology Division), University of Texas, Southwestern Medical Center, Dallas 75235.
Allison
P
P
Noble
S
S
Ashton
J
J
Golino
P
P
McNatt
J
J
Buja
L M
LM
Willerson
J T
JT
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000473:pathology*; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000473:pathology; D005231:Fatty Acids, Unsaturated; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010875:Pipecolic Acids; D013449:Sulfonamides; C046193:antithrombin III-protease complex; C045749:SQ 29548; D000990:Antithrombin III; D006493:Heparin; D001120:Arginine; D007650:Ketanserin; D010447:Peptide Hydrolases; D013917:Thrombin; C031942:argatroban