Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis.
Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
Golino
P
P
Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas 75235-9047.
Ashton
J H
JH
McNatt
J
J
Glas-Greenwalt
P
P
Yao
S K
SK
O'Brien
R A
RA
Buja
L M
LM
Willerson
J T
JT
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003327:Coronary Disease / Q000188:drug therapy*; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D004359:Drug Therapy, Combination; D004873:Ergolines / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000627:therapeutic use*; D015425:Myocardial Reperfusion; D010974:Platelet Aggregation / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004873:Ergolines; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D012701:Serotonin; D013928:Thromboxane A2; C045749:SQ 29548; D010959:Tissue Plasminogen Activator; C032663:LY 53857