sq-29548 and Coronary-Thrombosis

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Thrombosis; Cricetinae; Dogs; Fatty Acids, Unsaturated; Fibrinolysis; Hydrazines; Imidazoles; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxane-A Synthase; Tissue Plasminogen Activator

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)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Ergolines; Fatty Acids, Unsaturated; Hydrazines; Myocardial Reperfusion; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Serotonin Antagonists; Thromboxane A2; Time Factors; Tissue Plasminogen Activator

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of 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. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Fatty Acids, Unsaturated; Hydrazines; Ketanserin; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Thromboxane A2; Tissue Plasminogen Activator