Increased production of thromboxane A2 by coronary arteries after thrombolysis

doi:10.1016/0002-8703(93)90001-P

American Heart Journal

Volume 125, Issue 2, Part 1, February 1993, Pages 277-284

https://doi.org/10.1016/0002-8703(93)90001-P Get rights and content

Abstract

The coronary artery produces large amounts of prostacyclin (PGl₂) and a small amount of thromboxane A₂ (TXA₂); this high $PGl_{2} TXA_{2}$ ratio contributes to the antithrombotic properties of the coronary artery. This study was designed to determine whether this ratio changes after coronary artery thrombosis and thrombolysis and accounts for coronary artery reocclusion. Anesthetized dogs (N = 12) were subjected to electrically induced coronary artery thrombosis and tissue plasminogen activator-induced thrombolysis. Thrombolysis was achieved in 11 dogs, and the coronary artery reoccluded in five of these dogs after the initial reperfusion. Spontaneous and ionophore A23, 187-stimulated PGl₂ and TXA₂ synthesis in normal circumflex and ischemic-reperfused left anterior descending coronary artery segments was measured by radioimmunoassay of thromboxane B₂ and 6-keto-prostaglandin F_1α, respectively. Production of TXA₂ was 413% to 656% greater in left anterior descending segments (from the region of thrombosis and sites proximal and distal to the thrombus) compared with normal circumflex segments (p < 0.001). Production of PGl₂ was also increased but only by 46% to 80% in the left anterior descending segments compared with normal circumflex segments (p < 0.05). TXA₂ production was greater in coronary artery segments that reoccluded compared with segments that stayed open (p < 0.02). Scanning electron microscopy revealed platelet deposition in thrombosed left anterior descending segments but not in segments proximal or distal to the thrombus site, indicating that the vascular wall per se may be a source of increased production of TXA₂. In other experiments, normal coronary artery segments were exposed to thrombin and showed enhanced production of TXA₂, suggesting a role for thrombin in the increased production of TXA₂ in thrombosed-reperfused coronary arteries. In conclusion, increased TXA₂ production by coronary arteries after reperfusion may induce platelet aggregation and vasospasm and contribute to reocclusion after thrombolysis.

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The aim of this work was to evaluate the effects of BM-567 (N-pentyl-N′-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on both thromboxane A₂ (TXA₂) receptors (TP) and thromboxane synthase of human platelets. The drug affinity for TP receptors of human washed platelets has been determined. In this test, BM-567 showed a high affinity (IC₅₀: 1.1±0.1 nM) for the TP receptors in comparison with BM-531 (IC₅₀: 7.8±0.7 nM) and sulotroban (IC₅₀: 931±85 nM), two TXA₂ antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 μM) (ED₁₀₀: 0.20±0.10 μM), U-46619, a stable TXA₂ agonist (1 μM) (ED₅₀: 0.30±0.04 μM) and collagen (1 μg ml⁻¹) (% of inhibition: 44.3±4.3% at 10 μM) and inhibited the second wave of ADP (2 μM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100^®) was significantly prolonged (closure time: 215±21 s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 μM, BM-567 completely reduced the TXB₂ production from human platelets stimulated with AA (600 μM). These results indicate that BM-567 is a novel combined TXA₂ receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency.
Effects of a novel non-carboxylic thromboxane A<inf>2</inf> receptor antagonist (BM-531) derived from torasemide on platelet function
2000, Prostaglandins Leukotrienes and Essential Fatty Acids
In this study we examined the thromboxane A₂(TXA₂) receptor antagonist property of BM-531 (N-tert -butyl- N′-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on platelet function. The drug affinity for human washed platelet TXA₂receptors labelled with [³H]SQ-29,548 has been determined (IC50: 0.0078 μM) and demonstrated to be higher than sulotroban (IC50: 0.93 μM) and SQ-29,548 (IC50: 0.021 μM). The antiaggregatory potency has been confirmed since we demonstrated that BM-531 prevented platelet aggregation in human citrated platelet-rich plasma induced by arachidonic acid (600 μM) (ED100: 0.125 μM), U-46619, a stable TXA₂agonist (1 μM) (ED50: 0.482 μM) and collagen (1 μg mL⁻¹) (% of inhibition: 42.9% at 10 μM) and inhibited the second wave of ADP (2 μM). Moreover, when BM-531 was incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100^™) was significantly prolonged. These results suggest that BM-531 can be regarded as a novel non-carboxylic TXA₂antagonist with a powerful antiplatelet potency.
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NPC 15669, a member of the leumedins family, inhibits leukocyte adhesion to the endothelium by blockage of upregulation of a member of β2 integrin family Mac-1 (CD11b/CD18). Inhibition of neutrophil-endothelial interactions may alter the course of myocardial reperfusion injury. However, the effects of NPC 15669 supplementation on the hemostatic profile during ischemia-reperfusion are unknown. The aim of the present study was to define changes in the certain hemostatic factors in the natural course of preconditioned myocardial infarction. Twelve consecutive Yorkshire swine underwent myocardial stunning (8 min. Left anterior descending artery occlusion followed by 90 min. of reperfusion) and then preconditioned myocardial infarction (50 min. occlusion followed by 3 hours of reperfusion) experiments. NPC 15669 (10 mg/kg loading dose followed by constant infusion at 6 mg·kg⁻¹·h⁻¹) was administered in 6 animals; another 6 swine received saline and served as controls. Blood samples were obtained at baseline, twice during occlusion; and three times during reperfusion. The levels of antithrombin-III, Protein C, total Protein S, fibronectin, endothelin-1, as well as the stable metabolites of thromboxane (TxB₂) and prostacyclin (6-keto-PGF_1a), were determined. NPC 15669 treatment was associated with diminished endothelin-1, TxB₂ levels and increased fibronectin, 6-keto-PGF_1a, Protein C and total Protein S concentrations in the setting of preconditioned myocardial infarction. There were no changes in the plasma concentrations of antithrombin-III in NPC 15669 group when compared with controls. The increase in Protein C, total Protein S, and 6-keto-PGF_1a (favoring antithrombosis), and decrease in endothelin-1 and TxB₂ levels (favoring vasodilatation), following NPC 15669 may explain the reduction in infarct size previously reported with this agent.
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1999, Prostaglandins Leukotrienes and Essential Fatty Acids
The role of prostanoids in patients with ischemic heart disease including acute myocardial infarction (AMI) has been recognized. However, there is very limited knowledge of the baseline TXB₂and 6-keto-PGF_1aplasma levels in patients with AMI before therapy has been administered. We compared plasma levels of TXB₂and 6-keto-PGF_1aby enzyme immunoassay in 18 AMI patients before thrombolysis, with those of 13 healthy controls. Plasma levels of TXB₂(319.78±16.50 pg/ml) and 6-keto-PGF_1a(536.72±56.71 pg/ml) were heterogeneous, but significantly higher in the AMI patients than in controls (175.92±17.29 pg/ml and 192.08±26.11 pg/ml, respectively). In some patients, long-term aspirin therapy mildly inhibits baseline prostanoid levels, however, limited data prevents us from further speculations on this issue. Although, the contributions by prostanoids to the pathogenesis of AMI have been well proposed, their plasma concentrations are not uniformly elevated, and it is still unclear whether the resultant changes are indicative of clinically meaningful effects.
Serial changes of the plasma prostanoids during myocardial ischemia-reperfusion in swine. Effects of magnesium, diltiazem, and a novel Mac-1 inhibitor
1997, Prostaglandins Leukotrienes and Essential Fatty Acids
The key role of prostanoids has been recognized in patients with ischemic heart disease. However, serial changes of thromboxane and prostacyclin during both brief and prolonged ischemia-reperfusion are poorly known. These plasma prostanoids were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on the level of the stable metabolites of thromboxane (TXB₂) and prostacyclin (6-keto-PGF_1α) were elucidated. Forty-nine swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. The occlusion phase was associated with a decline of plasma prostanoids, followed by a significant increase during reperfusion. Mg and diltiazem similarly affected plasma prostanoids by reducing TXB₂ release at 1 h of reperfusion. There was, however, no effect on plasma 6-keto-PGF_1α. The Mac-1 inhibition was associated with stabilization of both antagonistic prostanoids as well. Ability of Mg, diltiazem, and leumedins to favorably modulate plasma prostanoid levels have direct clinical implications for the use of these agents in patients with coronary artery disease.

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^☆: Supported by a Merit Review Award from the VA Central Office and grants-in-aid from the American Heart Association, Florida Affiliate, the Swedish Medical Research Council, and the Swedish Society of Medicine.

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Increased production of thromboxane A2 by coronary arteries after thrombolysis☆

Abstract

Am Heart J

Prost Leuk Med

Thromb Res

Thromb Res

Biochem Biophys Acta

Thromb Res

Thromb Res

Prostaglandins

Biochem Biophys Acta

Biochim Biophys Acta

J Biol Chem

Eur J Pharmacol

A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction

Circulation

Intracoronary thrombus formation causes focal vasoconstriction of epicardial arteries in patients with coronary artery disease

Circulation

Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion

Circulation

Attenuated coronary relaxation after reperfusion: effects of superoxide dismutase and TXA2 inhibitor U63,557A

Am J Physiol

Increased production of thromboxane A₂ by coronary arteries after thrombolysis☆

Attenuated coronary relaxation after reperfusion: effects of superoxide dismutase and TXA₂ inhibitor U63,557A