Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis.

Abstract

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 ;&g/kg) followed by a continuous infusion (8 ag/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 < 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 < 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 < 0.001). TxB2 and 6-keto-PGFia, 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.

Rate of Vasoconstrictor Prostanoids Released by Endothelial Cells Depends on Cyclooxygenase-2 Expression and Prostaglandin I Synthase Activity

“…61 PGH 2 and TxA 2 stimulate proliferation of vascular smooth muscle cells in vitro. [62][63][64][65][66] Expression of COX-2 could also contribute to the myointimal hyperplasia observed in atherosclerosis by promoting the formation of PGH 2 (and transcellular TxA 2 ) and hydroxy linoleic acids, 19 which elicit smooth muscle cell mitogenesis. 67 In summary, our results show that resting HUVECs and HUVECs exposed to IL-1␤ produce only PGH 2 and PGI 2 enzymatically.…”

Regulation of Coronary Blood Flow

“…In particular, data from Ammar et al demonstrated essentially no effect of combined prostaglandin H 2 and thromboxane A 2 receptor blockade on coronary blood flow at rest or during dobutamine-induced increases in MVO 2 (10). Although there is no effect of these antagonists on coronary blood flow under normal physiologic conditions, numerous studies have implicated a pathophysiologic role for thromboxane A 2 and another vasoconstrictor, 5-hydroxytryptamine (i.e., serotonin), in response to platelet activation (21, 301, 379–381, 978, 979) as well as endothelial injury and coronary artery disease (502,573,979,980). These factors are also thought to play a role in coronary vasospasm (491, 580, 856, 941).…”

Emerging Therapeutic Approaches Multi-Targeting Receptor Tyrosine Kinases and G Protein-Coupled Receptors in Cardiovascular Disease

“…The most studied of these compounds are samixogrel and ridogrel. Ridogrel is effective in models of coronary thrombosis, it shortens the time of reperfusion when used in combination with tPA (tissue plasminogen activator) and reduces infarct size [53,54]. It has been tested as anti-thrombotic and anti-inflammatory agent in clinical trials [55,56], but has never been evaluated for its capacity to inhibit angiogenesis.…”