Inhibition of cyclic flow variations in stenosed canine coronary arteries by thromboxane A2/prostaglandin H2 receptor antagonists.

Abstract

We tested the hypothesis that thromboxane A 2 and thromboxane AJ/PGH2 receptor occupation are important in mediating cyclical reductions in coronary blood flow (CFVs) in concentrically narrowed canine coronary arteries. Two potent and selective thromboxane A2/PGH 2 receptor antagonists, SQ29,548 and SQ28,668 eliminated CFVs and restored a normal pattern of blood flow through the severely narrowed vessels in 77 and 75% of the dogs, respectively. CFVs were eliminated within several minutes of an intravenous bolus injection of SQ29,548 or SQ28,688. A continuous infusion of SQ29,548 (0.2 mg/kgmin) prevented the recurrence of CFVs throughout the duration of its infusion. Left atrial infusion of the thromboxane A 2 mimetic, U46619, restored CFVs in 5 of 8 SQ29,548-treated and in 5 of 7 SQ28,668-treated dogs. Circulating concentrations of the stable metabolites of TxA 2 and PGIj, TxBj and 6-keto-PGF la , respectively, were unaffected by administration of SQ29,548. However, stenosed vascular segments of the left anterior descending coronary artery (LAD) of SQ29,548-treated dogs produced significantly less thromboxane A 2 than comparable segments from untreated dogs. Morphologic studies showed that stenosed coronary arteries in which CFVs had been abolished by either SQ29,548 or SQ28.668 had relatively few adherent platelets, whereas comparable coronary segments removed from untreated animals had relatively large, platelet-rich mural thrombi. SQ29,548 did not alter the synthesis of Txfi 2 by platelets. 6-keto-PGF la concentrations in the stenosed LAD and nonstenosed circumflex coronary arteries were not altered by SQ29,548 administration. These data suggest that the thromboxane Aj/PGI^ receptor antagonists, SQ29,548 and SQ28,688, inhibit cyclic reductions in coronary blood flow in this model by preventing the accumulation of platelets at the site of a critical coronary arterial stenosis. The data also suggest that TxA 2 is important in mediating the interaction between platelets and the constricted coronary artery that is responsible for the development and maintenance of CFVs in this experimental model. (Circulation Research 1986;59:568-578) E VIDENCE from recent studies suggests that an important relation exists between the release of platelet-derived vasoactive substances during platelet aggregation and the development of acute coronary heart disease syndromes, such as unstable angina pectoris. Thromboxane A 2 (TxA 2 ), synthesized and released from platelets during aggregation, is a potent vasoconstrictor and platelet aggregating substance. 12 The transcardiac concentrations of thromboxane B 2 (TxB 2 ), the inactive metabolite of TxA 2 , are elevated in patients with active unstable angina pectoris. 3 An in vivo canine model of transient coronary flow

Aurintricarboxylic acid in a canine model of coronary artery thrombosis.

“…Conditioned dogs of both sexes weighing [20][21][22][23][24][25] kg were used in this study. The trisodium salt of aurintricarboxylic acid ( Figure 1) …”

Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group.

“…Trial therapy was discontinued for the following reasons: (1) major bleeding defined as transfusion of two or more units of blood, surgical correction, retroperitoneal or intracranial hemorrhage, or bleeding resulting in death or permanent disability, (2) minor bleeding that the study physician believed could not be remediated by adjusting the dose of antithrombotic therapy, (3) development of an end point (recurrent ischemia, myocardial infarction, or death) or of a cerebrovascular accident, (4) if after trial therapy was begun, a patient was found to have normal coronary arteries, nonobstructive coronary artery disease (no lesions .50%), or a negative maximal exercise tolerance test, or there was a clear reason other than progressive ischemic heart disease for the qualifying pain, eg, severe anemia unrecognized at the time of randomization, trial therapy was discontinued; if a patient was determined to have had a transmural infarction as the qualifying event, eg, a true posterior infarction, trial therapy was also discontinued, (5) surgical revascularization or angioplasty, (6) noncompliance with trial medication or missing two consecutive follow-up visits.…”

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.

“…In particular, studies from our laboratory with a canine model of concentrically stenosed and endothelially injured coronary arteries demonstrated the occurrence of a typical cyclic pattern of flow (CFVs) caused by alternating platelet aggregation and subsequent dislodgement of the thrombus and that TXA2 and 5HT are important mediators of CFVs. [17][18][19][20] Blockade of TXA2 usually results in the elimination of CFVs. [17][18][19][20] It is interesting to note that in the present study neither SQ29548 nor LY53857 alone significantly enhanced thrombolysis and prevented CFVs and reocclusion, whereas the combination of the two antagonists was very effective in both enhancing thrombolysis and preventing CFVs and reocclusion.…”

“…[17][18][19][20] Blockade of TXA2 usually results in the elimination of CFVs. [17][18][19][20] It is interesting to note that in the present study neither SQ29548 nor LY53857 alone significantly enhanced thrombolysis and prevented CFVs and reocclusion, whereas the combination of the two antagonists was very effective in both enhancing thrombolysis and preventing CFVs and reocclusion. This is in contrast with previous studies from our laboratory employing a model of concentrically stenosed and endothelially injured canine coronary arteries17-20 in which either TXA2-or 5HT-receptor blockade usually results in abolition of CFVs.…”

“…In particular, several studies from our laboratory have demonstrated that TXA2 and 5HT are important mediators of intracoronary platelet activation in an experimental preparation of concentrically stenosed canine coronary arteries and endothelial injury. [17][18][19][20] Accordingly, the present study was performed to investigate the role played by TXA2 and 5HT in mediating platelet activation and dynamic changes of the thrombus during administration of t-PA, thus affecting the speed of thrombolysis. To achieve this goal, SQ29548, a selective TXA2-PGH2-receptor antagonist, and LY53857, a selective 5HT2-receptor antagonist, were administered at the moment of initiating thrombolytic therapy rather than at the moment of reperfusion.…”