Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries

Recent studies suggest that platelet activation and subsequent thromboxane (TX) A₂ release play important roles in certain coronary syndromes. To further test this possibility, we examined the ability of a selective TXA₂-synthetase inhibitor, dazoxiben (UK-37-248), to abolish cyclic flow reductions (CFRs) that occur in experimentally stenosed canine coronary arteries. CFRs, which are characterized by progressive declines in coronary blood flow and interrupted by sudden and usually spontaneous restorations of flow, were produced by placing hard plastic cylindrical constrictors (5 mm long × 4.5 mm outer diameter) on the proximal left anterior descending or circumflex coronary artery in open-chest, anesthetized dogs. Coronary blood flow was measured with pulsed Doppler flow probes placed proximal to the constrictors and regional myocardial blood flow with 15 μm radiolabeled microspheres. CFRs were observed for 1 hr, during which coronary blood flow was monitored continuously. Regional myocardial blood flow was measured before constriction, when coronary blood flow appeared to be at its nadir, and after spontaneous restorations of flow. After 1 hr dazoxiben (2.5 mg/kg iv) or an equal volume of saline was given and coronary blood flow was monitored for another hour. Dazoxiben abolished CFRs completely in 18 of 28 dogs and significantly reduced their frequency in the dogs receiving the drug (10.1 ± 0.8 vs 3.2 ± 1.0 per hour [±SE]; p < .001, n = 28). The frequency and magnitude of variations in cyclic blood flow were unchanged after saline (8.8 ± 0.8 vs 9.0 ± 1.0 per hour; p = NS, n = 13). The lowest levels of coronary blood flow before and after dazoxiben were 8.6 ± 2.2% and 48.8 ± 5.4% of control, respectively (p < .001, n = 28), whereas this parameter remained unchanged after saline (18.7 ± 5.7% vs 13.4 ± 4.1%, respectively; n = 13). The levels of TXB₂ and 6-keto-prostaglandin (PG) F_1α (stable breakdown products of TXA₂ and prostacyclin, respectively) were measured in blood collected from aortic and distal coronary arterial catheters before coronary constriction (control), during CFRs, and after administration of dazoxiben. TXB₂ levels measured distal to the stenosis were increased fivefold during CFRs (352 ± 126 vs 71 ± 18 pg/ml plasma; p < .03) and were reduced to preconstriction (control) levels by dazoxiben (57 ± 12 pg/ml). Aortic TXB₂ levels almost doubled with CFRs and also returned to control levels after dazoxiben. Distal coronary arterial 6-keto-PGF_1α levels also increased significantly during CRFs (133 ± 22 to 344 ± 41 pg/ml plasma), but remained elevated (343 ± 82 pg/ml plasma) after dazoxiben treatment. Systemically administered dazoxiben (2.5 mg/kg iv) suppressed arachidonic acid-induced production of TXB₂ (but not PGE₂) by platelets. Dazoxiben (1 μM) did not affect PGI₂ synthesis by canine coronary arterial rings in vitro. Thus, dazoxiben eliminates or markedly attenuates cyclic flow reductions in stenotic canine coronary arteries and selectively inhibits TXA₂ synthesis. The data obtained in this study suggest that increases in coronary arterial TXA₂ concentration play a role in the genesis of cyclic flow reductions in this experimental model.

Circulation 69, No. 6, 1161-1170, 1984.