Reduction of stenosis-induced cyclic flow variations by inhibition of platelet-activating factor in dogs

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Abstract
Unstable angina and coronary reocclusion following thrombolysis or balloon angioplasty for acute myocardial infarction are frequent manifestations of coronary artery disease in patients with high-grade coronary stenoses. In dogs with induced coronary artery stenoses, cyclic flow variations reflect cyclic platelet aggregation and disaggregtion. Although several pharmacologic agents attenuate these cyclic flow variations, factors initiating and mediating platelet aggregation are still unclear. We evaluated the efficacy of alprazolam and triazolam, triazolobenzodiazepines which, in addition to their well-known anxiolytic and hypnogenic effects, are specific, potent inhibitors of platelet-activating factor. The left anterior descending coronary artery was instrumented in 23 dogs with a Doppler flow probe, and an external coronary stenosis sufficient in severity to induce cyclic flow variations was created. In 4 control dogs, baseline coronary flow variations averaged 12 ± 7 (SD) per 30 minutes and were stable in number and amplitude over a 3-hour observation period. Cyclic flow variations averaged 13 ± 3 and 17 ± 6 per 30 minutes at baseline and decreased to a nadir of 2 ± 2 and 3 ± 3 per 30 minutes after 10 mg/kg body weight orally of alprazolam (n= 10) and triazolam (n= 5), respectively (P< 0.005 for each, compared with baseline). In 3 dogs, serotonin infusion (0.5 mg/min) restored coronary flow variations after alprazolam from nadir to baseline levels but restored coronary flow variations were abolished with an additional dose of alprazolam (P<0.01). Accordingly, platelet-activating factor appears to contribute to the cyclic flow variations seen in the canine model of coronary stenosis and can be blocked with specific antagonists. It is possible that platelet-activating factor may directly contribute to cyclic occlusions that may occur in patients with coronary artery disease; this suggests an additional therapeutic approach for the treatment of patients with high-grade coronary stenoses in whom thrombus may be frequent.

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