Combined thromboxane A2synthetase inhibition and receptor blockade are effective in preventing spontaneous and epinephrine-induced canine coronary cyclic flow variations

Abstract

The purpose of this study was to test the hypothesis that combined thromboxane A2synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2synthetase inhibitor and thromboxane A2-prostaglandin H2receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070.Complete abolition of cyclic flow variations was achieved in 71% of dogs in Group I, 82% in Group II, 100% in Group III (p = 0.06 compared with Group I) and 50% in Group IV (p = 0.03 compared with Group III). Epinephrine was infused into dogs with abolished cyclic flow variations: all dogs in Group I had cyclic flow variations restored, 44% in Group II (p = 0.01 compared with Group I) and 64% in Group III (p = 0.04 compared with Group I). The plasma epinephrine levels required to restore cyclic flow variations were 2.2 ± 0.5 ng/ml (control 0.04 ± 0.01) in Group I, 8.7 ± 4.5 ng/ml (control 0.05 ± 0.02) in Group II and 7.4 ± 2.6 ng/ml (control 0.07 ± 0.02) in Group III. The epinephrine-restored cyclic flow variations in Group II and III dogs were abolished again by LY 53,857, a serotonin receptor antagonist. None of these dogs had cyclic flow variations restored even with plasma epinephrine concentrations as high as 25.1 ± 3.6 ng/ml in Group II dogs and 43.2 ± 9.4 ng/ml in Group III dogs. Serum thromboxane B2(the stable metabolite of thromboxane A2) concentrations decreased in both Group III and Group IV dogs from 2.2 ± 1.0 and 2.0 ± 1.0 ng/ml at control study to 0.8 ± 0.9 and 0.9 ± 1.0 ng/ml after the administration of R 68,070 or aspirin and R 68,070, respectively.Combined actions of thromboxane A2synthetase inhibition and receptor blockade may be more effective than thromboxane A2-prostaglandin H2receptor blockade alone in eliminating spontaneous canine coronary cyclic flow variations. Thromboxane A2synthetase inhibition alone or combined with receptor blockade provides more protection against epinephrine-induced canine coronary cyclic flow variations than a thromboxane A2-prostaglandin H2receptor antagonist alone. Prostacyclin might be an important contributing factor in preventing both spontaneous and epinephrine-induced cyclic flow variations when a combined thromboxane synthetase inhibitor and receptor antagonist is used in this experimental model. Furthermore, the addition of a serotonin receptor antagonist to a thromboxane synthetase inhibitor or combined thromboxane synthetase inhibition and receptor antagonist provides substantial protection against epinephrine-induced cyclic flow variations in such an experimental model.