Golino P, Buja L M, Ashton J H, Kulkarni P, Taylor A, Willerson J T
Department of Internal Medicine, University of Texas Health Science Center, Dallas 75235-9047.
Circulation. 1988 Sep;78(3):701-11. doi: 10.1161/01.cir.78.3.701.
We have reported previously that thromboxane A2 (TXA2) and serotonin (5-HT, 5-hydroxytryptamine) are important mediators of cyclic flow variations (CFVs) in a canine model of coronary artery stenosis and endothelial injury. The present study tested the hypothesis that a TXA2 receptor antagonist is more effective in reducing intracoronary platelet deposition at sites of endothelial injury and severe stenosis than a 5-HT2 receptor antagonist. CFVs developed after placing a plastic constrictor around the left anterior descending coronary artery (LAD) in 51 of 56 dogs. Autologous platelets labeled with 111In were injected in 48 animals. Ten control dogs (group 1A) were killed after CFVs were observed for 1 hour at the nadir of coronary blood flow. Five dogs (group 1B) did not develop CFVs after placement of the constrictor. CFVs were abolished with SQ 28668 (2.75 +/- 0.36 mg/kg, group 2) and SQ 29548 (0.45 +/- 0.1 mg/kg, group 3), two different TXA2 and PGH2 receptor antagonists, in eight of 10 and six of seven dogs, respectively. In eight of 10 dogs (group 4), CFVs were abolished with ketanserin (0.66 +/- 0.12 mg/kg), a 5-HT2 receptor antagonist. In group 2, 3, and 4 dogs, the respective drugs were given so that the minimal dose required to abolished CFVs was administered. In six of six dogs (group 5), a higher dose of ketanserin (i.e., 1.5 mg/kg) was used to abolish CFVs. At death, intracoronary platelet deposition was evaluated by calculating the LAD platelet accumulation ratio (111In activity in the LAD/111In activity in the circumflex coronary artery) in 43 dogs and, in 22 dogs, by microscopic examination of the LAD. A marked LAD platelet accumulation ratio was found in group 1A dogs at the stenotic site and in segments immediately distal to it. The LAD platelet accumulation ratio was significantly reduced by both the low and the high doses of ketanserin compared with group 1A dogs (p less than 0.001). However, the two TXA2 receptor antagonists further reduced the LAD platelet accumulation ratio compared with ketanserin-treated animals (p less than 0.01). Microscopic examination confirmed these findings. We conclude that SQ 28668 and SQ 29548, two different TXA2 receptor antagonists, reduce residual intracoronary platelet deposition associated with CFVs in this canine model more effectively than ketanserin, a 5-HT2 receptor antagonist.
我们之前曾报道过，在犬冠状动脉狭窄和内皮损伤模型中，血栓素A2（TXA2）和5-羟色胺（5-HT，5-羟色胺）是周期性血流变化（CFV）的重要介质。本研究验证了这样一个假设：与5-HT2受体拮抗剂相比，TXA2受体拮抗剂在减少内皮损伤和严重狭窄部位的冠状动脉内血小板沉积方面更有效。在56只犬中，有51只在左冠状动脉前降支（LAD）周围放置塑料收缩器后出现了CFV。48只动物注射了用111In标记的自体血小板。10只对照犬（1A组）在冠状动脉血流最低点观察到CFV 1小时后处死。5只犬（1B组）在放置收缩器后未出现CFV。两种不同的TXA2和PGH2受体拮抗剂SQ 28668（2.75±0.36 mg/kg，2组）和SQ 29548（0.45±0.1 mg/kg，3组）分别使10只犬中的8只和7只犬中的6只犬的CFV消失。10只犬中的8只（4组）使用5-HT2受体拮抗剂酮色林（0.66±0.12 mg/kg）使CFV消失。在2组、3组和4组的犬中，给予各自的药物以使消除CFV所需的最小剂量。6只犬中的6只（5组）使用更高剂量的酮色林（即1.5 mg/kg）来消除CFV。处死时，通过计算43只犬的LAD血小板积聚率（LAD中的111In活性/回旋支冠状动脉中的111In活性）以及对22只犬的LAD进行显微镜检查来评估冠状动脉内血小板沉积情况。在1A组犬的狭窄部位及其紧邻的远端节段发现了显著的LAD血小板积聚率。与1A组犬相比，低剂量和高剂量的酮色林均显著降低了LAD血小板积聚率（p<0.001）。然而，与酮色林治疗的动物相比，两种TXA2受体拮抗剂进一步降低了LAD血小板积聚率（p<0.01）。显微镜检查证实了这些发现。我们得出结论，两种不同的TXA2受体拮抗剂SQ 28668和SQ 29548在该犬模型中比5-HT2受体拮抗剂酮色林更有效地减少了与CFV相关的冠状动脉内残余血小板沉积。
