Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries.
Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries.
复制标题
选择性血栓素合成酶抑制剂达佐昔本对狭窄犬冠状动脉循环血流变化的影响。
DOI：
10.1161/01.cir.69.6.1161
复制
发表时间：
1984
期刊：
影响因子：
37.8
通讯作者：
Willerson,JT
中科院分区：
文献类型：
--
作者：
Bush,LR;Campbell,WB;Buja,LM;Tilton,GD;Willerson,JT
最近的研究表明，血小板活化和随后的血栓烷(TX)A2释放在某些冠脉综合征中起重要作用。为了进一步测试这种可能性，我们检测了选择性TXA2合成酶抑制剂达佐西本(UK-37-248)消除实验性狭窄犬冠状动脉中发生的循环血流减少(CFR)的能力。CFRS是在开胸麻醉犬冠状动脉左前降支或回旋支近端放置硬塑料圆柱缩窄器(长5 mm×外径4.5 mm)，以冠状动脉血流进行性下降为特征，并被突然的、通常是自发的血流恢复所中断。冠状动脉血流量用放置在缩窄器近端的脉冲多普勒探头测量，局部心肌血流量用15微米放射性标记微球测量。观察CFRS 1小时，连续监测冠脉血流量。分别在收缩前、冠脉血流最低点时和血流自发恢复后测量局部心肌血流量。1小时后静脉注射达唑西本(2.5 mg/kg)或等体积生理盐水，监测冠脉血流1小时。在28只狗中，有18只完全取消了CFRs，并显著减少了接受药物的狗的CFRs频率(每小时10.1+/-0.8vs3.2+/-1.0[+/-SE]；p<0.001，n=28)。生理盐水后循环血流改变的频率和幅度无变化(每小时8.8+/-0.8vs9.0+/-1.0；p=NS，n=13)。治疗前后冠脉血流量最低值分别为对照组的8.6+/-2.2%和48.8+/-5.4%(P<0.001，n=28)，而生理盐水治疗后冠脉血流量无明显变化(分别为18.7+/-5.7%和13.4+/-4.1%；n=13)。分别于冠脉缩窄前(对照组)、心肺复苏术(CFRS)和达唑西本给药后测定主动脉和冠状动脉远端血中TXB2和6-酮-前列腺素F1α(TXA2和前列环素的稳定分解产物)的水平。在CFRS期间，狭窄远端测得的TXB2水平增加了5倍(352+/-126vs71+/-18pg/ml血浆；p<0.03)，并被达唑西本(57+/-12pg/ml)降低到收缩前(对照)水平。服用达唑西苯后，主动脉血栓素B_2水平几乎翻了一番，也恢复到对照水平。
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 X 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 micron 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 less than .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 less than .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) F1 alpha (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 less than .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.(ABSTRACT TRUNCATED AT 400 WORDS)