Nitroglycerin stimulates synthesis of prostacyclin by cultured human endothelial cells.
Nitroglycerin stimulates synthesis of prostacyclin by cultured human endothelial cells.
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硝酸甘油刺激培养的人内皮细胞合成前列环素。
DOI：
10.1172/jci110093
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发表时间：
1981
期刊：
影响因子：
--
通讯作者：
Tack-Goldman,K
中科院分区：
文献类型：
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作者：
Levin,RI;Jaffe,EA;Weksler,BB;Tack-Goldman,K
硝酸甘油(NTG)是一种血管扩张剂，其作用机制尚不清楚，是治疗急性心绞痛最常用的药物。我们推测NTG可能诱导内皮细胞合成前列环素(PGI2)，前列环素是一种已知的血管扩张剂和血小板聚集抑制物。因此，培养的人内皮细胞与不同浓度的NTG孵育1-3分钟。采用体外血小板聚集抑制法检测血管内皮细胞上清液中PGI2的生物活性。用放射免疫法测定PGI2稳定的水解物6-酮-前列腺素F1α的浓度，单用NTG仅在血管上浓度(≥1μg/ml)时显著抑制血小板聚集和血栓素A2的合成。然而，当临床可获得的浓度(0.1-10 ng/ml)的NTG与内皮细胞孵育时，内皮细胞上清液以剂量依赖的方式抑制血小板聚集。该缓蚀剂对热不稳定。血管内皮细胞上清液中6-酮-前列腺素F1α的放射免疫分析表明，NTG可剂量依赖性地诱导内皮细胞合成PGI2，在10 pg/mlNTG时为13%，10 ng/mlNTG时为63%(P<；0.01，n=10)。用阿司匹林(50μM，作用120min)或前列环素合成酶抑制剂15-羟基过氧花生四烯酸(20μg/ml，作用15min)预处理内皮细胞，均可抑制血小板抑制物质的产生。NTG和PGI2之间在抑制血小板聚集方面的协同作用在临床可获得的NTG浓度下不存在。因此，在临床可获得的浓度下，NTG可引起内皮细胞合成PGI2的剂量依赖性增加。如果在体内发生这种现象，产生的PGI2可以通过引起外周血管扩张和减少心脏做功，抑制血小板聚集和血栓素A2的合成，并可能逆转冠状动脉血管痉挛来改善心肌缺血。
Nitroglycerin (NTG), the agent most commonly used to treat acute angina pectoris, is a vasodilator whose mechanism of action remains unknown. We hypothesized that NTG might induce endothelial cells to synthesize prostacyclin (PGI2), a known vasodilator and inhibitor of platelet aggregation. Therefore, cultured human endothelial cells were incubated with NTG at various concentrations for 1-3 min. PGI2biologic activity in the endothelial cell supernates was assayed by inhibition of platelet aggregation in vitro. The concentration of 6-keto-PGF1α, the stable hydrolysis product of PGI2, was measured by specific radioimmunoassay.NTG alone significantly inhibited platelet aggregation and thromboxane A2synthesis only at suprapharmacologic concentrations (≥1 μg/ml). However, when NTG at clinically attainable concentrations (0.1-10 ng/ml) was incubated with endothelial cells, the endothelial cell supernates inhibited platelet aggregation in a dose-dependent manner. The inhibitor was heat labile. Radioimmunoassay of the endothelial cell supernates for 6-keto-PGF1αdemonstrated that NTG elicited dose-dependent increments in the synthesis of PGI2by endothelial cells, ranging from 13% at NTG 10 pg/ml to 63% at NTG 10 ng/ml (P< 0.01,n= 10). Pretreatment of endothelial cells with either aspirin (50 μM for 120 min) or the prostacyclin synthetase inhibitor 15-hydroperoxyarachidonic acid (20 μg/ml for 15 min) abolished production of the platelet inhibitory substance. Synergy between NTG and PGI2in the inhibition of platelet aggregation was not present at clinically attainable concentrations of NTG.Thus, NTG at clinically attainable concentrations causes a dose-dependent increase in PGI2synthesis by endothelial cells. If this phenomenon occurs in vivo, the PGI2produced could ameliorate myocardial ischemia by causing peripheral vasodilation and decreasing cardiac work, inhibiting platelet aggregation and thromboxane A2synthesis, and possibly reversing coronary artery vasospasm.