Levin R I, Jaffe E A, Weksler B B, Tack-Goldman K
J Clin Invest. 1981 Mar;67(3):762-9. doi: 10.1172/JCI110093.
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 (PGI(2)), a known vasodilator and inhibitor of platelet aggregation. Therefore, cultured human endothelial cells were incubated with NTG at various concentrations for 1-3 min. PGI(2) biologic activity in the endothelial cell supernates was assayed by inhibition of platelet aggregation in vitro. The concentration of 6-keto-PGF(1alpha), the stable hydrolysis product of PGI(2), was measured by specific radioimmunoassay.NTG alone significantly inhibited platelet aggregation and thromboxane A(2) synthesis only at suprapharmacologic concentrations (>/=1 mug/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-PGF(1alpha) demonstrated that NTG elicited dose-dependent increments in the synthesis of PGI(2) by 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 muM for 120 min) or the prostacyclin synthetase inhibitor 15-hydroperoxyarachidonic acid (20 mug/ml for 15 min) abolished production of the platelet inhibitory substance. Synergy between NTG and PGI(2) in 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 PGI(2) synthesis by endothelial cells. If this phenomenon occurs in vivo, the PGI(2) produced could ameliorate myocardial ischemia by causing peripheral vasodilation and decreasing cardiac work, inhibiting platelet aggregation and thromboxane A(2) synthesis, and possibly reversing coronary artery vasospasm.
硝酸甘油（NTG）是治疗急性心绞痛最常用的药物，它是一种血管扩张剂，其作用机制尚不清楚。我们推测NTG可能诱导内皮细胞合成前列环素（PGI₂），一种已知的血管扩张剂和血小板聚集抑制剂。因此，将培养的人内皮细胞与不同浓度的NTG孵育1 - 3分钟。通过体外抑制血小板聚集来测定内皮细胞上清液中PGI₂的生物活性。通过特异性放射免疫测定法测量PGI₂的稳定水解产物6 - 酮 - PGF₁α的浓度。单独的NTG仅在超药理浓度（≥1μg/ml）时才显著抑制血小板聚集和血栓素A₂的合成。然而，当将临床可达到浓度（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。该抑制剂对热不稳定。对内皮细胞上清液进行6 - 酮 - PGF₁α的放射免疫测定表明，NTG引起内皮细胞合成PGI₂的剂量依赖性增加，范围从NTG 10 pg/ml时的13%到NTG 10 ng/ml时的63%（P < 0.01，n = 10）。用阿司匹林（50μM孵育120分钟）或前列环素合成酶抑制剂15 - 氢过氧花生四烯酸（20μg/ml孵育15分钟）预处理内皮细胞可消除血小板抑制物质的产生。在临床可达到的NTG浓度下，NTG与PGI₂之间不存在协同抑制血小板聚集的作用。因此，临床可达到浓度的NTG会导致内皮细胞合成PGI₂呈剂量依赖性增加。如果这种现象发生在体内，所产生的PGI₂可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合成以及可能逆转冠状动脉血管痉挛来改善心肌缺血。
