Nitroglycerin Stimulates Synthesis of Prostacyclin by Cultured Human Endothelial Cells

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Abstract
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. PGI2 biologic 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 A2 synthesis 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-PGF1α demonstrated that NTG elicited dose-dependent increments in the synthesis of PGI2 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 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 PGI2 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 PGI2 synthesis by endothelial cells. If this phenomenon occurs in vivo, the PGI2 produced could ameliorate myocardial ischemia by causing peripheral vasodilation and decreasing cardiac work, inhibiting platelet aggregation and thromboxane A2 synthesis, and possibly reversing coronary artery vasospasm.