Nitroglycerin Stimulates Synthesis of Prostacyclin by Cultured Human Endothelial Cells

Richard I. Levin; Eric A. Jaffe; Babette B. Weksler; Karen Tack-Goldman

doi:10.1172/JCI110093

Nitroglycerin Stimulates Synthesis of Prostacyclin by Cultured Human Endothelial Cells

Richard I. Levin, Eric A. Jaffe, Babette B. Weksler, and Karen Tack-Goldman

Published March 1, 1981 - More info

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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-PGF_1α, 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-PGF_1α 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.