Chirkov Y Y, Chirkova L P, Horowitz J D
Department of Cardiology, The Queen Elizabeth Hospital, University of Adelaide, S.A., Australia.
Am J Cardiol. 1997 Jul 15;80(2):128-31. doi: 10.1016/s0002-9149(97)00305-6.
Suppression of platelet aggregation may be an important component of the therapeutic effect of nitroglycerin (NTG). Because of the phenomenon of hemodynamic tolerance to NTG, we tested the hypothesis that the anti-platelet effects of NTG in humans are also subject to tolerance induction. In patients with stable angina who had not received nitrates for at least 24 hours before study, sublingual administration of NTG (300 microg; n = 17) attenuated the reversal of adenosine diphosphate-induced platelet aggregation by NTG applied in vitro. Three minutes after in vivo NTG administration, concentration of NTG producing 50% reversal of aggregation (C50) increased from 7.9 +/- 1.9 x 10(-5) to 5.5 +/- 0.3 x 10(-4) M (p <0.01); this change persisted for at least 60 minutes. There was no concomitant change in C50 values for sodium nitroprusside applied in vitro. Basal activity of platelet guanylate cyclase and its response to sodium nitroprusside were not affected after administration of NTG. Brief intravenous infusion of NTG (10 microg/min for 10 minutes) produced no significant changes in platelet responses to NTG in vitro. However, prolonged infusion of NTG (5 microg/min for 24 hours, patients with unstable angina pectoris, n = 11) caused suppression of in vitro platelet response to NTG. Platelets from patients receiving prophylactic nitrates (n = 19) were less responsive to the antiaggregatory effects of NTG in vitro than those from patients who had not received nitrates in the previous 24 hours (n = 21). Thus, clinical exposure to NTG, even in very low doses, induces tolerance to antiaggregatory effects of NTG. This phenomenon is not associated either with cross tolerance to sodium nitroprusside or with down-regulation of platelet guanylate cyclase.
抑制血小板聚集可能是硝酸甘油（NTG）治疗作用的一个重要组成部分。由于对NTG存在血流动力学耐受性现象，我们检验了NTG在人体中的抗血小板作用也会诱导耐受性这一假说。在研究前至少24小时未接受硝酸盐治疗的稳定型心绞痛患者中，舌下给予NTG（300微克；n = 17）减弱了体外应用NTG对二磷酸腺苷诱导的血小板聚集的逆转作用。体内给予NTG三分钟后，产生50%聚集逆转的NTG浓度（C50）从7.9±1.9×10⁻⁵增加到5.5±0.3×10⁻⁴M（p<0.01）；这一变化至少持续60分钟。体外应用硝普钠时C50值没有伴随变化。给予NTG后，血小板鸟苷酸环化酶的基础活性及其对硝普钠的反应未受影响。短暂静脉输注NTG（10微克/分钟，共10分钟）在体外对血小板对NTG的反应未产生显著变化。然而，长时间输注NTG（5微克/分钟，共24小时，不稳定型心绞痛患者，n = 11）导致体外血小板对NTG的反应受到抑制。接受预防性硝酸盐治疗的患者（n = 19）的血小板在体外对NTG抗聚集作用的反应性低于前24小时未接受硝酸盐治疗的患者（n = 21）。因此，临床接触NTG，即使是非常低的剂量，也会诱导对NTG抗聚集作用的耐受性。这种现象既不与对硝普钠的交叉耐受性相关，也不与血小板鸟苷酸环化酶的下调相关。
