NITROGLYCERIN TOLERANCE AT THE PLATELET LEVEL IN PATIENTS WITH ANGINA-PECTORIS

Suppression of platelet aggregation may be an important component of t he therapeutic effect of nitroglycerin (NTG). Because of the phenomeno n of hemodynamic tolerance to NTG, we tested the hypothesis that the a ntiplatelet effects of NTG in humans are also subject to tolerance ind uction. In patients with stable angina who had not received nitrates f or at least 24 hours before study, sublingual administration of NTG (3 00 mu g; n = 17) attenuated the reversal of adenosine diphosphate-indu ced platelet aggregation by NTG applied in vitro. Three minutes after in vivo NTG administration, concentration of NTG producing 50% reversa l of aggregation (C-50) 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 minut es. There was no concomitant change in C-50 values for sodium nitropru sside applied in vitro. Basal activity of platelet guanylate cyclase a nd its response to sodium nitroprusside were not affected after admini stration of NTG. Brief intravenous infusion of NTG (10 mu g/min for 10 minutes) produced no significant changes in platelet responses to NTG in vitro. However, prolonged infusion of NTG (5 mu g/min for 24 hours , patients with unstable angina pectoris, n = 11) caused suppression o f in vitro platelet response to NTG, Platelets from patients receiving prophylactic nitrates (n = 19) were less responsive to the antiaggreg atory effects of NTG in vitro than those from patients who had not rec eived nitrates in the previous 24 hours (n = 21). Thus, clinical expos ure to NTG, even in very low doses, induces tolerance to antiaggregato ry effects of NTG, This phenomenon is not associated either with cross tolerance to sodium nitroprusside or with down-regulation of platelet guanylate cyclase. (C) 1997 by Excerpta Medico, Inc.