Preservation of platelet responsiveness to nitroglycerine despite development of vascular nitrate tolerance

Abstract

Aims - Organic nitrates, via nitric oxide (NO) release, induce vasodilatation and inhibit platelet aggregation. Development of nitrate tolerance in some vascular preparations may be associated with diminished responsiveness to NO. To date it is not known to what extent vascular tolerance to organic nitrates is associated with acquired platelet hypo-responsiveness to NO. In the current study we compared the acute and chronic effects of sustained release (SR) isosorbide 5' mono-nitrate (ISMN) and transdermal nitroglycerine (TD-NTG) on blood vessels (effects on apparent arterial stiffness) and platelets (effects on responsiveness to NO donors) in patients with stable angina pectoris (SAP). Methods - Patients (n = 34) with SAP entered a blinded randomized crossover study of ISMN (120 mg) vs. intermittent TD-NTG (15 mg 24 h1). Effects of each nitrate on pulse wave reflection (augmentation index (AIx)), platelet response to adenosine di-phosphate (ADP 1 µmol l1), nitroglycerine (NTG 100 µmol l1) and the non-nitrate NO donor sodium nitroprusside (SNP 10 µmol l1), were measured pre-dose, 4 and 8 h post dose, on three occasions: 1) at the end of a pre-nitrate phase, 2) after dosing for 7 days and 3) following 14 days of full dose therapy with either nitrate. Results - Acutely, both ISMN and TD-NTG markedly reduced AIx. After 14 days, these effects were significantly attenuated (anova, P = 0.018) but not abolished, indicating development of nitrate tolerance. Neither nitrate preparation affected ADP (1 µmol l1)-induced platelet aggregation. Platelet responsiveness to NTG (100 µmol l1) and SNP (10 µmol l1) was not diminished during chronic nitrate therapy, and there was no evidence of 'rebound' hyper-aggregability during 'nitrate-free' periods. Conclusions Chronic therapy with either ISMN or TD-NTG is associated with development of vascular tolerance. Despite the induction of vascular tolerance, platelet responsiveness to NTG and SNP remains unaffected. Therefore, development of vascular tolerance is unlikely to compromise the anti-aggregatory effects of organic nitrates, or those of endogenous NO.