title: Preservation of platelet responsiveness to nitroglycerine despite development of vascular nitrate tolerance.
abstract: OBJECTIVE
  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 h(-1)). Effects of each nitrate on pulse wave reflection (augmentation index (AIx)), platelet response to adenosine di-phosphate (ADP 1 micromol l(-1)), nitroglycerine (NTG 100 micromol l(-1)) and the non-nitrate NO donor sodium nitroprusside (SNP 10 micromol l(-1)), 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 micromol l(-1))-induced platelet aggregation. Platelet responsiveness to NTG (100 micromol l(-1)) and SNP (10 micromol l(-1)) 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.
authors.affiliation: The Cardiology Unit, The Basil Hetzel Institute, The Queen Elizabeth Hospital, Department of Medicine, The University of Adelaide, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Holmes
authors.forename: Yuliy Y
authors.initials: YY
authors.lastname: Chirkov
authors.forename: Scott R
authors.initials: SR
authors.lastname: Willoughby
authors.forename: Susan
authors.initials: S
authors.lastname: Poropat
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pereira
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000097:blood / Q000188:drug therapy*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000008:administration & dosage*; D010974:Platelet Aggregation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D003692:Delayed-Action Preparations; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate