(Circulation. 2000;102:e87.)
© 2000 American Heart Association, Inc.
Correspondence |
Nitrate Resistance in Platelets From Patients With Stable Angina Pectoris
Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK
To the Editor:
The article by Chirkov and colleagues1 clearly indicates that platelets in plasma samples from patients with stable angina are resistant to the inhibitory effects of pharmacological concentrations of the nitric oxide (NO) donor drugs nitroglycerine (NTG) and sodium nitroprusside (SNP). Resistance was reversed by superoxide dismutase, suggesting that the effect might be due to superoxide-mediated inactivation of NO derived from NTG and SNP in the platelets of patients.
As the authors point out, this interesting observation does not
necessarily reflect platelet resistance to NTG in vivo. However,
even in the absence of nitrate resistance, organic nitrates are
notoriously poor inhibitors of platelet
aggregation2 because, unlike vascular tissue,
platelets lack the necessary metabolic pathway for NO
generation from nitrates.3 This issue is highlighted by
the need to use high concentrations (100 µmol/L) of NTG to
inhibit platelet aggregation in this study; the maximum estimated
plasma concentration with transdermal and sublingual NTG is several
orders of magnitude lower (
2 and 20 nmol/L, respectively).
Clearly, NTG is unlikely to have an impact on platelet aggregation
in angina pectoris, irrespective of nitrate resistance. It is
noteworthy that SNP is a significantly more potent
inhibitor of platelet aggregation; perhaps we should be
looking to SNP and platelet-selective NO donors such as
S-nitrosothiols4 as vasodilators with
antithrombotic activity, rather than organic nitrates.
References
1.
Chirkov YY, Holmes AS, Chirkova LP, et al. Nitrate
resistance in platelets from patients with stable angina pectoris.
Circulation. 1999;100:129–134.
2.
Drummer C, Valta-Seufzer U, Karrenbrock B, et al.
Comparison of anti-platelet properties of molsidomine,
isosorbide-5-mononitrate and placebo in healthy volunteers. Eur
Heart J. 1991;12:541–549.
3. Weber A-A, Neuhaus T, Seul C, et al. Biotransformation of glyceryl trinitrate by blood platelets as compared to vascular smooth muscle cells. Eur J Pharmacol. 1996;309:209–213.[Medline] [Order article via Infotrieve]
4. De Belder AJ, MacAllister R, Radomski MW, et al. Effects of S-nitroso-glutathione in the human forearm circulation: evidence for selective inhibition of platelet activation. Cardiovasc Res. 1994;28:691–694.[Medline] [Order article via Infotrieve]
Response
Department of Cardiology, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia
We thank Drs Megson and Webb for their interest in our article. With regard to the phenomenon of "nitrate resistance," it is certainly correct that reduced responsiveness to sodium nitroprusside (SNP) at the level of platelet aggregation in whole blood must have implications for endogenous nitric oxide (NO). Thus, we agree that one of the major conclusions to be drawn from our study is that patients with stable angina pectoris are more predisposed toward platelet aggregation by virtue of decreased platelet responsiveness to endogenous NO.
With regard to the implications of our findings for pharmacotherapy with NO donors, we do not agree that the antiaggregatory effects of nitroglycerin (NTG) are either nonexistent or trivial in the clinical context. There are numerous studies (for example, References R1 and R2 ) documenting in vivo and ex vivo antiaggregatory effects of NTG in both animals and humans. Although washed platelets do not bioconvert NTG, bioconversion in platelet-rich plasma produces sufficient NO to inhibitR3 and reverseR2 platelet aggregation.
We acknowledge that the concentrations of NTG and SNP utilized in our study for evaluation of inhibition of aggregation in vitro were far higher than those occurring with optimal clinical use of these agents. This disparity between efficacy of NTG in vivo and in vitro has never been adequately explained but may reflect the consequences of intense NTG bioconversion in blood vessels,R4 resulting in increased NO release.
Regarding the suggestion that SNP or S-nitrosothiols may be more suitable than NTG for therapeutic inhibition of platelet aggregation, it is certainly true that these agents are more potent than NTG. However, they are also more potent arteriolar dilators than NTG,R5 raising a theoretical concern about precipitation of coronary "steal." In view of unimpressive outcomes of clinical trials with SNP and with the "direct" NO donor linsidomine in acute myocardial infarction, we hesitate to make recommendations based on antiaggregatory effects in isolation.
References
1.
Folts JD, Stamler J, Loscalzo J.
Intravenous nitroglycerin infusion inhibits
cyclic blood flow responses caused by periodic platelet thrombus
formation in stenosed canine coronary arteries.
Circulation. 1991;83:2122–2127.
2. Chirkov YY, Naujalis JI, Sage RE, et al. Antiplatelet effects of nitroglycerin in healthy subjects and in patients with stable angina pectoris. J Cardiovasc Pharmacol. 1993;21:384–389.[Medline] [Order article via Infotrieve]
3. Chen LY, Mehta P, Mehta JL. Platelet inhibitory effect of nitroglycerin in platelet-rich plasma: relevance of glutathione-s-transferases in plasma. J Investig Med. 1996;44:561–565.[Medline] [Order article via Infotrieve]
4. Fung H-L, Chung S-J, Bauer JA, et al. Biochemical mechanism of organic nitrates actions. Am J Cardiol. 1992;70:4B–10B.[Medline] [Order article via Infotrieve]
5.
Harrison DG, Bates JN. The nitrovasodilators: new
ideas about old drugs. Circulation. 1993;87:1461–1467.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||