Mechanisms underlying nitroglycerin-induced superoxide production in platelets: some insight, more questions

Nitroglycerin (NTG) has been the foremost anti-ischemic agent used in clinical medicine for more than a century. NTG is a potent vasodilator of veins, arterial conductance vessels, and collaterals that has minimal effects on arteriolar tone. At the cellular level, NTG is biotransformed by a still unknown enzymatic process in endothelial cells, smooth muscle, and to some extent platelets, causing it to release the vasodilator and anti-aggregatory principle nitric oxide. The 2 major drawbacks of nitrate therapy that have been shown to be important are the rapid development of nitrate tolerance1 and endothelial dysfunction2,3⇓ within several days of prolonged NTG treatment. There is a growing body of evidence that both NTG-induced side effects may be at least in part secondary to NTG-stimulated production of oxygen-derived free radicals within vascular tissue.4–6⇓⇓ Increased oxidative stress correlates positively with increased cardiovascular event rates,7 which may, at least in part, explain why NTG-therapy either failed to improve or worsened the prognosis in patients with acute myocardial infarction and chronic ischemic heart disease, respectively. See p 208 For years, investigators have been debating whether NTG has significant antiplatelet activity. Several studies demonstrated that inhibition of platelet aggregation by NTG occurs in suprapharmacological dosis, denying any clinically relevant antiplatelet activity. Whether or not NTG inhibits platelet aggregation clearly depends on the chosen experimental conditions. For example, in washed platelets, the lowest effective concentrations of NTG that inhibit platelet aggregation are consistently in the μmol/L range and are therefore in concentrations that are 1000 times higher than those achieved with in vivo NTG therapy (nmol/L range), a finding which has raised doubt about the physiological significance of platelet inhibition by NTG. As mentioned above, NTG has to be biotransformed in order to release NO. The weak antiplatelet activity of NTG, …