Doubt about an essential role for constitutive nitric oxide synthase in nitroglycerin-mediated vasodilation

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In their recent PNAS article (1) Bonini et al. show that inhibition of endothelial NOS (eNOS) or removal of the endothelium impairs the nitroglycerin-mediated vasodilatation (see figure 2 in ref. 1). Although some data in the article are interesting, we believe that several points deserve further attention and discussion. The major issue is that the article contradicts a large body of previous literature and makes no effort to reconcile these differences. In fact, many articles have shown that endogenously produced NO antagonizes the effect of nitroglycerin. As an example, mechanical removal of the endothelium, which rids the vessel of NO production, has repeatedly been shown to enhance nitroglycerin vasodilatation, in contrast to the finding by Bonini et al. (1). Inhibition of NOS with agents such as L-NAME has also been shown to enhance nitroglycerin-induced vasodilatation, again contradicting the findings of Bonini et al. (1). Finally, mice lacking the endothelial isoform of NOS exhibit augmented vasodilatation to nitroglycerin (2, 3), and overexpression of this enzyme in transgenic mice paradoxically reduces nitroglycerin- and sodium nitroprusside-induced vasodilatation (4). We have made similar observations and found nitroglycerin potencies (pD2 values) of 6.85 ± 0.05 and 7.4 ± 0.1 in aorta from wild-type and eNOS-deficient mice, respectively (Fig. 1). Additionally, there is an appreciable discrepancy between nitroglycerin-mediated vasodilation and NO formation (reviewed in ref. 5). Although the hemodynamic data presented by Bonini et al. (1) are interesting, they completely contradict previous results on pharmacological, mechanical, and knockout-induced eNOS inhibition and nitroglycerin potency.