Actions of Nitrates Yin and Yang?
Abstract & Commentary
Source: Gori T, Parker JD. Nitrate-induced toxicity and preconditioning: a rationale for reconsidering the use of these drugs. J Am Coll Cardiol. 2008;52:251-254.
Nitroglycerin and organic nitrate formulations have long been mainstays for therapy of patients with angina, documented CAD, and selected subjects with congestive heart failure. Furthermore, it has been generally believed that these drugs are safe without causing serious side effects other than hypotension due to vascular dilatation and acute lowering of blood pressure. Many nitrate formulations are available to clinicians: sublingual, buccal spray, transdermal, oral, intravenous. While the attitudes towards these agents have sobered somewhat over the past decades, nitrates, in one form or another, are part of many physicians' customary therapies.
The advent of nitrate tolerance as a major problem surfaced in the 1980s, resulting in a small number of clinical trials confirming that short or long exposure to these agents resulted in blunted or even absent clinical vasodilation responses. Nevertheless, nitrate use has remained a staple in many to most physician practices, in part because many take the view that "no harm" exists with nitrate administration, although perhaps little to no real benefit.
Evidence that nitrate "tolerance" might be less benign than we think has come from basic science investigations rather than large clinical trials. In this regard, many researchers have suggested that chronic, and even acute, nitrate exposure induces free radical production, with subsequent loss or elimination of desired clinical responses, particularly coronary artery vasodilation. Furthermore, more recent studies suggest that nitrate exposure may do harm, triggering endothelial dysfunction, increased sensitivity to vasoconstrictors, and activation of important enzymes involved in the regulation of vascular homeostasis, such as SOD, protein kinase C, prostaglandin synthase, and MMP, a physiologic shift favoring sympathetic actions and impaired heart rate variability. Observational data from Japan, while far from conclusive, have suggested an adverse effect of chronic nitrate exposure in post-myocardial infarction patients.
Gori and Parker from Italy and Canada, respectively, discuss the new science relating to nitrate biotransformation and adverse responses of the vasculature in the presence of tolerance. Their research has formulated a theory of reversed vasodilation and decreased arterial responsiveness with chronic nitrate dosing. Basic science studies have suggested mechanistic pathways resulting in increased free radical production, impaired arterial vasodilation, but also a yin-yang effect relating to a favorable preconditioning state serving as a potentially beneficial action!
Gori and Parker have suggested a variety of both positive and negative responses to organic nitrate exposure. In addition to the best known effects of impairing endothelial vasodilation action in the vasculature, including the coronary arteries, the oxidative stress hypothesis has received considerable support. Increased arterial sensitivity to vasoconstrictors and other adverse actions are associated with clinically relevant nitrate-induced oxidative stress. Enzymes such as SOD, protein kinase C, matrix metalloproteinase, and prostaglandin synthase develop impaired nitrate actions in the presence of tolerance due to oxidative stress. Alterations in sympathetic and vagal activity result in sympathetic predominance, impaired baroreflex function, and heart rate variability. These phenomena have been associated with worse prognosis and enhanced coronary artery hypo-responsiveness to acetylcholine. Gori and Parker point out that such alterations are not necessarily wholly due to nitrate tolerance; they call for larger trials regarding long-term nitrate therapy on clinical outcomes.
In contrast to the adverse effects of nitrates, intravenous or transdermal nitrates appear to "trigger" a protective phenotype similar to that produced in ischemic preconditioning "after just one dose or controlled exposure to nitrate. Anti-ischemia vascular phenomena are actually enhanced by nitrates" surprisingly due to release of oxygen free radicals. Thus, these actions can be protective, but not through the traditional mechanisms of arterial and venous vasodilation.
Gori and Parker suggest that there are positive and negative effects of nitrates, occurring with prolonged nitrate administration, whereas sub toxic doses alter the mitochondrial milleu due to "sub toxic gene activation," resulting in a phenotype similar to ischemic preconditioning. "Taken together, these lines of evidence suggest that nitrate-induced free radical production seems to explain both of the acutely protective, but chronically deleterious effects of these drugs."
Gori and Parker emphasize the relatively poor database available dealing with long-term therapy. They cite several Japanese studies which suggest adverse outcomes in post-MI populations. They call for more studies that are double-blind and long-term. They suggest the possibility that co-administration of antioxidants might be a reasonable strategy to enhance desirable nitrate mechanisms. Finally, increased research into nitrate preconditioning is urged.
Commentary
Nitrates have been used in medicine since the late 1800s. They were used for hypertension in the first half of the last century. Tolerance to nitrates became a highly controversial issue in the 1980s and 1990s; it is generally believed that the decreased response to nitrate vascular actions is harmless and difficult to observe in clinical patients.
Tolerance has been subjected to much research, with inconclusive clinical data. Acute nitrate therapy, such as NTG, spray, or transdermal application, is usually effective, but typically employed with many other therapies, making it difficult to impossible to tease out the specific nitrate effects. Recent data, unknown to most physicians, are consistent with enzyme modification and a role of nitrates in enhancing a preconditioning effect, which could be favorable. Clearly, much more basic and clinical research is necessary to resolve the yin and the yang suggested by this viewpoint review. These "old" drugs may result in a potentially new paradigm, as suggested by successful use of a free radical quenching agent such as hydralazine, which appears to be the key to therapy in the A-Heft trial. It appears that the organic nitrates are not dead, and subsequent investigations into nitrate mechanisms and ideal clinical applications will help resolve the yin and yang of these interesting old friends.
Nitroglycerin and organic nitrate formulations have long been mainstays for therapy of patients with angina, documented CAD, and selected subjects with congestive heart failure.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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