Special Feature
Nitrate Tolerance: Can Studies of Vascular Biology Resolve the Conundrum?
By Jonathan Abrams, MD
For the past several years, interesting experimental data have accumulated regarding mechanisms of nitrate tolerance, indicating that arterial endothelial cells become dysfunctional due to oxidant stress in the presence of prolonged nitrate exposure. In the presence of tolerance, endothelial cell endothelin production is stimulated and protein kinase C is activated, with a resultant marked heightened sensitivity to a variety of vasoconstrictors, including angiotensin II and catecholamines. While the mechanisms for these phenomena are still being evaluated, it appears that increased oxygen free radicals, produced by the endothelial cells themselves, are stimulated in the presence of nitrate tolerance. This results in enhanced degradation of nitric oxide and the formation of peroxynitrate, which can destroy nitric oxide. Some researchers have suggested that there may be activation of vasoconstictor prostenoids in the presence of nitrate tolerance. Many of these studies indicate impaired endothelial-dependent dilator responses as well as diminished or absent organic nitrate action in the setting of tolerance. Furthermore, recent work suggests that there may be overt vasoconstriction in the presence of nitrate tolerance, particularly when there is associated oxidant stress, such that nitrates may actually induce constriction in coronary and systemic arteries instead of vasodilation. These observations open the door to a variety of interventions that might ameliorate or prevent tolerance. Antioxidants, such as vitamin C, vitamin E, and carvedilol, have recently been used with success in humans. ACE inhibitors and angiotensin receptor blockers (ARB) have also been effective in some, but not all, studies.
Watanabe and associates, from Japan, have presented or published a series of studies dealing with this issue. These workers have developed a cyclic GMP platelet assay to assess platelet cGMP responses to nitrate administration as well as during nitrate tolerance. In the presence of nitrate tolerance, platelet cGMP concentrations are decreased after exposure to nitroglycerin (NTG), accompanied by a concordant reduction in vasodilator activity. Recently, this group has demonstated that both vitamin E and vitamin C are able to prevent nitrate tolerance in normal volunteers.1 In a recent issue of Circulation, Watanabe et al report a randomized, double-blind, placebo-controlled trial of vitamin C in patients with heart failure, and they demonstrate that co-administration of intravenous ascorbate was able to prevent the development of hemodynamic tolerance after a sustained infusion of intravenous NTG.2 Twenty patients with heart failure were randomized to intravenous ascorbate or placebo; all received an infusion of NTG for 24 hours. Hemodynamic studies were carried out at baseline and serially, with maintenance infusion rate after stabilization of hemodynamics, using an initial end point of a 30% reduction in pulmonary capillary wedge pressure (PCWP). At this point, the NTG infusion was continued at a rate of 1.5 ± 0.5 mcg/kg for 24 hours. The results indicate a loss of hemodynamic effects in the NTG-placebo group beginning 12 hours after infusion, with return of PCWP and systolic blood pressure to baseline. However, ascorbate-treated patients maintained the beneficial hemodynamic effects of intravenous NTG with systolic blood pressure and PCWP remaining at their lowest levels for the entire 24-hour infusion period.
Assays of platelet cGMP indicated the characteristic rise in cGMP concentrations with initial nitroglycerin exposure and a late fall-off beginning at six hours in the placebo-treated patients who continue to receive NTG. However, in the ascorbate group, the platelet cGMP levels remained elevated, at least two-fold greater than baseline. Furthermore, plasma vitamin E (alpha-tocopherol) levels were found to decrease at the onset of hemodynamic tolerance in the placebo patients but not in the ascorbate group. Watanabe et al conclude that ascorbate was able to prevent nitrate tolerance, presumably acting through a scavenging effect on reactive oxygen molecules, and favorably altering the intracellular redox state through its interactions with glutathione.
Other investigators have previously shown the benefits of vitamin C in nitrate tolerance. It has also been previously demonstrated that vitamin E levels fall in the presence of tolerance, presumably because of an effect of free radicals on alpha-tocopherol. In a preliminary report, Japanese investigators have shown that carvedilol, but not a generic beta blocker, was able to prevent nitrate tolerance in hypertensives.3 This was felt to be due to the antioxidant effects of carvedilol.
There is considerable exciting new research in this area; interested readers are referred to a recent symposium on nitrate tolerance.4 In particular, a summary of the vascular biology experiments of Munzel and associates is extremely informative regarding the latest recent developments in mechanisms of tolerance. Assuming that oxidant stress is a major culprit with respect to the development of nitrate tolerance, it makes sense that antioxidant strategies be assessed to prevent or reverse tolerance. These preliminary data are encouraging, but, clearly, considerable more clinical studies are necessary. Though Munzel et al have shown in animal models that ARBs are effective in preventing tolerance, a new preliminary study was unable to prevent tolerance in normal volunteers with an ARB.5 Furthermore, another preliminary report from the same group was unable to reverse tolerance with vitamin C and failed to demonstrate oxidative stress metabolites.6
Several new observations suggest that in the presence of nitrate tolerance, there may actually be a vasoconstrictor response to administered nitrates. Parker and colleagues have shown that coronary arteries constrict to acetylcholine after nitrate tolerance was induced.7 Other new data also suggest that in the presence of oxidative stress induced by prolonged NTG exposure, there is paradoxical arterial vasoconstriction. Thus, it may be that nitrate tolerance is more hazardous than previously thought. In other words, in addition to neutralizing the desired effects of nitrates, in the presence of full-blown tolerance, there may actually be constrictor responses modulated through endothelial dysfunction, possibly induced by oxidant stress that is related to sustained nitrate exposure. We shall follow this story with considerable interest. As of now, the anti-oxidant approach to tolerance remains to be substantiated in more human trials.
References
1. Watanabe H. Circulation 1998;97:29-36.
2. Watanabe H. Circulation 1997;96:2545-2550.
3. Watanabe H. J Am Coll Cardiol 1998;31:114A.
4. Watanabe H. Am J Cardiol 1998;81A:1A-76A.
5. Milone SD. J Am Coll Cardiol 1998;31:15A.
6. Milone SD. J Am Coll Cardiol 1998;31:395A.
7. Caramori, PRA. J Am Coll Cardiol 1998;31:4A.
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