(Circulation. 1998;98:1350-1353.)
© 1998 American Heart Association, Inc.
Antioxidants and Nitrate Tolerance
Dario Giugliano, MD;
; Raffaele Marfella, MD
Department of Geriatrics and Metabolic Diseases Second
University of Naples,
Naples, Italy
To the Editor:
We read with interest the recent report of Watanabe et
al1 demonstrating that nitrate tolerance, as
shown by reduced vasodilating and platelet cGMP responses after
sublingual 0.3-mg nitroglycerin tablets, develops
quickly in both normal subjects and patients with ischemic
heart disease; a 3-day application of a 10-mg/24-hour
nitroglycerin tape is sufficient to induce these
effects. Concomitant treatment with vitamin E (200 mg TID) for 3 days
prevented the development of nitrate tolerance during continuous
nitrate therapy, pointing to the potential usefulness of this
antioxidant approach. Although vitamin E may have vascular effects of
its own linked to its interaction with specific
endothelial receptors,2 the
conclusions of the authors seem supported by the data
presented.
The development of nitrate tolerance represents a major
therapeutic limitation inherent to the use of organic nitrates. Recent
experimental data demonstrated that continuous
nitroglycerin treatment is associated with increased
vascular superoxide anion production and consequent inhibition
of nitric oxide–mediated vasodilation induced by both
endogenous and exogenous nitrates.3
If enhanced steady-state concentration of vascular superoxide anion is
inherent in nitrate tolerance, one would expect reduced vascular
effects of nitrates in any condition associated with an increased
production of free radicals. Diabetes mellitus is a state of
oxidative stress resulting from enhanced free radical formation and/or
defects in antioxidants defenses.4 Impaired
forearm vasodilatory response to nitroglycerin has been
seen in patients with type 2 diabetes
mellitus.5
In addition to its hemodynamic effects,
nitroglycerin improves some rheological properties of
the normal blood because it reduces blood viscosity and increases blood
filterability.6 None of these effects is seen in
type 2 diabetic patients, in whom a paradoxical deterioration occurs
after sublingual or transdermal nitroglycerin
administration. Both vitamin E (300 mg/d) and glutathione (600 mg/d)
for 7 days normalize the vascular responses to
nitroglycerin in diabetic patients.
Taken together, the data of Watanabe et al1 and
our previous results6 suggest that tolerance to
the vascular effects of nitrates may be prevented by high doses of
vitamin E (300 to 600 mg/d). The evidence that 2 structurally unrelated
antioxidants, vitamin E and glutathione, can normalize nitrate
tolerance suggests a reduced vascular level of superoxide anion as a
likely mechanism of action.
References
1.
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y.
Randomized, double-blind, placebo-controlled study of supplemental
vitamin E on attenuation of the development of nitrate tolerance.
Circulation. 1997;96:2545–2550.[Abstract/Free Full Text]
2.
Kunisaki M, Umeda F, Yamauchi T, Masakado M, Nawata H.
High glucose reduces specific binding for
D-alpha-tocopherol in cultured aortic
endothelial cells. Diabetes. 1993;42:1138–1146.[Abstract]
3.
Munzel T, Giaid A, Kurz S, Stewart D, Harrison D.
Evidence for enhanced vascular superoxide anion production in
nitrate tolerance. J Clin Invest. 1995;95:187–194.
4.
McVeigh G, Brennan G, Hayes R, Johnston D. Primary
nitrate tolerance in diabetes mellitus. Diabetologia. 1994;37:115–117.[Medline]
[Order article via Infotrieve]
5.
Giugliano D, Ceriello A, Paolisso G. Oxidative stress
and diabetic vascular complications. Diabetes Care. 1996;19:257–267.[Abstract]
6.
Giugliano D, Marfella R, Verrazzo G, Acampora R,
Donzella C, Quatraro A, Coppola L, D'Onofrio F. Abnormal rheologic
effects of glyceryl trinitrate in patients with non–insulin-dependent
diabetes mellitus and reversal by antioxidants. Ann Intern
Med. 1995;123:338–343.[Abstract/Free Full Text]
Response
Hideki Watanabe, MD, PhD
Department of Cardiology KINU Medical Association
Hospital,
Mitsukaido, Japan
Masaaki Kakihana, MD, PhD
Ibaraki Prefectural University of Health Sciences Ami, Japan
Sadanori Ohtsuka, MD, PhD;
; Yasuro Sugishita, MD, PhD, FACC
Cardiovascular Division,
Department of Internal Medicine,
Institute of Clinical Science,
University of Tsukuba,
Tsukuba, Japan
We appreciate the interest shown by Drs Giugliano and Marfella
in our article1 and their supportive comments
regarding our findings.
They reported in their articles2 3 that the
beneficial rheological effects of nitroglycerin were
impaired in patients with type 2 diabetes mellitus and that vitamin E
and glutathione normalized the vascular responses to
nitroglycerin. We reported in our recent
article1 that intracellular production of
cGMP was impaired in normal volunteers and patients with
ischemic heart disease and that vitamin E normalized the
response of cGMP production to
nitroglycerin.
We recently reported that ascorbate, as well as vitamin E, normalized
the response to nitroglycerin in normal volunteers and
patients with ischemic heart disease.4 In another
report,5 we showed that concomitant
administration of ascorbate with nitroglycerin
prevented the development of nitrate tolerance on
hemodynamics and cGMP production in patients
with congestive heart failure. Moreover,
hydralazine6 7 8 9 and
carvedilol,10 both of which have antioxidant
properties, have been reported to similarly prevent the development of
nitrate tolerance. These data support the finding that oxidative stress
caused by increased superoxide is an important mechanism of nitrate
tolerance. We agree that supplementation with antioxidants is
potentially useful for prevention of nitrate tolerance.
We again thank Drs Giugliano and Marfella for comments supporting our
findings.
References
1.
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y.
Randomized, double-blind, placebo-controlled study of supplemental
vitamin E on attenuation of the development of nitrate tolerance.
Circulation. 1997;96:2545–2550.
2.
Giugliano D, Marfella R, Verrazzo G, Acampora R,
Donzella C, Quatraro A, Coppola L, D'Onofrio F. Abnormal rheologic
effects of glyceryl trinitrate in patients with non-insulin-dependent
diabetes mellitus and reversal by antioxidants. Ann Intern
Med. 1995;123:338–343.
3.
Giugliano D, Ceriello A, Paolisso G. Oxidative stress
and diabetic vascular complications. Diabetes Care. 1996;19:257–267.
4.
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y.
Randomized, double-blind, placebo-controlled study of the preventive
effect of supplemental oral vitamin C on attenuation of development of
nitrate tolerance. J Am Coll Cardiol. 1998;31:1323–1329.[Abstract/Free Full Text]
5.
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y.
Randomized, double-blind, placebo-controlled study of ascorbate on the
preventive effect of nitrate tolerance in patients with congestive
heart failure. Circulation. 1998;97:886–891.[Abstract/Free Full Text]
6.
Elkayam U. Prevention of nitrate tolerance with
concomitant administration of hydralazine. Can J
Cardiol. 1996;12(suppl C):17C–21C.
7.
Gogia H, Mehra A, Parikh S, Raman M, Ajit U, Johnson
J, Elkayam U. Prevention of tolerance to hemodynamic
effects of nitrates with concomitant use of hydralazine in
patients with chronic heart failure. J Am Coll
Cardiol. 1995;26:1575–1580.[Abstract]
8.
Parker JD, Parker AB, Farrell B, Parker JO. The effect
of hydralazine on the development of tolerance to continuous
nitroglycerin. J Pharmacol Exp
Ther. 1997;280:866–875.[Abstract/Free Full Text]
9.
Münzel T, Kurz S, Rajagopalan S, Thoenes M,
Berrington WR, Thompson JA, Freeman BA, Harrison DG.
Hydralazine prevents nitroglycerin tolerance by
inhibiting activation of a membrane-bound NADH oxidase: a new action
for an old drug. J Clin Invest. 1996;98:1465–1470.[Medline]
[Order article via Infotrieve]
10.
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. The
preventive effect of carvedilol on nitrate tolerance in patients with
congestive heart failure. Eur Heart J.
1997;19(suppl):400. Abstract.
