Slow nitrates: NAC and alpha lipoic acid may prevent tolerance

Jacob Schor, ND, FABNO

February 24, 2020

A goal in treating coronary artery disease is to increase delivery of oxygen to the myocardium and the way this is often accomplished is by increasing blood flow in the coronary vessels by stimulating vasodilation. 

A drug called isosorbide mononitrate used to treat angina chest pain secondary to cardiovascular disease does just that. This drug belongs to a class of drugs called nitrates. Another drug in this class used for a somewhat similar purpose, that is more familiar, is nitroglycerin. Isosorbide is slower acting and will provide symptom relief for hours where nitroglycerin is fast-acting. Think of isosorbide as slow release nitroglycerine.  Both drugs supply the body with a rush of nitrates and lead to an increase in nitric oxide (NO), which in turn, causes vasodilation and increases blood flow. The rapid increase in nitric oxide causes vasodilation, increased blood flow and increased oxygen reaching the muscle tissue, and this is what leads to symptom relief.

These nitrate drugs have been used for a long time; nitroglycerin since 1847.[1]  The various slower acting nitrates have been employed for more than half a century.


The idea that slow-release nitrates might be useful for treating cardiac arterial disease has been adopted in our naturopathic world. Beet juice and beet powders are so high in nitrates that some studies simply refer to them as dietary nitrates and until you read the full text you may not realize that the nitrates the participants consume are just powdered beets. [2]

Beets are the new panacea for heart health….

Beets aren’t the only trick we employ to raise nitric oxide production. We employ l-arginine to treat CVD as it also supplies the body with the required nitrates needed to produce NO.[3]  The fact that nuts are super high in l-arginine has been suggested as the reason why eating them lowers risk for heart disease.[4]  This idea that supplying nitrates is good for the heart because of increased NO production should be old news for most of us.

But there’s something we can learn from studying the way this drug isosorbide mononitrate is prescribed. Recall a lot of people have been taking it for many years. Some clinical tricks have been figured out over this time. This drug is supposed to be prescribed once a day. If twice, then at breakfast and lunch, but it should not be evenly divided over the day. A person’s vascular walls quickly build up a tolerance to nitric oxide and the dilatory effects diminish.  

If you take isosorbide once a day it works quite well at reducing angina.[5]  If nitrates are administered around the clock, tolerance to their effects develops rapidly.[6] [7] If you take isosorbide 3-4 times per day the drug doesn’t work nearly as well. Thus, the recommendation is to have 12-14 hours a day that are drug-free to avoid creating tolerance. Is it the drug itself that creates tolerance or is the tolerance to nitric oxide? It appears that the tolerance is to the NO triggered vasodilation.[8] Thus an educated guess would be that NO made from any substrate would still trigger tolerance.

Now if we were to be prescribing these nitrate drugs, we should be cautioning patients to be sure that for half the day they need their serum concentration to drop back to normal. When it comes to the supplements that we use to raise NO levels, as far as I can tell, the same cautions should apply. If we spread doses of our natural nitrates across the day, we will likely see diminished effect. Thus, for l-arginine, l-citrulline, beet powder and other clever natural NO strategies we might choose to enhance NO production, we still need to make sure that this is a half time strategy, that half the day we are doing nothing that will increase NO.

Someone is going to ask me about nuts. Nuts supply arginine and so increase nitric oxide, right? I now think nuts might provide more heart protection as a once a day snack rather than something one grazes on all day long.

There are two other interesting things we should note regarding isosorbide and NO. At least with isosorbide, the NO tolerance is prevented by treatment with N-actylcysteine (NAC) and possibly alpha lipoic acid. 

Going back to 1989, Svendsen et al reported that doses of NAC increased exercise tolerance in people taking isosorbide mononitrate and prevented tolerance. Their study used large doses, nearly 5 grams per day.[9]  Although Parker had been unable to demonstrate this effect in 1987, a 1994 study by Mehra did confirm benefits, reporting a “… substantial NAC-mediated potentiation…” of isosorbide’s effect.[10]  Nizomov reported that a combination of l-arginine and NAC was helpful in 1995 against acute coronary syndrome.[11]  In a 2008 report we see the NAC and l-arginine combination being helpful in lowering blood pressure by improving vascular function.[12]

Dudek et al reported in 2008 that at least in rats, alpha lipoic acid prevented tolerance to nitroglycerine.   They offer a window into the chemical mechanisms involved in this tolerance:

“The most recent studies have suggested that mitochondrial lipoate/dihydrolipoate system-dependent aldehyde dehydrogenase-2 plays a key role in nitric oxide release from [nitroglycerin]…. The aldehyde dehydrogenase-2 performs three enzymatic activities of dehydrogenase, esterase and reductase. The reductase activity is responsible for bioactivation of organic nitrates, such as [nitroglycerine] yielding nitrite and dinitrate ……”[13]

But for more simple minds, both these supplements, NAC and lipoic acid, are recognized for increasing levels of glutathione in the body; NAC by supplying cysteine and lipoic acid by recycling glutathione once it is reduced.  The common denominator of treatment that prevent nitroglycerin tolerance appear to be antioxidants that target Complex 1 pathways in the mitochondria providing protection against reactive oxygen species.[14] Sadly that may be too much of an oversimplification as it appears that the addition of the oxidant hydrogen peroxide in experimental models may also counter nitrate tolerance.[15]  That fact should be confusing.

What can we learn from all this trivia? 

If you have patients taking slow release prescription nitrate drugs, make sure they get that daily drug break. Consider adding NAC to reduce the development of tolerance. Perhaps a single serving a day of nuts in the morning or mid-day might have a better effect than grazing on nuts all day long? We don’t know that as no one has likely ever considered the possibility before. We should translate this into naturopathic medical practice: if using supplements such as l-arginine or beets to increase nitric oxide, to treat CVD, consider this same daily break to allow NO to fall and so prevent tolerance. In the patients where these supplements may have not had the desired impact, consider trying them again, but with careful dose timing.  Our routine instructions to divide supplements evenly over the day may have backfired initially.  Also, consider the addition of NAC and lipoic acid to a range of supplements that we employ to provide benefit through increasing nitric oxide.

Also consider using alpha lipoic acid.  There are plausible arguments that alpha lipoic acid could also be helpful to CAD patients, at least in people suffering from type 2 diabetes. In a 2015 published trial Dworacka et al used 600 mg/day and saw significant changes in a group of DM-2 patients that suggested improvements in cardiac angiogenesis. [16]  Evidence also suggests lipoic acid limits the damage caused when researchers trigger simulated heart attacks (at least in rats). [17]  Not a bad thing to be protected against…..

Links to related articles:


Exercise performance: NMJ 2017


nuts and olive oil: NMJ 2013

Pistachios and lipid profile: NMJ 2014

Nuts may reduce cancer risk: NMJ 2015

Walnuts and mortality: NMJ 2014


[1] Berlin R. Historical aspects of nitrate therapy. Drugs. 1987;33 Suppl 4:1-4.

[2] Jackson J, Patterson AJ, MacDonald-Wicks L, McEvoy M. The role of inorganic nitrate and nitrite in CVD. Nutr Res Rev. 2017 Dec;30(2):247-264.

[3] Pahlavani N, Jafari M3, Sadeghi O et al. L-arginine supplementation and risk factors of cardiovascular diseases in healthy men: a double-blind randomized clinical trial. Version 2. F1000Res. 2014 Dec 12 [revised 2017 Jun 22];3:306.

[4] Bitok E, Sabaté J. Nuts and Cardiovascular Disease. Prog Cardiovasc Dis. 2018 May – Jun;61(1):33-37.

[5] Thadani U, Prasad R, Hamilton SF, et al. Usefulness of twice-daily isosorbide-5-mononitrate in preventing development of tolerance in angina pectoris. Am J Cardiol. 1987 Sep 1;60(7):477-82.

[6] Bassett K, Rhone ML. The efficacy and effectiveness of sustained release oral nitroglycerin in comparison to regular delivery isosorbide dinitrate for the prophylactic treatment of stable angina pectoris. Health Technology Review. BCOHTA 94:1T, September 1994

[7] Rudolph W, Dirschinger J, Reiniger G, Beyerle A, Hall D. When does nitrate tolerance develop? What dosages and which intervals are necessary to ensure maintained effectiveness? European Heart Journal. 1988; 9(Suppl. A):63-72.

[8] Poulsen HE, Aldershvile J, Laursen JB et al. Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo. ELSEVIER Cardiovascular Research 31 (1996) 8 14-8 19

[9] Svendsen JH, Klarlund K, Aldershvile J, Waldorff S. N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients evaluated by exercise testing. J Cardiovasc Pharmacol. 1989 Feb;13(2):320-3.

[10] Mehra A, Shotan A, Ostrzega E, et al. Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure. Circulation. 1994 Jun;89(6):2595-600.

[11] NizomovA, Ganiyev U, Kenjaev M, Gulyamova K. Effect of L-arginine in combination with N-acetylcysteine on oxidative stress and left ventricular function in patients with acute coronary syndrome with st segment elevation Atherosclerosis. July 2015Volume 241, Issue 1, Pages e222–e223

[12] Martina V, Masha A, Gigliardi VR, et al. Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes. Diabetes Care. 2008 May;31(5):940-4.

[13] Dudek M, Bednarski M, Bilska A, et al. The role of lipoic acid in prevention of nitroglycerin tolerance. Eur J Pharmacol. 2008 Sep 4;591(1-3):203-10. 

[14] Garcia-Bou R, Rocha M, Apostolova N, et al. Evidence for a relationship between mitochondrial Complex I activity and mitochondrial aldehyde dehydrogenase during nitroglycerin tolerance: effects of mitochondrial antioxidants. Biochim Biophys Acta. 2012 May;1817(5):828-37. 

[15] Ghatta S, Hemmer RB, Uppala S, O’Rourke ST. Role of endogenous hydrogen peroxide in the development of nitrate tolerance. Vascul Pharmacol. 2007 Apr;46(4):247-52. 

[16] Dworacka M, Iskakova S, Krzyżagórska E, et al.  Alpha-lipoic acid modifies circulating angiogenic factors in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2015 Feb;107(2):273-9. 

[17] Deng C, Sun Z, Tong G, et al. α-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway. PLoS One. 2013;8(3):e58371.