These popular prescription and over the counter medications may contribute to the loss of nitric oxide (NO) production and availability and increase adverse cardiovascular events such as heart attacks and strokes.

Over a decade ago, a number of clinical trials showed that NSAIDs that block COX-2 increased adverse cardiovascular events. This led to a recall of drugs like Vioxx by the FDA. The side effects were linked to decreased expression of endothelial NO synthase (eNOS) activity, which inhibited the release and function of NO.

The utility of other non-specific NSAIDs such as aspirin, naproxen, diclofenac and others is also limited due to their GI side effects (i.e. peptic ulcer / GI bleeding). Although the association of these drugs with NO loss is less clear, it’s been demonstrated that providing NO via dietary nitrate and nitrite ameliorates the damage caused by these NSAIDs by protecting the integrity of the mucosal barrier

PPI Perils

Recently, the third-highest selling class of drugs, the Proton Pump Inhibitors (PPIs), is again under scrutiny for cardiovascular related side effects. One in every 14 Americans uses a PPI. They are the most common type of heartburn (acid-reflux, GERD) drugs and include, Nexium, Prevacid, Prilosec, Protonix and Aciphex.

A newly released study by Stanford University researchers, published in the journal PLoS ONE (June 2015), links PPI use to about a 20% increased risk of heart attack in PPI users. According to one author, Dr. Nick Leeper, “The AHA (American Heart Association) estimates a heart attack happens every 34 seconds in America. If we’re estimating this risk is increasing by 20% [with PPI use], the public health impact is substantial”.

The study also implied that anyone on PPIs may be at an increased risk for heart attack, not just those patients on clopidogrel (Plavix) blood thinners, other medications, or with a predisposing cardiovascular risk.

The findings of this new research, which involved nearly 3 million adults, supports previous researchpublished in 2013 in the journal Circulation by the current study co-authors John Cooke and Yohannes Ghebremariam. That study found PPIs result in decreased NO production, thereby elevating the risk of adverse cardiovascular events such as heart attack and stroke.

PPI -Mechanism of Action

PPIs elevate plasma asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of the nitric oxide synthase (NOS) family of enzymes, which convert L-arginine to NO predominantly in the cardiovascular, immune, and nervous systems.

Additionally, as far back as 1994, it was reported that NO was formed from nitrite (protonation) in the acidic stomach and that this reaction was abolished by proton pump inhibitors. The pH at which nitrite becomes NO (pKa) is approximately 3.3, hence the stomach must be acidic in order to effectively generate gastric NO, which confers a broad range of function but in particular, it increases stomach mucosal blood flow and protective mucus production.

Neo40® -Mechanism of Action

As healthcare practitioners realize the significance of NO, they naturally want to know what impacts its production and how can it be optimally maintained for a lifetime. At least one important reason for NO loss involves the chronic use of certain medications such as NSAIDS and PPIs. Add to this, the NO-hostile influence of an unsupportive diet, lifestyle, and other factors.

Prescription and over-the-counter PPIs impair NO production and contribute to NO deficiency. The stark physiological impact of having potentially both pathways for the production of NO compromised through PPI use, demonstrates the grave need for an exogenous source of NO in these patients.

Currently, Neo40® is the only safe and effective NO donor technology in the world, having been created with substantiated science in a research setting (Texas Therapeutic Institute, UT School of Medicine at Houston) over 15 years. Neo40® is backed by 5 published peer-reviewed clinical trials and multiple patents, verifying its efficacy.

There is a percentage of the patient population who will continue to use PPIs. Neo40® delivers vital NO to these patients who cannot otherwise generate their own.


  1. Jansson EA, et al. Free Radical Biology and Medicine 2007;42:510–8
  2. PLoS One June 10, 2015 [E pub ahead of print]
  3. Ghebremariam YT, et al. Circulation. 2013;128(8):845-53

Source: PPIs: Raising Your Risk