Compromised blood vessel function caused by cigarettes and e-cigarettes is mediated by lung irritation

Cigarettes and e-cigarettes deliver the addictive drug nicotine to the lungs where it is absorbed and rapidly delivered to the brain. The holy grail of the idea that e-cigarettes are a form of harm reduction is that the e-cigarette aerosol has fewer specific bad chemicals than cigarette smoke.  New research from Pooneh Nabavizadeh and colleagues at UCSF (including  me), “Impairment of Endothelial Function by Cigarette Smoke Is Not Caused by a Specific Smoke Constituent, but by Vagal Input from the Airway,” raises doubts about that idea, at least in terms of adverse effects on blood vessels, an important cause of cardiovascular disease.

Nabavizadeh and colleagues exposed rats to various substances found in tobacco smoke or e-cigarettes, including nicotine, menthol, the gases acrolein and acetaldehyde (two chemicals found in both tobacco smoke and e-cigarette vapors), and inert carbon nanoparticles that represent the tiny particles in smoke and e-cigarette aerosol.

We measured the ability of arteries to enlarge to accommodate increases in blood flow when needed to deliver more blood to the body when exercising, which is known as flow mediated dilation (FMD) before and after having the rats breathe the different substances. 

We found that blood vessel dilation was reduced after use of all four types of exposures, with the extent of the reduction ranging from 20–46%.  Nicotine was not required for impairment of vascular function, however, higher nicotine levels were associated with a greater decrease in FMD than lower nicotine levels and menthol was associated with a lower decrease in FMD than non-menthol products.

Surprisingly, these effects were not due to direct effect of these toxins on the cells lining the blood vessels, but rather were caused by lung airway irritation due to inhalation of a foreign substance, rather than a specific component of the cigarette smoke or e-cigarette aerosol.

When Nabavizadeh and colleagues exposed rats  to smoke after cutting the vagus nerve, a long nerve extending from the brain that connects the airway to the rest of the nervous system and plays a key role in heart rate, breathing, and other functions, FMD was no longer reduced, demonstrating the nerve’s key role in this process. In other words, the compromised ability of arteries to expand in response to the need to deliver more blood appears to be caused by airway irritation that triggers biological signals in the vagus nerve that somehow leads to blood vessel damage, possibly through an inflammatory process.

Menthol resulted in less severity of flow-mediated dilation impairment, but this does not suggest that menthol is a beneficial additive in cigarettes and e-cigarettes because the impairment was still substantial and menthol has other harmful effects.

The rats were also exposed to two of the main gases found in both smoke and e-cigarette aerosol as well as clean carbon nanoparticles to evaluate the effects of those types of components on blood vessel dilation. The gases and carbon particles had similar impairment effects to whole tobacco smoke, despite representing completely different chemical and physical components of smoke.

The lack of a specific toxin that accounts for vascular impairment means that regulatory agencies like the FDA cannot rely on prohibiting specific ingredients to avoid adverse effects of inhaled products on vascular function.

Here is the abstract:

Background: Exposure to tobacco or marijuana smoke, or e-cigarette aerosols, causes vascular endothelial dysfunction in humans and rats. We aimed to determine what constituent, or class of constituents, of smoke is responsible for endothelial functional impairment.

Methods: We investigated several smoke constituents that we hypothesized to mediate this effect by exposing rats and measuring arterial flow-mediated dilation (FMD) pre- and post-exposure. We measured FMD before and after inhalation of sidestream smoke from research cigarettes containing normal and reduced nicotine level with and without menthol, as well as 2 of the main aldehyde gases found in both smoke and e-cigarette aerosol (acrolein and acetaldehyde), and inert carbon nanoparticles.

Results: FMD was reduced by all 4 kinds of research cigarettes, with extent of reduction ranging from 20% to 46% depending on the cigarette type. While nicotine was not required for the impairment, higher nicotine levels in smoke were associated with a greater percent reduction of FMD (41.1±4.5% reduction versus 19.2±9.5%; P=0.047). Lower menthol levels were also associated with a greater percent reduction of FMD (18.5±9.8% versus 40.5±4.8%; P=0.048). Inhalation of acrolein or acetaldehyde gases at smoke-relevant concentrations impaired FMD by roughly 50% (P=0.001). However, inhalation of inert carbon nanoparticles at smoke-relevant concentrations with no gas phase also impaired FMD by a comparable amount (P<0.001). Bilateral cervical vagotomy blocked the impairment of FMD by tobacco smoke.

Conclusions: There is no single constituent or class of constituents responsible for acute impairment of endothelial function by smoke; rather, we propose that acute endothelial dysfunction by disparate inhaled products is caused by vagus nerve signaling initiated by airway irritation.

The full citation is: Nabavizadeh P, Liu J, Rao P, Ibrahim S, Han DD, Derakhshandeh R, Qiu H, Wang X, Glantz SA, Schick SF, Springer ML. Impairment of Endothelial Function by Cigarette Smoke Is Not Caused by a Specific Smoke Constituent, but by Vagal Input From the Airway. Arterioscler Thromb Vasc Biol. 2022 Nov;42(11):1324-1332. doi: 10.1161/ATVBAHA.122.318051. Epub 2022 Oct 26. PMID: 36288292; PMCID: PMC9616206.  It is available here.

Here are press releases from NIH and AHA about the study:

And an editorial by Dan Conklin, “How Irritating! Electronic Cigarettes Not “95% Safer” Than Combustible Cigarettes: Recent Mechanistic Insights Into Endothelial Dysfunction,” that puts the paper into the broader scientific context.

Published by Stanton Glantz

Stanton Glantz is a retired Professor of Medicine who served on the University of California San Francisco faculty for 45 years. He conducts research on tobacco and cannabis control and cardiovascular disease/

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