Impairment of endothelial function by cigarette smoke is not caused by a specific smoke constituent, but by vagal input from the airway

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 two of the main
aldehyde gases found in both smoke and e-cigarette acrolein (acrolein and
acetaldehyde), and inert carbon nanoparticles. Results: FMD was reduced by
all four kinds of research cigarettes, with the extent of reduction
ranging from 20–46% 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% percent
reduction vs. 19.2±9.5%; p=0.047). Lower menthol levels were also
associated with a greater percent reduction of FMD (18.5±9.8% vs.
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.