TRPA1 and Sympathetic Activation Contribute to Increased Risk of Triggered Cardiac Arrhythmias in Hypertensive Rats Exposed to Diesel Exhaust

Abstract

Background: Diesel exhaust (DE), which is emitted from on- and off-road sources, is a complex mixture of toxic gaseous and particulate components that leads to triggered adverse cardiovascular effects such as arrhythmias.Objective: We hypothesized that increased risk of triggered arrhythmias 1 day after DE exposure is mediated by airway sensory nerves bearing transient receptor potential (TRP) channels [e.g., transient receptor potential cation channel, member A1 (TRPA1)] that, when activated by noxious chemicals, can cause a centrally mediated autonomic imbalance and heightened risk of arrhythmia.Methods: Spontaneously hypertensive rats implanted with radiotelemeters were whole-body exposed to either 500 μg/m3 (high) or 150 μg/m3 (low) whole DE (wDE) or filtered DE (fDE), or to filtered air (controls), for 4 hr. Arrhythmogenesis was assessed 24 hr later by continuous intravenous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR) and electrocardiogram (ECG) were monitored.Results: Rats exposed to wDE or fDE had slightly higher HRs and increased low-frequency:high-frequency ratios (sympathetic modulation) than did controls; ECG showed prolonged ventricular depolarization and shortened repolarization periods. Rats exposed to wDE developed arrhythmia at lower doses of aconitine than did controls; the dose was even lower in rats exposed to fDE. Pretreatment of low wDE–exposed rats with a TRPA1 antagonist or sympathetic blockade prevented the heightened sensitivity to arrhythmia.Conclusions: These findings suggest that a single exposure to DE increases the sensitivity of the heart to triggered arrhythmias. The gaseous components appear to play an important role in the proarrhythmic response, which may be mediated by activation of TRPA1, and subsequent sympathetic modulation. As such, toxic inhalants may partly exhibit their toxicity by lowering the threshold for secondary triggers, complicating assessment of their risk.

Oxidative Stress, Inflammatory Biomarkers, and Toxicity in Mouse Lung and Liver after Inhalation Exposure to 100% Biodiesel or Petroleum Diesel Emissions

“…Reductions in pulmonary function have also been reported following occupational exposures in chronic studies (Rudell et al, 1996). In addition, diesel PM has been associated with changes in heart rate, increased incidence of arrhythmias, impairment of vasodilation, increase in blood pressure, and systemic inflammation (Hazari et al, 2011;Peretz et al, 2008;Tornqvist et al, 2007;Nemmar et al, 2007;Carll et al, 2013;Harkema et al, 2009;Knuckles et al, 2011). Human studies by Mills et al (2005Mills et al ( , 2007aMills et al ( , 2007b) demonstrated a dose-dependent increase in prothrombotic effects and acute myocardial ischemia upon exposure to diesel exhaust.…”

Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma

“…It has been shown that components of urban PM, such as diesel exhaust PM (DEP), activate airway neurons that express transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-1 (TRPV1) (1)(2)(3)(4)(5)(6)(7)(8). TRPA1 and TRPV1 are members of the TRP family of ion channels.…”

“…This family of receptors appears to function as environmental sensors and mediate protective responses in the respiratory tract that include stimulation of the cough reflex, suppression of respiratory drive, and the initiation of immune responses; TRPA1 and TRPV1 also trigger pulmonary edema via the release of substance P and neurokinin A (9). TRPA1 has also been implicated in cardiovascular dysfunction associated with pulmonary DEP exposure in rats (8). TRPA1 and TRPV1, as well as other TRP channels, are expressed by various airway epithelial and alveolar cells in addition to airway neurons.…”

The Pathophysiological Implications of TRP Channels in Cardiac Arrhythmia

“…Abrogation of these cardiac effects by a selective TRPV1 antagonist capsazepine suggested that TRPV1-mediated autonomic reflexes play a central role therein (Ghelfi et al, 2008). In another study employing a gaseous pollutant (Hazari et al, 2011), one-day exposure of rats to diesel exhaust gas resulted in increased heart rate with pro-arrhythmic ECG changes of prolonged action potential and shorted repolarization. Notably, these rats showed much heightened sensitivity to aconitine challenge that can induce moderate to lethal ventricular tachyarrhythmias dose-dependently.…”