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.

Figure 1

A single exposure to DE increases aconitine-triggered arrhythmia in hypertensive rats. Constant infusion of aconitine (2 μg/min) triggers VPB, followed by VT, VF, and progression to cardiac arrest (CA) in FA-exposed SH rats. The cumulative dose of aconitine necessary to trigger arrhythmia and CA in SH rats exposed to high wDE or fDE (A) or low wDE or fDE (B) was lower than for FA-exposed rats. Values are mean ± SE; n = 5–6. *p < 0.05 compared with FA controls.

Figure 2

Heightened arrhythmia sensitivity after DE exposure is mediated by TRPA1. Constant infusion of aconitine (2 μg/min) triggers VPB, followed by VT, VF, and progression to cardiac arrest (CA) in FA-exposed SH rats. The cumulative dose of aconitine necessary to trigger arrhythmia and CA in SH rats exposed to low wDE was lower than for those exposed to FA; (A) this response was blocked by the TRPA1 antagonist (Ant; HC030031; A). The TRP antagonist RR caused a significant decrease in sensitivity relative to FA (B), but the TRPV1 antagonist SB366791 only reduced sensitivity to VPB and VT (C). The drugs had no effect on controls. Values are mean ± SE. *p < 0.05 compared with the corresponding FA control.

Figure 3

Heightened arrhythmia sensitivity after DE exposure is mediated by sympathetic activation. Constant infusion of aconitine (2 μg/min) triggers VPB, followed by VT, VF, and progression to cardiac arrest (CA) in FA-exposed SH rats. The increased arrhythmia response to aconitine after low wDE was prevented by acute sympathetic blockade with guanethidine (Guan; A) but not by muscarinic blockade with atropine (B). Vagotomy only partially reduced the low wDE–induced proarrhythmic response (C). Sympathetic blockade had no effect in FA-exposed animals (A); however, muscarinic blockade (B) and vagotomy (C) increased aconitine-induced arrhythmia sensitivity in FA rats. Values are mean ± SE. *p < 0.05 compared with the corresponding FA control.

Figure 4

Simplified depiction of how exposure to air pollutants is proposed to sensitize the sensory-to-autonomic reflex arc and alter subsequent responses. Activation of airway sensory nerves (A) causes local effects and stimulates neurons in the midbrain (B). Neural circuits within the midbrain process the signals and then activate the preganglionic autonomic neuron (C); postganglionic autonomic neurons (D) carry the signal to the heart. Air pollution may increase the excitability of neuron A (sensitization), which would potentiate transmission in neuron B and, in turn, increase/decrease central nervous system outflow by neuron C thereafter (autonomic imbalance). Adapted from Undem et al. (2000).