Nociceptive pulmonary‐cardiac reflexes: role of autonomic nervous system and hypertension

It is already known that air pollution has been growing considerably over the years and it is considered one of the greatest environmental threats. Unfortunately, this problem is directly related to cardiovascular diseases (CVDs). Excessive exposure to pollution can significantly increase the risk of atherosclerosis, myocardial infarction and hypertension. These comorbidities are a consequence of increased oxidative stress, inflammation, endothelial dysfunction and autonomic nervous system (ANS) imbalance (Rajagopalan et al. 2018). Inhalation of pollutants results in cardiovascular system responses through a reflex, directly related to the respiratory system, in which nociceptive afferents of the lower airways trigger responses in cardiac function. This reflex called the nociceptive cardiopulmonary reflex is largely controlled by ANS (Hooper et al. 2019). Although there is ample evidence regarding the impact of this reflex on healthy animals, the effects of pollution on the modulation of cardiac function in CVD remain unclear. In this sense, looking to fill this gap in the literature, Hooper et al. (2019) investigated whether a pre-existing CVD – hypertension – modifies nociceptive pulmonary-cardiac reflexes. This study was recently published in The Journal of Physiology and has gained our interest. Using spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats, Hooper et al. (2019) performed an elegant and meticulous experimental design to explore the mechanisms involved in the cardiopulmonary reflex against inhalation of noxious substances. For this, diaphragmatic electromyography (dEMG) and electrocardiogram radiotelemetry (ECG) were used. These evaluations were recorded for 30 min wherein the animal was exposed (for 10 min) to ambient air, nebulized vehicle (4% ethanol in PBS) and either capsaicin (0.9 mg ml−1) or allyl isothiocyanate (AITC) (4.3 mg ml−1) made up in 4% ethanol and PBS. First, they compared the nociceptive pulmonary-cardiac reflexes evoked by inhaled irritants – transient receptor potential channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) agonists – between 15-week-old conscious normotensive and hypertensive rats. As a first result, R–R interval (RRi) was lower in the SH group compared to WKY under ambient conditions, and inhalation of the vehicle caused bradycardia in both WKY and SH rats. The authors also analysed the number of atrial-ventricular (AV) block events, the percentage of tachycardic beats, and the number of premature ventricular contractions (PVCs). There was no AV block during vehicle exposure in WKY and SH rats. PVC was very rare during vehicle treatment in both groups. On the other hand, inhalation of selective TRPA1 agonist AITC increased RRi and the number of dropped beats due to AV block in WKY rats compared to the vehicle. In SH rats, inhalation of AITC caused unstable and chaotic crises of both bradycardia and tachycardia. Importantly, the RRi response evoked by the AITC was significantly lower in SH rats compared to WKY rats. The effects of exposure to the selective TRPV1 agonist capsaicin were similar. However, capsaicin did not increase the percentage of tachycardic RRi in SH rats compared to vehicle, even though this measure was significantly higher when compared to WKY rats. Additionally, AITC caused increased blood pressure in SH rats. These findings indicate differences between healthy and hypertensive rats in cardiac reflexes following nociceptive stimulation. After that, the authors analysed the role of muscarinic and adrenergic signalling in differential pulmonary-cardiac reflexes. Muscarinic acetylcholine receptors were evaluated using the selective muscarinic inhibitor atropine (1 mg kg−1, i.p.), while the effects of β1-adrenergic receptors in the tachyarrhythmia evoked by AITC were evaluated using atenolol (0.5 mg kg−1, i.p.). In ambient conditions, atropine did not change RRi, but decreased the RRi variability in both groups. Atropine also attenuated the bradycardia induced by vehicle inhalation. With atropine, AITC did not increase RRi or evoke any AV block in WKY rats. Also, atropine eliminated AV block and bradycardia evoked by AITC in the SH group, triggering tachycardia. On the other hand, atenolol increased RRi in ambient and vehicle conditions, and increased AITC-evoked bradycardia and AV block in SH rats. These data suggest that the reflexes evoked by the AITC are mediated by muscarinic receptors. Moreover, in SH rats, AITC also evokes adrenergic drug-mediated tachyarrhythmia. In a preliminary study, the authors evaluated the treatment with captopril (30 mg kg−1 day−1, p.o.) for 48 h in three SH rats. Captopril failed to inhibit the brady–tachy responses caused by inhalation of AITC, and significantly increased the AITC-evoked RRi variability, AV block and PVCs. In this case, steady-state hypertension is not required for aberrant pulmonary-cardiac reflexes in SH rats. For future studies, it would be interesting to repeat these analyses in normotensive rats. In sequence, the animals underwent bilateral cervical vagotomy. In this case, there was no difference in resting RRi between the two groups. After that, the animals were subjected to vagal electrical stimulation (2–32 Hz, 2 ms duration). Although RRi was increased in WKY and SH rats, electrical stimulation of the vagus did not change the percentage of tachycardic beats in either strain. Thus, the authors have shown that vagal efferent activity is not capable of evoking tachyarrhythmia. In other experiments, the authors compared the effect of AITC inhalation and AITC injection via a jugular vein catheter in WKY and SH rats. Inhalation of AITC (300 µl, 9 µmol) decreased breathing rate in WKY rats and increased the time spent in bradypnoea. In SH rats, inhalation of AITC increased the time spent in bradypnoea but did not decrease breathing rate. Unlike the effects of AITC inhalation already mentioned, the injection of AITC did not induce tachyarrhythmia in SH rats. Thus, the authors point out that there are differences between respiration regulation in WKY and SH rats following AITC inhalation. On the other hand, intravenous irritants do not have the same effects as irritants that have been inhaled. The authors also studied the effects of AITC inhalation and AITC injection in isoflurane-anaesthetized WKY and SH rats. Anaesthesia ceased the pulmonary-cardiac aberrant reflexes evoked by inhaled AITC in SH rats since inhaled AITC failed to increase the percentage of tachycardic beats and the number of PVCs. Only AITC injection increased RRi and hypotension in WKY and SH rats. Injection of AITC also did not increase the percentage of tachycardic beats or the number of PVCs in SH rats. Thus, Hooper et al. (2019) show that anaesthesia alters nociceptive responses following cardiopulmonary irritants. Lastly, Hooper et al. (2019) carried out precollicular decerebration of the SH rats, during which they were atropinized, subjected to neuromuscular blockade and mechanically ventilated. Under these conditions, inhalation of AITC caused hypertension and decreased RRi. After that, animals were subjected to vagotomy abolishing the AITC-evoked effects on blood pressure and RRi. Thus the authors showed that tachyarrhythmia evoked by AITC inhalation in hypertension was dependent on vagal afferent nerves. The findings of this study elucidate mechanisms involved in the reflex regulation of heart rate evoked by cardiopulmonary irritants, complementing the literature data that emphasize the autonomic imbalance in hypertension. The data presented by Hooper et al. (2019) are especially important when for the first time a study showed that inhalation of TRPA1 and TRPV1 agonists culminates in different cardiorespiratory responses in normotensive and hypertensive rats, and these effects are modulated by ANS. An article previously published by the same research group had shown that AITC caused substantial bradycardia with prolonged RRi, in Sprague-Dawley rats (Hooper et al. 2016). They also showed that activation of ionic channels present in the nociceptive sensory nerves of the airways could modulate the ANS culminating in cardiovascular effects. However, until then, there was no evidence that pre-existing hypertension shifts nociceptive pulmonary-cardiac reflexes towards sympathoexcitation. Since sympathoexcitation is one of the leading causes of hypertension, several studies have shown the importance of autonomic modulation in the control of cardiovascular parameters. Thus, many therapies were proposed: vagal electrical stimulation (as shown in this study), physical exercise, and some drugs as acetylcholinesterase inhibitors (Feriani et al. 2018). Special attention has been given to physical exercise since it is a non-pharmacological therapy that significantly improves cardiorespiratory variables and plays an essential role in the autonomic balance. However, although improvements from exercise are essential, it is important to note that exposure to pollution during physical activity is not indicated. In this sense, another study showed that exposure to traffic-related air pollution during physical activity was associated with increased blood pressure and decreased heart rate variability, suggesting again that pollution may contribute to changes in autonomic function (Weichenthal et al. 2014). Additionally, the sympathetic response to exercise may be exaggerated in hypertension due to the abnormal exercise pressor reflex, which may culminate in adverse cardiovascular events (Mizuno et al. 2016). Given this, the question raised is: besides exercise, what other non-pharmacological and non-invasive strategies could be used to modulate ANS, especially in cardiovascular diseases? In conclusion, Hooper et al. (2019) were able to elucidate mechanisms involved in cardiopulmonary reflexes evoked by inhaled irritants. This work deserves attention for the novel insights into autonomic modulation of normotensive and hypertensive rats against nociceptive stimuli. Altogether, the data presented in this article demonstrated the importance of parasympathetic activation in the management of hypertension and shed new light on possible autonomic modulation therapies. In this perspective, further studies should be performed aiming at proposing new approaches that positively modulate ANS. The authors have no conflicts of interest to declare. Both authors contributed to the design, writing and data collection for this work. Both authors were in agreement with the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship and all those who qualify for authorship are listed. The authors received funding for this work from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ). We are grateful to Dr Bruno Rodrigues for all his help in this process.