Irritant-evoked reflex tachyarrhythmia in spontaneously hypertensive rats is reduced by inhalation of TRPM8 agonists l-menthol and WS-12

Abstract

Inhalation of noxious irritants activates nociceptive sensory afferent nerves innervating the airways, inducing reflex regulation of autonomic networks and the modulation of respiratory drive and cardiovascular (CV) parameters such as heart rate and blood pressure. In healthy mammals, irritant-evoked pulmonary-cardiac reflexes cause parasympathetic-mediated bradycardia. However, in Spontaneously Hypertensive (SH) rats irritant inhalation also increases sympathetic drive to the heart. This remodeled pulmonary-cardiac reflex may contribute to cardiovascular risk caused by inhalation of air pollutants/irritants in susceptible individuals with cardiovascular disease (CVD). Previous studies have shown that the cooling mimic L-menthol, an agonist for the cold-sensitive transient receptor potential melastatin 8 (TRPM8), can alleviate nasal inflammatory symptoms and respiratory reflexes evoked by irritants. Here, we investigated the impact of inhalation of TRPM8 agonists L-menthol and WS-12 on pulmonary-cardiac reflexes evoked by inhalation of the irritant allyl isothiocyanate (AITC) using radiotelemetry. L-menthol, but not its inactive analog D-menthol, significantly reduced the AITC-evoked reflex tachycardia and premature ventricular contractions (PVCs) in SH rats, but had no effect on the AITC-evoked bradycardia in either SH or normotensive Wistar-Kyoto (WKY) rats. WS-12 reduced AITC-evoked tachycardia and PVCs in SH rats, but this more potent TRPM8 agonist also reduced AITC-evoked bradycardia. L-menthol had no effect on heart rate when given alone, whereas WS-12 evoked a minor bradycardia in WKY rats. We conclude that stimulation of TRPM8-expressing afferents within the airways reduces irritant-evoked pulmonary-cardiac reflexes, especially the aberrant reflex tachyarrhythmia in SH rats. Airway menthol treatment may be an effective therapy for reducing pollution-associated CV exacerbations.

Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation

“…Additionally, scientific evidence has substantiated the pain‐relieving properties of menthol in countering chemical stimulation and inflammation through a TRPM8‐dependent mechanism 39–41 . Notably, the absence of analgesic effects of menthol in TRPM8 knockout mice and the complete absence of analgesia induced by WS‐12 (a selective TRPM8 agonist) further support these findings 42,43 . The potential antimigraine properties of butterbur may be attributed to the selective activation of the TRPA1 channel by Isopetasin, the primary constituent of its extract, leading to subsequent notable neuronal desensitization 44 .…”

“… 39 , 40 , 41 Notably, the absence of analgesic effects of menthol in TRPM8 knockout mice and the complete absence of analgesia induced by WS‐12 (a selective TRPM8 agonist) further support these findings. 42 , 43 The potential antimigraine properties of butterbur may be attributed to the selective activation of the TRPA1 channel by Isopetasin, the primary constituent of its extract, leading to subsequent notable neuronal desensitization. 44 The TPR channel presents itself as a promising area of investigation for analgesic drug development, and further exploration of its involvement in tumor‐induced pain holds potential benefits for affected patients.…”

Disruption of Atrial Rhythmicity by the Air Pollutant 1,2-Naphthoquinone: Role of Beta-Adrenergic and Sensory Receptors

“…Over the last few years, evidence has linked transient receptor potential channels, mainly TRPV1 and TRPA1 channels, as potential targets for AP-induced risk factors/side effects, particularly in the airways [86][87][88] and to a lesser extent in the cardiovascular system [28,89,90]. A number of studies provided robust evidence that different-sized PM from traffic-related air pollution increases intracellular calcium levels by interacting with calcium channels like TRP channels, G protein-coupled receptors such as β-adrenoceptors, TLR4, and protease-activated receptor 2 [PAR-2]) [90][91][92].…”