Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies

Abstract

Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases.

Keywords: acute myocardial infarction; arrhythmia; atherosclerosis; capsaicin; cardioprotection; heart failure; ischemic heart disease; transient receptor potential vanilloid type 1 (TRPV1) receptor.

Figure 1

Localization of the transient receptor potential vanilloid type 1 (TRPV1) channel in different cells of the cardiovascular system. Panel (A): Cell bodies of primary sensory neurons innervating the heart are localized in the dorsal root ganglia (DRG) and transmit sensory signals to the nucleus tractus solitarius (NTS), as well as act as sensory efferents in the heart and the vasculature. Sensory nerves are coupled anatomically to sympathetic nerves which are derived from the brain stem reticular formation (BSRF), as well as to the vagus nerve (green), which projects afferents to the nucleus ambiguus (NA) and possesses motor efferents from dorsal motor nucleus (DMN). SG, sympathetic ganglion; NG, nodose ganglion. Panel (B): Several receptors co-localized with TRPV1 on the capsaicin-sensitive sensory nerve endings, which mediate a myriad of inflammatory signals including cytokines like tumor necrosis factor alpha (TNF-α) and interleukins (e.g., IL-1β), bradykinin (BrK), histamine (His), nerve growth factor (NGF; acting on Tropomyosin receptor kinase A—TrkA receptors), prostaglandins (e.g., PGE2, PGI2), serotonin (5-HT), and purine mediators (acting at P2 × 3 purinergic receptors). Noxious stimuli such as ischemia/hypoxia, increased level of reactive oxygen species (ROS), noxious heat (> 43 °C), increased levels of K+ or H⁺ activate TRPV1, and H⁺ also stimulate acid-sensitive ion channels (ASIC). Further ion channels, such as voltage-gated Na⁺ and Ca²⁺ channels (VGSC, VGCC) may also increase intracellular Na⁺ and Ca²⁺ levels, thereby inducing the release of peptide mediators, including calcitonin gene related peptide (CGRP), substance P (SP), somatostatin (SST), and pituitary adenylate cyclase-activating polypeptide (PACAP). Panel (C) demonstrates the localization of TRPV1 channels on different cell types of the heart (CECs, cardiac endothelial cells; VSMCs, vascular smooth muscle cells).