The spice of life is at the root of cardiac pain (2003)

Normally, we do not think of the heart as a sensory organ, but it possesses a rich supply of heterogeneous nerve endings that communicate the mechanical and chemical state of the heart to the brain via both the vagus nerves and the spinal cord. These pathways mediate powerful and opposing cardiovascular reflexes that contribute to cardiovascular homeostasis, but they can evoke potentially deleterious and even lethal reflex responses under adverse conditions such as myocardial infarction. Depending upon the location and extent of the ischaemia, the vagal afferents can evoke hypotension, bradyarrythmias, nausea and vomiting while the ischaemia-sensitive sympathetic (spinal) afferents can evoke hypertension, tachyarrhythmias and the pain of angina pectoris.

The mechanisms by which these nerve endings in the heart are stimulated by ischaemia have never been fully resolved. The complexity in addressing this question can be appreciated by the large number of potential ischaemic mediators that exist, the disparity in the fibre types and sensory modalities of the cardiac nerve endings that respond to ischaemia, and the uncertainty of the location and micro-environment surrounding these nerve endings in cardiac tissue.

In this issue of The Journal of Physiology, Zahner et al. (2003) describe a new and significant insight into this issue. They provide immuno-histochemical evidence that a large population of afferent nerve endings innervating the epicardial regions of the rat heart possess the vanilloid receptor (VR1 or TRPV1), and that pharmacological desensitization of these nerve endings with resiniferatoxin, a highly specific VR1 agonist, abolishes the cardiogenic sympathoexcitatory reflex (CSR). These observations illustrate for the first time that VR1 endings are a major component of the sensory modality of the CSR, which is responsible for the perception of cardiac pain.

VR1 is a ligand-gated non-selective cation channel that is a member of the transient receptor potential (TRP) channel family. Certain ligands for this channel possess a vanillyl moiety. Capsaicin, the ‘hot’ component of chilli peppers, is the most commonly known ligand of this class. VR1 is highly expressed in nociceptive sensory neurons and is regarded as a primary mediator in the perception of chemical and thermal pain.

Although we have known for decades that certain small C- and Aδ-fibre endings in the heart can be stimulated by capsaicin, their function has generally been treated as a pharmacological curiosity. Our ability to now ascribe VR1-expressing neurons in the heart as a major component of the CSR raises new and exciting questions. Foremost are the identities of endogenous ligands for cardiac VR1 and the molecular/physiological processes that cause their activation.

In cutaneous nociceptors, heat, lipids and protons can be considered as endogenous modulators of VR1. While the heart certainly has little utility for noxious heat sensors, myocardial ischaemia can induce lactic acidosis and the liberation of lipid and other inflammatory mediators. Extracellular acidification has been shown to regulate VR1 gating, and lactic acidosis is an important mediator in the depolarization of CSR neurons (Pan et al. 1999; Benson & Sutherland, 2001). Furthermore, H+ is debated to be the primary mediator in the activation of skeletal muscle ergo-receptors (capsaicin-sensitive afferents) in response to muscle contraction (Kaufman, 2003). However, other ion channels have been implicated in mediating the effect of H+ on cardiac afferents (Benson & Sutherland, 2001), and the function of VR1 in skeletal muscle afferents has not been extensively explored. Whether VR1 serves as a pH sensor in cardiac and skeletal muscle remains to be resolved.

Alternatively, recent studies have shown that several products of lipoxygenases directly activate the VR1 channel in isolated membrane patches (Hwang et al. 2000). In this regard, Sun et al. (2001) have shown that the lipoxygenase pathway contributes to the activation of cardiac afferents during myocardial ischaemia. Also, we have shown that capsaicin-sensitive nerve endings in the heart respond to reactive oxygen species liberated during myocardial ischaemia and reperfusion (Schultz & Ustinova, 1996), and that VR1 mediates this free-radical effect (Schultz & Ustinova, 1998).

VR1 in cardiac sensory terminals is also likely to be susceptible to enzyme gating. Protein kinase C (PKC) and PKA activation by bradykinin and prostaglandins, respectively, enhances the activation of VR1, resulting in the sensitization of cutaneous nociceptors. Evidence also suggests that the nitric oxide-cGMP system plays a role in the sensitization of cutaneous nociceptors. The role of these mediators in the activation of VR1-mediated cardiac afferent responses needs to be clearly defined.

Vanilloid-sensitive nerves have two distinct subdivisions, a peptidergic population, characterized by the coexpression of VR1 with neuropeptides in their sensory terminals, and a purinergic one, coexpressing VR1 with the ATP-gated ion channel P2X3. Activation of VR1 triggers vesicular release of neuropeptides from the peptidergic sensory terminals. The present study by Zahner et al. (2003) does not address this issue. However, nerve endings containing neuropeptides are found in cardiac tissue. These observations may provide further insight into the function of VR1-expressing nerve endings within the myocardium. These neuropeptides can evoke potent coronary vasodilatation and decrease cardiac contractility to facilitate blood flow and energy conservation. Indeed, we have shown that capsaicin-sensitive nerve endings in the heart liberate neuropeptides during ischaemia and thereby facilitate post-ischaemic recovery of the heart (Ustinova et al. 1995).

The paper by Zahner et al. (2003) brings to our attention the prospect that VR1 nerve endings in the heart are far more important than previously regarded. They are likely to serve an important protective function in the myocardium by evoking compensatory cardiovascular reflexes, signalling the perception of cardiac pain and liberating cardioprotective neuropeptides. The functional role of cardiac VR1 sensory neurons in health and disease, particularly during myocardial ischaemia and heart failure, may well provide insights towards the more effective prevention and management of cardiac failure and angina.