Carotid body and sympathetic activation in heart failure: a story of sensors and sensitivity.

The carotid body (CB) is a peripheral chemoreceptor organ that contains clusters of electrically excitable secretory cells, the glomus cells, which express several types of membrane ion channels that influence its excitability. These cells act as sensors or chemotransducers, detecting different chemical stimuli and triggering an action potential in the afferent fibres that lie in synaptic apposition. The main stimulus for glomus cells are constant falls in arterial partial pressure of oxygen (PaO2), in opposition to the highly sensitive partial pressure of carbon dioxide (PaCO2) chemoreceptors at the central nervous system (CNS). The afferent nerve supply of the CB, which is accompanied by the afferent fibres from carotid sinus baroreceptors, provides a highly O2-dependent input to the CNS. 1 CB exhibits great sensitivity to hypoxia (low threshold and high gain) that is accompanied by great resistance to its deleterious effects, being possible to detect nervous activity up to 30 min after an animal’s death; owing to this fact, the CB has been called ‘ultimum moriens’ (the last to die). In chronic heart failure (CHF) the sympatho-humoral activation that, at the initial phases of this syndrome, is directed to attenuate systemic hypoperfusion may ultimately exacerbate the progression of cardiac dysfunction that subsequently increases the extra-cardiac abnormalities, a positive feedback cycle of progressive deterioration, or less euphemistically, a vicious cycle with ominous consequences. It was thought that much of the increase in the sympathetic nerve activity (SNA) in CHF was based on the increase of sympathetic flow at the CNS and on the depression of arterial baroreflex function. However, in the past several years, it has been demonstrated that an increase in the sensitivity of peripheral chemoreceptors activity also plays an important role in the enhanced SNA that occurs in CHF. Perhaps surprisingly, but not paradoxically, chemoreflexes that are dedicated under normal conditions to correcting hypoxia contribute to increase the sympathetic tone in CHF, even under normoxic conditions. The understanding of how abnormally enhanced sensitivity of the CB contributes to the tonic elevation in SNA in CHF has come from several studies that in some instances have been contradictory because of the differences in the animal models employed. According to the more accepted scheme, the local angiotensin (Ang) II—Ang II type 1 (AT1) receptor system plays a fundamental role in the enhanced CB chemoreceptor sensitivity in CHF, as the NADPH oxidasederived superoxide signalling pathway is the one that mediates the effects of Ang II by suppressing outward voltage-gated Kþ currents (Ik) of the membrane of glomus cells from CHF rabbits. As reported in this issue of the journal, Ding et al. employed a model of pacing-induced cardiomyopathy to examine whether the decreased expression of a superoxide anion scavenger, CuZnSOD, which is an intracellular isoform of the superoxide dismutase (SOD), contributes to CB chemoreceptor hypersensitivity in CHF. In addition, the authors showed that successful adenovirus-mediated CuZnSOD gene transfer to the CB tissue enhanced the expression of the enzyme. The increase in the amount of CuZnSOD was accompanied by an effective reduction of the elevated superoxide anion levels that finally resulted in reversion of the enhanced CB chemoreceptor hypersensitivity and reflex function during normoxia and isocapnic hypoxia. This was accompanied by an increase of the previously suppressed IK of the glomus cell in the CB of CHF rabbits. The present study suggests that CuZnSOD downregulation, mediated by the elevated superoxide anion levels, as well as the increased Ang II–NADPH oxidase-derived superoxide anion signalling, contribute to signalling in the enhanced chemoafferent and reflex function of the CB in CHF. In this paper, the authors offer an interesting hypothesis and a nice set of experiments in a rabbit model of CHF with very well-controlled conditions for the study of chemoreflex function. Despite the fact that the mechanisms provoking depression of myocardial function are not well known, and that cardiac dysfunction is at least partially reversible after cessation of pacing, the model of pacing-induced biventricular cardiomyopathy in the rabbit has proven to be almost ideal for these kinds of pathophysiological studies. This model simulates, in a very reproducible and predictable fashion, many aspects of human CHF with moderate functional repercussion. Pacing-induced CHF, which minimizes uncontrolled cardiac damage owing to The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology. Corresponding author. Tel: þ34 93 2746212; fax: þ34 93 2746244. E-mail address: [email protected]