Lactate sensing by Carotid Bodies: Is it necessary for ventilatory responses to exercise?

During metabolic challenges such as hypoxia and exercise, important cardiovascular and respiratory adaptations are made to achieve tissue oxygen (O2) demand, as a substrate for aerobic metabolism, and to maintain carbon dioxide (CO2) clearance in defence of acid–base balance. A widely accepted concept in the literature is that ventilatory responses to exercise result from the recruitment of multiple central and peripheral mechanisms, including the central command and sensory feedback from various peripheral sites (Dempsey et al., 2022). The Carotid Bodies (CBs) have emerged in recent decades as a polymodal sensor, detecting multiple chemical signals present in arterial blood, such as O2, CO2/pH, glucose, insulin and pro-inflammatory cytokines, among others. It has been suggested recently that lactate, a product of anaerobic metabolism released into the systemic circulation during high-intensity exercise and hypoxic conditions, activates the CBs to promote ventilatory adjustments through the generation of active inspiratory and expiratory responses (López-Barneo, 2022). Recent studies have proposed that glomus cells detect increases in blood lactate through activation of the olfactory receptor Olfr78 (López-Barneo, 2022). However, subsequent work demonstrated that the O2 sensing by glomus cells is independent of Olfr78 and that lactate represents a weak ligand for this receptor (López-Barneo, 2022). Experiments conducted by our research group found no effects of lactate on outward K+ currents or membrane potential of dissociated glomus cells. Furthermore, using an in situ preparation in which CBs were intact, we observed no significant changes in respiratory and sympathetic activities in response to applications of lactate into the CBs (not in the perfusion; Spiller et al., 2021). The recent study by Andrade et al. (2025) published in The Journal of Physiology explored whether the CBs act as a metabolic sensor during high-intensity exercise, facilitating O2 uptake. Initially, the authors characterized the ventilatory responses to the arterial–venous lactate clamp in anesthetized rats. They demonstrated that the infusion of 1.2 m lactate generated a concentration of approximately 16 mm lactate in the femoral artery. The authors also observed that the changes in tidal volume, ventilatory frequency and pulmonary ventilation in response to lactate were abolished following the bilateral removal of CBs. By transfecting the CBs to induce the expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in glomus cells, the authors investigated whether glomus cell inhibition also affected the ventilatory responses to intravenous infusion of 1.2 m lactate and O2 consumption of unanaesthetized rats. The study demonstrated that glomus cell inhibition significantly reduced ventilatory responses to lactate, without affecting O2 consumption. On the other hand, glomus cell inhibition drastically reduced O2 consumption during an incremental treadmill exercise, without affecting its performance. The data presented by Andrade et al. (2025) are interesting, but there are important considerations. (i) Although there is evidence that the lactate concentration measured in the femoral artery closely reflects the concentration at the carotid artery bifurcation, there was no measurement of lactate concentration in vessels closer to the carotid vessels, such as in the aortic arch, which would more accurately reflect the amount of lactate. (ii) Given that lower concentrations of lactate (5 and 10 mm) were able to produce robust activation of glomus cells isolated from rats and mice (López-Barneo, 2022), the use of high concentrations of lactate (16 mm) may non-specifically modulate ion channels in glomus cells. In this sense, high concentrations of lactate might be rapidly converted to pyruvate in glomus cells, increasing intracellular NADH concentrations to supraphysiological levels. NADH is a signalling molecule that modifies the conductance of several ion channels in a concentration-dependent manner (Kilfoil et al., 2013). Therefore, the use of a high concentration of lactate can modulate ion channels in glomus cells that are not normally activated at physiological levels of lactate (López-Barneo, 2022), such as during exercise. (iii) There was no control of off-targeting transfection of tissues also expressing tyrosine hydroxylase around the bifurcation of the common carotid artery (e.g. the superior cervical ganglion) that control CBs activity (López-Barneo, 2022). The provided immunostaining images suggest a very low level of CBs transfection, and quantification of the number of transfected glomus cells was not performed. In addition, there were no data showing that the activation of inhibitory DREADDs hyperpolarized and eliminated the glomus cell responses to lactate. (iv) The use of a mild current stimulus to encourage the animals to run on a treadmill might be considered a stressful situation, generating increases in the release of lactate into the blood beyond those stimulated by exercise (Gerdle et al., 2014). (v) There was no measurement of the blood lactate concentration during the applied exercise protocol. Therefore, it is not possible to confirm whether the increases in O2 consumption during the applied exercise protocol are produced by lactate acting on CBs. Based on the considerations above, the following questions remain controversial. (i) Given that lactate sensing by glomus cells is independent of mitochondrial activity and that the knockout of specific mitochondrial subunits increases arterial blood lactate concentration (∼4 mm) in mice (López-Barneo, 2022), why do these animals exhibit no changes in basal ventilatory parameters, despite the complete abolition of the ventilatory response to hypoxia? (In fact, these knockout animals show an ∼10% reduction in basal respiratory rate; López-Barneo, 2022.) (ii) Since the authors did not measure any chemical changes in arterial blood during exercise, what is the contribution of other chemical signals present in arterial blood, which increase significantly during high-intensity exercise (K+, osmolality, glucose, among others), to the CBs-dependent metabolic adjustments observed by Andrade et al. (2025) (Dempsey et al., 2022)? In conclusion, the results described by Andrade et al. (2025) are consistent with the elegant mechanistic data presented by Professor López-Barneo's group (López-Barneo, 2022). However, given the conflicting points and negative studies presented earlier, caution is still needed before drawing a definitive conclusion about the role of CBs in detecting elevated blood lactate concentrations. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. The authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. The work was supported by grants from São Paulo Research Foundation (FAPESP) to P.F.S. (grant #2025/03833-0) and D.J.A.M. (grant #2021/06886-7) and from National Council for Scientific and Technological Development (CNPQ) to D.J.A.M. (grant #314231/2023-4).