Disrupting the peripheral chemoreflex increases brachial blood flow during exercise in participants with treated hypertension

Hypertension narrows and damages blood vessels and arteries, increasing the risk of stroke, vision loss, kidney failure and cardiovascular disease. The devastating impact of high blood pressure on global health has fostered a need to discern risk factors and therapeutic strategies to combat its prevalence. There are numerous biological and environmental factors underlying the risk of developing hypertension including genetics, age, obesity, diet, alcohol, tobacco and exercise. The treatment of hypertension is dependent on blood pressure, comorbidities, lifestyle and genetics. Stage 2 hypertension, defined as a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, is controlled with several classes of medication, while stage 1 hypertension and people with elevated blood pressure are often encouraged to lower blood pressure through pharmacological-free approaches (Carey et al., 2022). Pharmacological-free approaches include dietary changes and increasing aerobic exercise activity. Although routine exercise is linked to lowering blood pressure and protecting against cardiovascular diseases, people with high blood pressure are at an increased risk of stroke and heart failure as they are more sensitive to exercise-induced increases in blood pressure. Exercise-dependent surges in blood pressure are facilitated through the exercise pressor reflex and chemoreflex. The exercise pressor reflex involves the stimulation of group III and IV sensory afferents in the active skeletal muscles that feed back to brainstem centres and evokes increases in heart rate, ventilation and blood pressure. The peripheral chemoreflex is classically recognised as being activated by decreases in blood oxygen and pH, and was recently implicated in the neural control of the circulation during exercise (Sayegh et al., 2024). It is hypothesized that people with high blood pressure have heightened sympathetic nerve activity, increasing peripheral chemoreflex sensitivity to restrain blood flow to exercising muscles. Although it is known that hypertension restricts blood flow to muscles, it was unknown whether the peripheral chemoreflex restrains blood flow to exercising muscles in humans. For this reason, in a recent issue of The Journal of Physiology, Sayegh et al. (2024) blocked the peripheral chemoreflex through infusions of low-dose dopamine (2 µg kg−1 min−1) and assessed blood flow to exercising muscles. To achieve this, the group recruited 14 participants diagnosed with stage 2 hypertension and treated with at least one anti-hypertensive medication. The participants were subject to a strict exclusion criteria based on body mass index, lifestyle and comorbidities. Low-dose dopamine or 0.9% saline (vehicle control) were administered intravenously prior to being subject to isocapnic hypoxia rebreathing and rhythmic handgrip contraction trials. Compared with saline, dopamine infusions reduced oxygen saturation, end-tidal oxygen tension, minute ventilation and feelings of breathlessness, while increasing end-tidal carbon dioxide tension, heart rate, brachial blood flow and vascular conductance. During the isocapnic hypoxia rebreathing, on-target effects of dopamine were confirmed as dopamine infusion significantly decreased peripheral chemoreflex sensitivity and blocked the increase in mean blood pressure. Although force production, blood pressure, heart rate and minute ventilation were unchanged by dopamine infusion, it augmented the increase in brachial blood flow and vascular conductance evoked by rhythmic handgrip exercise. In summary, low-dose dopamine antagonized the peripheral chemoreflex leading to an increase in brachial artery blood flow and vascular conductance at rest and during exercise. The chemoreflex is activated when hypoxia stimulates carotid body glomus cells to release excitatory neurotransmitters such as acetylcholine. These excitatory neurotransmitters generate action potentials that relay commands to increase minute ventilation, vasoconstriction and blood pressure (Giannoni et al., 2023). As such, by decreasing each participant's blood oxygen levels and pH through isocapnic hypoxia rebreathing, the saline infusion experimental condition was designed to initiate the chemoreflex. However, dopamine infusion antagonizes the excitatory neurotransmitters disrupting the chemoreflex. Participants subject to the low-dose dopamine infusion experimental condition displayed increased blood flow compared with the saline control group during rhythmic handgrip exercise. Given that differences between brachial blood flow and vascular conductance were observed between saline and dopamine experimental conditions during exercise, the authors suggest that participants with high blood pressure may have abnormally heightened peripheral chemoreflex sensitivity. The immediate limitation of heightened sympathetic responses in people with high blood pressure is deprivation of nutritive blood flow, exercise intolerance and increased fatigue. More concerning is the risk of organ dysfunction as people with hypertension are unable to redistribute cardiac output to maintain blood pressure at safe levels. Therefore, targeting the carotid chemoreceptor and suppressing the chemoreflex in people with high blood pressure may improve exercise tolerability and safety (Bardsley et al., 2022). Elevated sympathetic activity and increased carotid chemoreceptor reflex sensitivity are associated with many cardiorespiratory diseases. In addition to cardiovascular and respiratory functions, carotid chemoreceptors are active in glucoregulation during exercise as low-dose dopamine blocked chemoreceptor activity, resulting in a reduction of circulating blood glucose. Furthermore, carotid chemoreceptor overactivity is linked to insulin resistance and impairs glucose uptake in skeletal muscles. For these reasons, targeting carotid chemoreceptors is under investigation. In human trials, unilateral surgical resection of carotid bodies demonstrated anti-hypertensive effects, which diminished over time due to compensation from the remaining carotid body. Bilateral surgical resection ablated ventilatory reactivity to hypoxia and improved exercise tolerance but worsened sleep apnoea. Due to the risks of irreversibly removing the carotid bodies, there is now preclinical work exploring the impact of Kruppel-like Factor 2 viral gene transfer and inhibition of purinergic P2 × 3 receptors within carotid bodies. Although these experimental approaches have yet to reach human clinical trials, the numerous processes regulated by carotid chemoreceptors makes targeting them problematic. In fact, inhibiting carotid chemoreceptors did not improve exercise tolerance in patients with chronic heart failure, suggesting that targeting their activity may only be therapeutic for select pathologies (Bardsley et al., 2022). Sayegh et al. (2024) were the first to explore the impact of the peripheral chemoreflex on exercising humans medically treated for hypertension, which increases the clinical relevance and need for a therapeutic remedy. The authors hypothesized that heightened peripheral chemoreflex sensitivity in hypertensive individuals contributes to the restraint of blood flow to exercising muscles. This hypothesis is well-grounded in existing literature and provided a strong foundation for the study's focus on therapeutic interventions that could potentially improve exercise tolerance and overall cardiovascular health in people with hypertension. The clarity and clinical relevance of the study's aims make it particularly valuable in understanding how targeting the chemoreflex could enhance exercise safety for patients with high blood pressure. Additionally, the detailed physiological measurements provide robust empirical support for the study's conclusions and allow for a nuanced understanding of the effects of peripheral chemoreflex inhibition. Despite this, there are some limitations and caveats with the findings, which future studies should investigate further. For instance, the authors antagonized the peripheral chemoreflex using a single low-dose dopamine intravenous infusion. Given that the dopamine treatment regimen was not optimized for each participant and many of the observations could be explained by dopamine stimulating dopaminergic receptors, future studies should test the reproducibility of these results utilizing different antagonists of carotid chemoreceptors. Also, despite previous studies demonstrating the utility of the rhythmic handgrip exercise, the muscle group stimulated is limited. Activating more muscle groups may exacerbate differences between the saline and low-dose dopamine infusion experimental conditions. Therefore, future work should investigate adding knee extension exercises in combination with the rhythmic handgrip exercise. The authors are interested in further exploring the role of anti-hypertensive medications on the peripheral chemoreflex inhibition. To increase the physiological significance and clinical relevance, future studies should also recruit healthy control groups to assess how both medications and pathology impact carotid chemoreceptor response to stimulation and blockade. Another limitation is that the impact of the exercise pressor reflex was not considered. This is problematic as both the peripheral chemoreflex and exercise pressor reflex mediate exercise-induced surges in blood pressure. Although the relationship between the exercise pressor reflex and chemoreflex remain largely elusive, their interaction for blood pressure, heart rate and peripheral haemodynamics is described as additive (Wan et al., 2020). Therefore, future studies should explore the impact of targeting both pathways on cardiovascular and respiratory functions. This will also improve our understanding of carotid chemoreceptor physiology as well as the therapeutic merit in targeting these reflexes as treatments for cardiovascular diseases. This study assessed whether inhibiting the peripheral chemoreflex using low-dose dopamine would increase blood flow to exercising muscles in participants medically treated for hypertension. Indeed, the authors identified that dopamine increased brachial blood flow and vascular conductance evoked by rhythmic handgrip exercise. Therefore, in people medically treated for hypertension, the peripheral chemoreflex may be hyperactive, restraining blood flow to exercising muscles. While the study offers significant strengths in terms of its clear hypothesis, innovative use of pharmacology, and detailed physiological measurements, it is also limited by the absence of a healthy control group, the use of a single non-optimized dopamine dose, and the narrow focus on rhythmic handgrip exercise. Future studies would benefit from addressing these limitations to enhance the generalizability and clinical relevance of the findings. 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. Trelford C.B. and Webb J.D. prepared and edited the manuscript. Each author has read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any of the work are appropriately investigated and resolved. There was no funding to complete this journal club entry.