Putting the HYPE in hypertension: peripheral chemoreflex constraint of skeletal muscle blood flow

The peripheral chemoreceptors are the primary oxygen sensors in the body. Peripheral chemoreflex hypersensitivity is characteristic of several conditions including heart failure, pulmonary arterial hypertension, chronic obstructive pulmonary disease and essential hypertension. Hypersensitivity of the peripheral chemoreflex independently predicts adverse prognosis and, as such, the carotid body as a therapeutic target has become of great clinical interest. Traditionally, the peripheral chemoreflex is thought to play a critical role in ventilatory control. However, growing work has implicated it as a key modulator of blood flow distribution in health and disease at rest and during exercise (Stickland et al., 2007). Stimulation of the peripheral chemoreflex increases sympathetic nerve traffic directed toward the skeletal muscle vasculature, inducing regional vasoconstriction, and ultimately a reduction in skeletal muscle blood flow. Conversely, inhibition of the peripheral chemoreflex induces skeletal muscle vasodilation, secondary to sympathoinhibition. While individuals with hypertension exhibit compromised skeletal muscle blood flow responses to exercise compared with healthy controls (Sidhu et al., 2019), whether tonic hyperactivation and hypersensitivity of the peripheral chemoreflex contributed to this impaired peripheral haemodynamic response remained unknown. In this issue of The Journal of Physiology, Sayegh et al. (2025) explored the impact of the peripheral chemoreflex on the regulation of skeletal muscle blood flow during exercise in patients with treated essential hypertension. Peripheral chemoreflex sensitivity was calculated as the slope of minute ventilation (V̇E) by oxygen saturation (SPO2) during isocapnic hypoxia at rest. Low-dose dopamine (2 µg·kg·min−1) was used to inhibit tonic peripheral chemoreceptor activity during (1) normoxic rest, (2) isocapnic hypoxia, and (3) 3 min of normoxic rhythmic handgrip exercise at 50% of maximal voluntary contraction force. Forearm blood flow was determined via doppler ultrasound of the brachial artery. The authors found that low-dose dopamine reduced peripheral chemoreflex sensitivity and increased brachial blood flow under resting conditions. Furthermore, during exercise, inhibiting the peripheral chemoreflex elicited increases in skeletal muscle blood flow relative to the saline control condition. Collectively, these data indicate that the peripheral chemoreflex restrains skeletal muscle blood flow among people with treated hypertension at rest and during exercise. The significance of the sympathetic nervous system's control of blood flow distribution during exercise cannot be understated. Specifically, sympathetic nervous system activation induces increases in cardiac output as well as regional vasoconstriction of circulatory beds with relatively low metabolic demand to ensure sufficient oxygen delivery to active skeletal muscle while tightly regulating arterial blood pressure. However, hyperactivity of the sympathetic nervous system, as observed in hypertension, can also induce excessive vasoconstriction in areas of higher metabolic demand, such as the skeletal muscle. Indeed, previous work has shown that despite similar cardiac output between hypertensive and normotensive adults, hypertensive patients demonstrated blunted muscle blood flow during exercise that was normalized following attenuation of the exercise pressor reflex (via intrathecal fentanyl) (Sidhu et al., 2019). Sayegh et al. have advanced this work by demonstrating that skeletal muscle blood flow increased during exercise with low-dose dopamine without concomitant increases in heart rate (and likely cardiac output), suggesting that tonic peripheral chemoreflex hyperactivity also negatively impacts blood flow distribution during exercise in people with hypertension. To further examine the impact of the peripheral chemoreflex on blood flow distribution, it would be of great interest to simultaneously measure cardiac output and muscle blood flow during chemoreflex inhibition in people with hypertension. A strength of the study by Sayegh et al. (2025) was the selection of people who were receiving pharmacotherapy for essential hypertension, as early studies were conducted in people with chronic conditions without pharmacotherapy. This is important, as anti-hypertensive medications (e.g. angiotensin receptor blockers) have been found to independently attenuate peripheral chemoreflex sensitivity (Li et al., 2006). Despite study participants receiving anti-hypertensive pharmacotherapy, Sayegh et al. (2025) found that the peripheral chemoreflex restrained skeletal muscle blood flow at rest in these hypertensive participants, something that is not observed in healthy populations (Stickland et al., 2007). Altogether, the current study aligns with growing evidence which suggests that current pharmacological management of hypertension may not appropriately mitigate the aberrant autonomic cardiovascular control that is hallmark of this chronic condition, particularly during exercise. As such, this study effectively highlights that more work is required to better understand how anti-hypertensive medications may impact the peripheral chemoreceptor/sympathetic control of cardiovascular function at rest and during exercise. Sayegh and colleagues (2024) should be commended on completing a challenging integrative physiological study that has advanced our understanding of the broader physiological implications of heightened peripheral chemoreflex activity among people with treated hypertension. Given that poor blood flow distribution contributes to premature fatigue (and likely exercise intolerance) in this patient population (Thurston et al., 2024), this study lends support to the pursuit of the carotid body as a therapeutic target in hypertension to address the underlying autonomic imbalance that is characteristic of this chronic condition. All in all, we can appreciate that this study has re-invigorated the hype surrounding the role of the peripheral chemoreflex as a modulator of blood flow distribution in humans. 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. A.W.D. and M.K.S. conceived and designed this work; drafted and critically revised the work for important intellectual content; provided final approval of the version to be published; and agree to be accountable for all aspects of the work. A.W.D. is funded by the Natural Sciences and Engineering Research Council of Canada. M.K.S. is funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. Due to the restriction in the number of articles that can be cited in this Perspective, not all relevant literature is cited.