New insights into arterial baroreflex function during acute exercise: role of central angiotensin II

The arterial baroreceptors, originating in the carotid bodies and aorta, are important in the rapid regulation of the cardiovascular system, buffering short-term changes in arterial blood pressure (BP). Beat-to-beat increases and decreases in BP cause conformational changes in the arterial baroreceptors, ultimately leading to changes in sympathetic efferent neuronal firing. During exercise, the arterial baroreflex resets in an intensity-dependent manner, enabling parallel increases in BP and heart rate (HR) to facilitate an increase in cardiac output. This resetting of the arterial baroreflex during exercise is mediated by both the feed-forward mechanism of central command and the feed-back mechanism of skeletal muscle afferents (i.e. exercise pressor reflex) (Fadel & Raven, 2012). Together, these two mechanisms drive the increase in sympathetic outflow that raises BP and HR, thereby regulating haemodynamic mechanisms during exercise. Exaggerated haemodynamic responses during exercise may be caused by excess free radical production, and previous animal literature suggests centrally acting angiotensin II (Ang II) may play a role in the excess free radical production, and in the resetting of the arterial baroreflex (Case et al. 2017). However, these mechanisms have not been elucidated in humans. Therefore, the focus of a recent study published in The Journal of Physiology by Moralez et al. (2018) examined the role of centrally acting Ang II in modulating arterial baroreceptor function during dynamic exercise. As described by Moralez et al. (2018), nitric oxide (NO) inhibits sympathetic outflow through its actions on the nucleus tractus solitarii (NTS) and the rostral ventral lateral medulla (RVLM), two key structures in the brain that are responsible for basal and reflex control of sympathetic outflow and cardiovascular regulation. However, reactive oxygen species (ROS) produced during acute exercise, such as superoxide (O2−), can react rapidly with NO, reducing its ability to inhibit sympathetic outflow and resulting in an increase in BP. A recent study (Notay et al. 2017) translated the importance of central NO in humans by demonstrating that acute dietary nitrate (NO3−) reduces muscle sympathetic nerve activity (MSNA) at rest and during static handgrip exercise in a normotensive population. Presumably, the mechanism of action was through reduction of NO3− to NO, which resulted in modulation of sympathetic outflow. Importantly, this milieu may contribute to the exercise paradox (i.e. regular physical exercise has a plethora of health benefits, but acute strenuous exercise increases risk of cardiovascular events). Mechanistic insight into the sources of ROS that reduce NO bioavailability has been provided by rodent studies demonstrating that Ang II elicits increased measures of central O2−, resulting in augmented sympathetic outflow and BP. Ang II-dependent increases in sympathetic outflow and BP can be attenuated by O2− scavenging targeted to the brain or central AT1 receptor blockade (Case et al. 2017). Further, these effects are exacerbated by a knockdown of anti-oxidant enzymes in specific brain structures (e.g. superoxide dismutase knockdown in the subfornical organ), demonstrating a critical role of downstream ROS (Case et al. 2017). A greater elevation in plasma Ang II during maximal exercise is associated with greater peak systolic and diastolic BP responses in normotensive middle-aged adults (Shim et al. 2008). However, it is unclear whether central Ang II resets the arterial baroreflex by acting on cardiovascular control centres (e.g. RVLM, NTS) in humans. The study by Moralez et al. (2018) was an ambitious undertaking to determine the role of central Ang II in modulating sympathetic outflow and BP at rest and during exercise. This was accomplished by using microneurography at the radial nerve to assess MSNA, and pharmacological inhibition of angiotensin converting enzyme (ACE) to prevent the formation of active Ang II. Equivalent doses of perindopril (a highly lipid soluble ACE inhibitor (ACEi) that crosses the blood–brain barrier) and captopril (an ACE inhibitor which has a low lipid solubility compared to perindopril) were used to interrogate the role of central Ang II specifically. The trial was randomized and placebo-controlled. Neck pressure and neck suction were used to manipulate blood pressure and model an arterial baroreflex function curve. The hypothesis of the study was that the perindopril would reduce Ang II within the central nervous system. It was further hypothesized that the decreased central Ang II would result in a decrease in MSNA and a reduction in the magnitude of arterial baroreflex resetting during dynamic exercise. To accomplish the goals of the study, 14 (11 male/3 female) young, healthy participants completed all the pharmacological protocols (placebo, perindopril and captopril) and corresponding acute exercise trials. Exercise was performed on a stationary recumbent cycle ergometer in three stages: baseline, acute exercise workload (30 min constant workload obtained at the HR of 120 beats min−1), and prolonged exercise workload (additional 30 min of exercise at constant workload obtained at the HR of 150 beats min−1). Peripheral venous O2− was measured by electron spin resonance spectroscopy as a measure of systemic oxidative stress. Due to the difficult nature of the methods, complete sets of MSNA recordings were obtained in seven participants while complete sets of venous O2− measures were obtained in eight participants. As expected, acute exercise elicited an intensity-dependent increase in systemic O2−. Neither ACEi reduced systemic O2− concentrations at baseline or during exercise. However, perindopril significantly attenuated burst frequency (bursts per minute) and the arterial BP (ABP)–mean arterial pressure (MAP) response curve (operating point pressure) during moderate and higher intensity steady-state exercise compared to placebo and captopril. Captopril did not affect MSNA nor the ABP–MAP relation. Together, these data suggest that centrally acting Ang II influences arterial baroreflex resetting of MSNA during dynamic exercise. This novel finding has clinical implications and may provide insight into autonomic dysregulation during exercise. The present study suggests a role of Ang II in resetting the arterial baroreflex during exercise. Moreover, low-pressure mechanically sensitive stretch receptors (the cardiopulmonary baroreflex) may also play a role in regulating MSNA and BP responses during dynamic exercise (Fadel & Raven, 2012). Findings suggest that increases in central blood volume during leg exercise sensed by the cardiopulmonary baroreflex alters the operating point of the ABP–MAP curve and influences arterial baroreflex resetting. Thus, an impaired cardiopulmonary baroreflex could increase sympathetic and BP responses (Fadel & Raven, 2012). Nonetheless, the current findings improve our understanding of arterial baroreflex function during dynamic exercise. Regular exercise confers positive effects on many physiological systems. However, the elderly and clinical populations are at a higher risk for cardiovascular complications related to strenuous acute exercise (Moralez et al. 2018). Understanding the mechanisms underlying cardiovascular adjustments during dynamic exercise is clinically relevant. In fact, an exaggerated blood pressure response during dynamic exercise, even in those with normal resting BP, is a predictor of future hypertension, and has been associated with greater increases in Ang II during peak exercise (Shim et al. 2008). Interestingly, perindopril reduced diastolic and mean arterial BP during both exercise intensities in the present study. Apart from reducing the BP response during acute exercise, it could be that reducing sympathetic vasoconstrictor responses directed at skeletal muscle arterioles may permit greater blood flow during exercise and improve exercise capacity in populations with low exercise tolerance. This study also provides rationale for several future directions with ACEi and acute exercise haemodynamic responses. Future studies are warranted to provide insight into the clinical implications of ACEi in at-risk populations. This is important because perindopril may lead to even greater reductions in sympathetic nerve activity and BP in populations that have exaggerated sympathetic outflow and greater BP reactivity during acute exercise. Studies using a centrally acting ACEi with and without other pharmacological agents targeting O2− and NO (e.g. ascorbic acid and dietary nitrate) should be done for more specific insight into the underlying central mechanisms contributing to the sympathetic and BP responses during acute dynamic exercise in humans. Further, oral ingestion of the ACEi did not reduce free radical production in this study (Moralez et al. 2018). Future studies may assess the usage of antioxidant as a means to reduce free radical production and concurrent exaggerated responses during dynamic exercise. Additionally, the present study had only three female participants. Additional studies are necessary to examine if there are sex differences or differences across the menstrual cycle. Lastly, as the authors noted, it is technically difficult to measure central Ang II (∆ arterial–venous differences could be a potential surrogate and even these measures are highly invasive). However, future studies could measure Ang II in the plasma when using ACEi to determine if plasma values align with the MSNA findings which suggest central Ang II was reduced. The authors have no conflicts of interests to disclose. Both authors have 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 part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. The authors apologize for not citing all relevant articles due to reference limitations. We would like to thank Dr William B. Farquhar, Matthew C. Babcock and Joseph C. Watso for their critical evaluation and feedback during the preparation of this manuscript.