Potentiated respiratory metaboreflex in older males and females: afferent or efferent mechanisms?

Abstract

High-intensity work of the inspiratory or expiratory muscles of breathing evokes reflex changes in cardiovascular function, collectively termed the respiratory metaboreflex. The sympathetically mediated pressor response and tachycardia are accompanied by a redistribution of cardiac output characterized by reductions of blood flow to inactive muscles in favour of the working muscles. Interestingly, it is established during loaded breathing in dynamic exercise that the respiratory muscles prove greedy, grabbing the lion's share of the redistributed blood flow and ‘stealing’ flow from active locomotor muscles. Blood pressure and heart rate responses to increased inspiratory workload are attenuated in young adult females compared with young adult males. This observation is consistent with the widely recognized sex differences in cardiovascular control, generally attributed to the actions of oestrogen on autonomic control and/or peripheral effects of the sex steroid on the vasculature (Joyner et al., 2015). It is increasingly evident that cardiovascular advantage in females is dramatically lost after the menopause. In this issue of The Journal of Physiology, Leahy et al. (2023) expand our appreciation of the respiratory metaboreflex in meticulously performed studies in young and older male and female participants, exploring the influences of age and sex on heart rate and blood pressure responses to inspiratory pressure threshold loading (60% of maximum inspiratory pressure) to task failure. Young females were tested in the mid-luteal phase of the menstrual cycle, and older females were postmenopausal (>6 months since last menstrual cycle). The authors hypothesized that the pressor response to inspiratory loading would be increased in older participants. Moreover, given the decline in sex steroids in the postmenopausal state, it was reasoned that sex differences expected in young adults would be fully resolved in older adults. The findings of the study are clear cut. Carefully controlling for relative workloads between groups the authors report that: (i) ageing is associated with an increased pressor response to inspiratory loading in both sexes, expressed within the considerably shorter time to task failure in older participants compared with young adults; and (ii) the respiratory metaboreflex is attenuated in young females compared with young males, but elevated pressor responses to inspiratory loading in older participants are equivalent between male and female participants. Studies of this nature are, understandably, limited in their capacity to proffer complete mechanistic insight. The authors reasonably conclude that the equivalent elevated pressor responses to inspiratory loading in older male and female participants relate to reduced sex hormone concentrations in postmenopausal females. It is plausible that loss of oestrogen relieves an inhibitory influence on reflex-mediated sympathoexcitation, with wider ramifications for blood pressure homeostasis, consistent with the widely appreciated increased risk of cardiovascular morbidity in postmenopausal females. It is also likely that the precipitous decline in sex steroid signalling after the menopause disrupts adrenoceptor control of the vasculature, which, alone or in combination with changes in sympathetic nervous outflow, can readily explain the robust cardiovascular responsiveness of older participants. Additional studies are required to probe these issues. An obvious issue worthy of pursuit is whether hormone replacement in postmenopausal females blunts the respiratory metaboreflex. Interestingly, and consistent with the general reasoning of Leahy et al. (2023) in the consideration of their findings, oestrogen replacement in postmenopausal females lowers the pressor response to isometric hand-grip exercise (Fadel et al., 2004). Additionally, one wonders whether the potentiated metaboreflex in ageing is driven by afferent mechanisms. The authors consider but largely discount this premise with fair reasoning. However, age-related decline in muscle architecture and metabolism, ‘inflammaging’ of muscle and/or loss of oestrogenic signalling in muscle after the menopause that can elaborate redox imbalance and oxidative stress might be at least part players. Conceivably, alterations at the level of stimulus (and/or conduction and integration of the same) could contribute to potentiated responses. However, it appears that the contribution of type III/IV afferents to the exercise pressor response is unaltered by ageing, but efferent mechanisms differ between young and older participants, with a greater contribution by vasomotor mechanisms in older participants (Sidhu et al., 2015). It remains to be determined whether a similar scenario applies to the respiratory metaboreflex. On that front, there is a startling deficit in our understanding of the role of phrenic afferents in the control of breathing and blood pressure. Another notable gap in the knowledge base is the dearth of studies seeking to characterize the physiology of healthy older males and females. It is therefore particularly pleasing to see further evidence of a response to The Journal’s call to action ensuring a wider appreciation of human physiology across the lifespan (O'Halloran, 2020). Whatever the mechanism(s) of the potentiated metaboreflex in older males and females, the findings of Leahy et al. (2023) remind us of age-related remodelling and emerging vulnerability of the cardiovascular system. Documenting the full portfolio of responses across a wide demographic, delineating the underlying mechanisms and designing effective interventions to mitigate adverse outcomes will be important to pave a successful path to healthy ageing and increased healthspan. 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. Sole author. None. Open access funding provided by IReL.