Ageing uncompensated: exercise, nitric oxide and hypoxia

The vast majority of research comparing skeletal muscle haemodynamics during exercise in young and older adults has been done under normoxic conditions. These studies provided novel insight into regulatory mechanisms of skeletal muscle blood flow, but leave untested circumstances when arterial oxygen saturation may be limited by environmental conditions or medical pathologies. Enhanced vasodilatation in response to hypoxia has been termed compensatory vasodilatation. Compensatory vasodilatation allows for an adequate amount of oxygen to be delivered to the working musculature and is, in part, nitric oxide (NO) dependent (Casey et al. 2010). Ageing is associated with changes in cardiovascular regulation that may alter NO-mediated dilatation (Schrage et al. 2007) and thereby reduce vasodilatory responses to hypoxia during exercise. Any alterations to the regulation of skeletal muscle blood flow may limit functional capacity and impair the ability to perform exercise with ageing. It was previously unknown whether older adults exhibit reduced compensatory vasodilatation or the regulatory mechanisms responsible for any impairment. In a recent article in The Journal of Physiology, Casey et al. (2011) explored the contribution of NO to forearm vasodilatation during exercise in ageing humans under conditions of hypoxia. To test the hypothesis that skeletal muscle compensatory vasodilatation is blunted in ageing humans, Casey et al. (2011) assessed forearm vascular conductance (FVC) in 11 healthy older subjects (55–70 years). FVC was measured under normoxic and hypoxic (80% arterial oxygen saturation) conditions during graded forearm exercise (10% and 20% of maximal effort); data were compared with findings from young adults presented previously (Casey et al. 2010). Results showed hypoxic compensatory vasodilatation (% change in ΔFVC) was maintained in older adults at 10% and absent at 20% effort. These findings suggest attenuated hypoxic vasodilatation in ageing humans presents with increasing exercise intensity. Casey et al. predicted that altered NO signalling in the ageing group contributed to the attenuated compensatory vasodilatation. To test this hypothesis, the group infused l-NMMA at rest to inhibit NO synthesis. In the young adults, l-NMMA reduced compensatory vasodilatation to hypoxic exercise at 10% and 20% effort (Casey et al. 2010); l-NMMA had no effect on compensatory vasodilatation in the older adults. This form of analysis suggests that reduced NO signalling may be responsible for attenuated compensatory vasodilatation with ageing. However, it is important to acknowledge when analysed as a change in FVC (ΔFVC), the older group showed significantly reduced hypoxic FVC with l-NMMA infusion at 10% effort (but not at 20%). Thus, a portion of the increase of FVC at 10% effort in older adults may be due to NO signaling; however, any increase in FVC at 20% cannot be attributed to NO considering l-NMMA did not alter vascular responses. The authors further explored the vasodilatory role of NO in ageing by infusing acetylcholine during l-NMMA or saline administration. l-NMMA reduced endothelial-dependent vasodilator responses to acetylcholine in the young adults compared to the response with saline (Casey et al. 2010). Conversely, l-NMMA did not significantly alter the vasodilator response in the older adults; this again suggests attenuated NO signalling with ageing, although irrespective of hypoxia. In summary, novel findings from the current study demonstrate that hypoxia-induced compensatory vasodilatation is attenuated in ageing subjects during moderate-intensity exercise (20% effort). The authors attributed the decrease in compensatory vasodilatation to diminished NO signalling. This conclusion was reinforced by the lack of significant reduction in ΔFVC with l-NMMA infusion at 20% effort. The authors provide readers with a thorough analysis of data from ageing adults, including absolute FVC measures and both delta (Δ) and per cent (%) changes from normoxic levels. The representation of hypoxia-mediated compensatory vasodilatation (per cent change in ΔFVC from respective normoxic responses) may seem convoluted. However, it is probably the most appropriate means to compare results between groups with varying absolute flows. In this way, variability in resting flow is heeded and results are presented within the context of normoxic exercise vasodilatation. However, considering the hypothesis of the current study, the authors presented few direct statistical comparisons of ageing and young subjects – leaving conclusions based solely upon compensatory (% change in ΔFVC) analysis. Providing additional between-group analyses from available data could have added key information regarding apparent differences in haemodynamic responses to hypoxia. Whereas these findings suggest the importance of NO to hypoxic vasodilatation is attenuated with ageing, the methods used do not allow for understanding of vascular control during hypoxic exercise. When nitric oxide synthase (NOS) inhibition occurs prior to the onset of hypoxia at rest, redundant signals are capable of compensating to produce a normal hyperaemic response (Markwald et al. 2011). However, when combined with exercise, Casey and colleagues suggest NOS inhibition attenuates hypoxic exercise dilatation in young adults (2010) while minimally impacting older adults (2011). Though novel, these findings cannot rule out the possibility of compensatory mechanisms capable of masking the normal contribution of NO to steady-state flow. Thus, current results may underestimate the importance of NO to hypoxic dilatation in either study population. Follow-up studies should consider local inhibition of NO synthesis during hypoxic handgrip exercise, in addition to the exploration of compensatory mechanisms. Consistent with the concept of signal redundancy, the possible contribution of β-adrenergic or prostaglandin-mediated vasodilatation remains untested. In young adults, β-receptor activation is responsible for a substantial portion of hypoxic dilatation during low-intensity forearm exercise (10% effort, Wilkins et al. 2008); a portion of this dilatation occurs through an NO-dependent pathway. As a result, the exact mechanisms behind NO-mediated compensatory vasodilatation at 10% effort may be group-specific if altered β-adrenergic sensitivity or receptor expression occur with ageing. Furthermore, prostaglandins are known to play a role in resting hypoxic vasodilatation in young adults (Markwald et al. 2011) and their contribution to normoxic exercise vasodilatation is reduced with age (Schrage et al. 2007). Future studies are necessary to fill the gap in knowledge and elucidate the individual roles of both β-adrenergic and prostaglandin-mediated mechanisms on hypoxic vasodilatation in ageing adults. Neurovascular control of hypoxia-mediated blood flow is a balance between adrenergic constriction and dilatation. Thus, it is important to acknowledge that ageing subjects presented 2-fold higher venous noradrenaline levels compared to young adults – probably due, in part, to age-related increases in sympathetic nerve activity. Given the observed increase, it is possible that enhanced adrenergic vasoconstriction contributed to blunted compensatory vasodilatation in the ageing subjects. However, the authors show similar heart rate and blood pressure responses to hypoxia between groups (Casey et al. 2011). Whereas these observations are unlikely to confound current conclusions, one should consider the potential clinical implications in disease states presenting increased sympathetic nerve activity (diabetes, heart failure, hypertension). Interestingly, the authors note significant between-group differences in baseline blood pressures. Given that both ageing and hypertension are known to increase sympathetic nerve activity and independently reduce NO-mediated dilatation, the current cohort does not allow for differentiation between these manifestations. Despite attenuated compensatory vasodilatation in ageing adults, results from the current study suggest that oxygen consumption is maintained during forearm exercise. Thus, older adults are able to meet metabolic demand through combined changes in oxygen delivery and extraction. Although vasodilatory responses to environmental stressors and the mechanisms behind vascular control are altered with ageing, reduced haemodynamics do not appear to compromise older adults’ ability to meet oxygen demand. Whether this continues to apply at higher exercise intensities or under more severe hypoxia, and the clinical implications of such changes, have yet to be assessed. In conclusion, Casey et al. (2011) provide novel insight to hypoxia-mediated dilatation during forearm exercise and the effects of ageing on mechanisms of vascular control. This, combined with their previous work, begins to describe complex interactions in vascular control. Future studies might aim to examine the relative importance of alternative vascular control mechanisms and the effect of differences in sympathetic nerve activity between groups. Clinically, this information provides further understanding of the impact of ageing and the role of NO in skeletal muscle blood flow under circumstances when local or systemic arterial oxygen saturation may be limited by exercise, environmental conditions or medical pathologies.