Metaboreceptor polymorphisms: do genes determine your blood pressure response to exercise?

The exercise pressor reflex (EPR) plays a key role in the regulation of blood pressure (BP) during exercise. This reflex consists of group III and IV skeletal muscle afferents, which detect mechanical (pressure, stretch, etc.) and metabolic (H⁺, ATP, etc.) stimuli via mechanoreceptors and metaboreceptors, respectively. Activation of these receptors during exercise leads to increased afferent firing to the brainstem, which contributes to intensity‐dependent increases in sympathetic outflow, and BP (Fisher et al. 2015). It is well known that activation of the metabolically sensitive receptors (i.e. muscle metaboreflex) plays a predominant role in mediating the sympathetic nerve activity and BP responses to isometric exercise in humans. Importantly, in disease populations (e.g. hypertension, type 2 diabetes), exercise can evoke exaggerated increases in BP, and there is evidence to suggest that an overactive metaboreflex drives these exaggerated BP responses. This has led to a concerted research effort to examine the mechanisms of an overactive muscle metaboreflex activation in clinical populations (Murphy et al. 2011).

Notably, young healthy individuals demonstrate high inter‐individual variability in BP responses to exercise performed at the same relative intensity, with some individuals exhibiting quite large increases in BP (Notay et al. 2018 b). This is important because heightened pressor responses to exercise in healthy individuals have been associated with future development of hypertension. In addition, augmented BP responses also increase the risk of acute cardiovascular events, both during and after exercise. The underlying mechanisms contributing to these variable pressor responses in healthy adults remain incompletely understood. Since these otherwise healthy individuals do not present overt cardiovascular risk factors, exaggerated BP responses to exercise may be of genetic origin, an area that has been widely overlooked. In this regard, tremendous advances in the field of genomics have allowed for detection of genetic variations as small as a single nucleotide at a specific position in the genome sequence (single nucleotide polymorphism; SNP). Accordingly, it is possible that polymorphisms in the genes encoding metaboreceptors may lead to an overactive muscle metaboreflex and thus an exaggerated BP response to exercise. However, this had never been studied until now.

In the current issue of The Journal of Physiology, Notay et al. (2018 a) uniquely combined genotyping with laboratory measurements of cardiovascular responses to isometric handgrip exercise, in order to explore the potential role of genetic variance in mediating augmented exercise pressor responses in otherwise healthy subjects. The authors tested the hypothesis that SNPs in genes encoding metaboreceptors located on group III and IV skeletal muscle afferents can influence the exercise pressor response. Two hundred young healthy men and women were genotyped for SNPs in the genes encoding five different metaboreceptors: transient receptor potential vanilloid 1 (TRPV1), acid‐sensing ion channels (ASIC), bradykinin (BDKRB2), prostaglandin (PTGER2) and purinergic (P2RX4) receptors. Subjects performed 2 min of static handgrip exercise at 30% maximal voluntary contraction (MVC) followed by 2 min of post‐exercise circulatory occlusion (PECO) to isolate muscle metaboreflex activation. BP responses during exercise and PECO were compared to those during mental stress, a non‐exercise BP raising stimulus. The authors found that subjects with SNPs in TRPV1 and BDKRB2 had greater BP responses during isometric handgrip exercise, while those with polymorphisms in ASIC3, P2RX4 and PTGER2 did not. Interestingly, TRPV1 and BDKRB2 polymorphisms only augmented BP responses in men, as women showed no effect of these two SNPs. None of the metaboreceptor polymorphisms showed an effect on BP responses to mental stress in men or women. These findings provide novel insight into potential underlying mechanisms contributing to the inter‐individual variability in the pressor response to exercise.

The work by Notay et al. (2018 a) has advanced the current understanding of BP regulation during exercise by identification of metaboreceptor variants that may contribute to augmented BP responses in young healthy adults. At the same time, like all good studies, it also raises several questions. For example, it is interesting that subjects with SNPs in TRPV1 and BDKRB2 metaboreceptors had an augmented BP response only during isometric exercise (when both the mechano‐ and metaboreflex were activated together) and not during isolated metaboreflex activation. While the reason for this is unclear, it could be, in part, due to the workload performed (30% MVC), which might not be sufficient to elicit a muscle metaboreflex response in all individuals. The impact of these SNPs on metaboreflex‐induced pressor responses would presumably be greater during higher exercise intensities and therefore could also reveal their influence on BP responses during isolated metaboreflex activation. Furthermore, since some muscle afferents respond to both mechanical and metabolic stimuli (Kaufman & Hayes, 2002), it is possible that, although these metaboreceptor SNPs do not augment BP responses during isolated muscle metaboreflex activation, they are capable of making the muscle afferents more sensitive to mechanical stimulus in the presence of metabolite accumulation. That is, muscle afferents with metaboreceptor SNPs may be more responsive to the combination of mechanical and metabolic stimuli, as occurs during handgrip. However, once the mechanical stimulus is removed during PECO, the metabolic stimulus alone is not sufficient to elicit exaggerated BP responses (at least at the intensity of 30% MVC). Additional studies are needed to further investigate these possibilities.

Interestingly, men who had SNPs in both TRPV1 and BDKRB2 metaboreceptors had a greater BP response than either individual SNP alone, suggesting an additive effect of these SNPs. This may not be surprising as previous work has suggested that accumulation of multiple metabolites together evoked robust responses, whereas accumulation of each metabolite individually (ATP, lactic acid and protons) had minimal effect (Pollak et al. 2014). In this regard, it is plausible that some metaboreceptor SNPs, when occurring individually, may not increase BP responses to exercise. This could explain why subjects with SNPs in ASIC3, P2RX4 and PTGER2 did not exhibit an exaggerated exercise pressor response. Notably, Notay et al. (2018 a) only tested the integrative effect of the two metaboreceptor variants that contributed to greater BP responses when occurring individually (i.e. TRPV1 and BDKRB2). As such, it would be interesting to know whether other combinations of the metaboreceptor SNPs probed (e.g. TRPV1, BDKRB2 and ASIC3) may reveal a more marked pressor response, during both exercise and isolated muscle metaboreflex activation. Such analyses might also provide further insight into differences between men and women. However, this was not tested in the current study and awaits further investigation.

In summary, Notay and colleagues should be commended on their novel, ‘state of the art’ approach to examining the potential contribution of genetic variance to the heightened BP response to exercise found in otherwise healthy young subjects. They have identified two potential metaboreceptor SNPs that may contribute to the augmented BP responses in young, healthy adults. More importantly, they have initiated an approach to significantly advance this area of research, paving the way for investigating the role of metaboreceptor polymorphisms in exaggerated BP responses in health and disease.

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Competing interests

No conflicts of interest, financial or otherwise, are declared by the authors.

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