Sex, drugs and blood pressure control: the impact of age and gender on sympathetic regulation of arterial pressure

Cardiovascular disease is the leading cause of death in developed countries. Numerous studies confirm that increases in blood pressure occur with ageing, and are associated with an increased risk of cardiovascular events. The effects of ageing on the cardiovascular system and blood pressure control differ between males and females, but the mechanisms underlying this remain unclear (Hart et al. 2009a). Starting in puberty, men tend to have higher blood pressures compared with women; this difference continues until women reach menopause, at which point the incidence of hypertension begins to increase rapidly, often exceeding that of men (Hart et al. 2009a). This has led to the suggestion that female sex hormones exhibit a cardio-protective effect in younger women, although this has not been proven. This article focuses on a recent paper published in The Journal of Physiology by Hart et al. (2011) that illustrates the specific cardiovascular parameters that underlie sex- and age-related differences in sympathetic activity and resting blood pressure. The paper also provides novel mechanistic insight into the role of the sympathetic nervous system in the development of hypertension with age, with a particular emphasis on the effect of menopause on the risk of hypertension in women. We will first examine the findings of this article in context with previous studies in this field, and then provide a thoughtful discussion on the complexity of this article's findings.

The use of muscle sympathetic nerve activity (MSNA) has provided an effective tool to evaluate the relationship between sympathetic outflow and blood pressure. Specifically, correlations between MSNA and total peripheral resistance (TPR), cardiac output (CO) and blood pressure have been uncovered (Fig. 1A–F) (Matsukawa et al. 1998; Narkiewicz et al. 2005; Hart et al. 2009a,b, 2011). One might expect that individuals with greater MSNA would have higher blood pressure, and this is generally reported to be the case in older adults (Fig. 1B). However, in young men and women there is no such relationship (Fig. 1A) (Narkiewicz et al. 2005; Hart et al. 2009a). This apparent protection from elevated blood pressure in young adults with high MSNA is of particular interest in understanding how the sympathetic nervous system is implicated in the dramatic rise in hypertension risk with ageing.

Figure 1. Theoretical relationships between blood pressure (BP, A and B), total peripheral resistance (TPR, C and D), cardiac output (CO, E and F) and muscle sympathetic nerve activity (MSNA) in young men and women, older men and post-menopausal women.

*Data from Narkiewicz et al. (2005) depicting the relationship between MSNA and mean arterial pressure. ^†Data from Hart et al. (2009b). Relationships between MSNA and diastolic arterial pressure (a) and systolic arterial pressure (b) are depicted.

Young males and females with heightened MSNA seem to use different mechanisms to protect against elevations in blood pressure (Fig. 1A). In young males high MSNA is transmitted into increases in TPR, suggesting that the elevated sympathetic activity is translated into increased vascular tone (Fig. 1C). However, an accompanying reduction in CO appears to compensate for the increased resistance, such that blood pressure does not rise (Fig. 1E) (Hart et al. 2009a). These relationships are different in young females in whom elevations in resting MSNA do not result in elevations in TPR (Fig. 1C), suggesting compensation within the vasculature. Accordingly, there is no relationship between MSNA and CO in young females (Fig. 1E).

In older males there is no relationship between MSNA and both TPR and CO (Fig. 1D and F) (Hart et al. 2009b). The relationship between MSNA and blood pressure in older males, however, remains controversial. Narkiewicz et al. (2005) found a positive relationship between MSNA and mean arterial pressure (MAP), but did not evaluate relationships with TPR and CO (Fig. 1B). Conversely, Hart et al. (2009b) found no relationship between systolic arterial pressure and MSNA, a positive relationship between diastolic arterial pressure and MSNA (Fig. 1B), and did not report the relationship between MAP and MSNA. Large inter-individual differences in this group probably contribute to the confusion in the existing literature (Hart et al. 2009b). Certainly, a positive relationship between MSNA and blood pressure is incompatible with the observed relationships between MSNA and TPR and CO in this group. Hart et al. (2009b) interpret this as evidence of uncoupling of baroreflex control of blood pressure and heart rate in older males, such that the normal relationships between MSNA, TPR and CO are disrupted in this population. However, this seems unlikely, and given the lack of agreement in the literature as to the nature of these relationships in older men, we feel further work is required in a large cohort of older men in order to clarify these apparently paradoxical findings.

Until now, these relationships had not been studied in older postmenopausal women. It is clear that the means by which MSNA influences blood pressure are quite different between males and females, thus an understanding of these sex-specific mechanisms is paramount. It is known that oestrogen elicits vasodilatation via direct effects on the vasculature, as well as indirect effects through increases in nitric oxide bioavailability or enhanced β₂-adrenergic vasodilatation (Hart et al. 2009a). Furthermore, animal studies suggest that progesterone may exert a vasodilatory effect via increased β₂-adrenergic receptor expression (Hart et al. 2011). Therefore, it is postulated that sex hormones in females may play a role in blood pressure regulation (Hart et al. 2009a, 2011).

The present work by Hart et al. (2011) addressed a fundamental shortcoming in previous research by examining blood pressure parameters and MSNA in older post-menopausal women. The primary aim of the study was to examine whether β-adrenergic receptors modulate the relationships between MSNA, CO and TPR in young males and females and whether this was altered in post-menopausal women. The authors hypothesized that β-adrenergic receptors play an important role in mediating the relationship between MSNA and blood pressure in young women. It was further hypothesized that β-blockade would increase forearm vasoconstrictor responses in young women, but have no effect in young men and post-menopausal women.

The key findings of this study are: (1) in older post-menopausal women elevations in resting MSNA are associated with increases in TPR and blood pressure; (2) in young women, β-blockade unmasked the relationship between MSNA and TPR, with the consequence that those with elevated MSNA also had higher blood pressure, as in post-menopausal women (Fig. 1B, D and F). These alterations were not observed in either the young men or post-menopausal women when exposed to β-blockers. This provides valuable evidence that β-adrenergic receptors may play an important role in buffering the translation of elevated resting MSNA into increases in TPR in young women. The addition of post-menopausal women confirms that the mechanism mediating the relationship between MSNA and blood pressure appears to be different between older men and women. This provides support that female sex hormones exhibit a cardio-protective effect in modulating the influence of sympathetic activity on blood pressure in younger females, and that this effect is probably mediated via a β-adrenergic mechanism.

While Hart et al. (2011) have undoubtedly advanced the field in terms of our understanding of age-related hypertension, this paper raises a number of additional questions. The use of propranolol, a non-selective β-blocker, confirms the role of β-adrenergic receptors in mitigating the translation of elevations in MSNA in young women into elevations in TPR, but the precise nature of this relationship remains to be determined. It is likely that much of this relationship is mediated via an effect on β₂-receptors (Hart et al. 2009a). However, in the present study the effect of β₁-blockade is also evident in all groups, because there are significant decreases in CO and stroke volume during testing. Although alluded to as an inconsequential limitation of the study, it is possible that β₁-blockade could alter the relationships between MSNA, TPR and blood pressure. Furthermore, if differences in β₂-receptor sensitivity exist between these groups as postulated, it is quite possible that β₁-receptor sensitivity may also be affected differentially between groups. In order to mitigate some of the confounding effects of simultaneous β₁-receptor blockade, a selective β₂-antagonist, if available, would present an interesting experimental paradigm.

One aspect of the response to β-blockade in young men and post-menopausal women was somewhat unexpected. In these groups the previous association between MSNA and blood pressure was lost during β-blockade. One might expect this relationship to be maintained despite β-blockade in these individuals, since it is hypothesized that any role of β₂-adrenergic receptors in mediating the translation of MSNA into blood pressure via female sex hormones would be less. Therefore, although it seems evident that β-receptors play a role in blood pressure regulation in young women, their contribution in the other two groups is less clear.

Post-menopausal women were chosen as a model of low oestrogen and progesterone levels, to determine whether female sex hormones do indeed influence the relationships between β-adrenergic sensitivity, MSNA, TPR and blood pressure. While this is a logical first step, further evaluation is necessary to evaluate the role of other potential confounders in this population. For example, age-related changes in the vasculature, such as atherosclerosis and arterial stiffening, may affect CO, TPR and blood pressure. Age-matched older males may provide a possible control but without the influence of the female sex hormones. However, it is likely that these age-related vascular changes would also show gender differences.

Finally, female sex hormone levels were not measured in this study, and there is normally considerable variability of oestrogen and progesterone levels between individuals, as well as during the transition into menopause. These states may exert different effects on the vasculature and blood pressure regulation and should be controlled for and quantified in future studies. Another interesting addition to the data set would be testing in pre-pubescent children, or other populations in whom the levels of female sex hormones can be manipulated, such as post-menopausal women taking hormone replacement therapy, or younger women using hormonal contraceptives. The opportunity to determine blood pressure control mechanisms in these populations in whom the levels of circulating sex hormones are very different might aid the understanding of the role of female sex hormones in blood pressure regulation.

It is clear that there are a number of contributing factors to blood pressure regulation that differ between the sexes and with age. Hart et al. have demonstrated a novel mechanism that may explain the relative protection against the development of hypertension in young women, and which may be lost in healthy ageing. However, the relationships between MSNA, TPR and blood pressure are complex and require further investigation before the relative roles of female sex hormones and β-adrenergic receptors are completely understood. Ultimately, with an increasing population of elderly individuals, the impact of such research will be invaluable in understanding the precursors to life-threatening cardiovascular diseases such as hypertension.