Experimental Physiology

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1 Exp Physiol (2016) pp Symposium Report Symposium Report Sex differences and blood pressure regulation in humans Michael J. Joyner 1, B. Gunnar Wallin 2 and Nisha Charkoudian 3 1 Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA 2 Institute of Neuroscience and Physiology, The Sahlgren Academy at Gothenburg University, Göteborg, Sweden 3 Thermal and Mountain Medicine Division, US Army Research Institute of Environmental Medicine, Natick, MA, USA Experimental Physiology New Findings What is the topic of this review? Over the past decade, our team has investigated interindividual variability in human blood pressure regulation. What advances does it highlight? In men, we have found a tight relationship between indices of sympathetic activity and vascular resistance across the age span. This relationship is absent in young women but seen in postmenopausal women. These sex and age differences in vascular resistance are largely a result of changes in the balance of vasodilating and vasoconstricting adrenergic receptor tone. When these changes are considered along with cardiac output, a coherent picture is beginning to emerge of why blood pressure rises more with age in women than men. Arterial pressure is a key regulated variable in the cardiovascular system with important health implications. Over the last 12 years, we have used physiological measurements, including muscle sympathetic nerve activity (MSNA), to explore the balance among mean arterial blood pressure, cardiac output and total peripheral resistance (TPR) in normotensive humans. We have shown that these determinants of blood pressure can vary widely in different subjects and how they vary depends on sex and age. In young men, there is a direct relationship between MSNA and TPR but no relationship with blood pressure. This is because cardiac output is proportionally lower in those with high MSNA and TPR. In contrast, in young women there is no relationship between MSNA and TPR (or cardiac output); this is because β-adrenergic vasodilator mechanisms offset α-adrenergic vasoconstriction. Thus, blood pressure is unrelated to MSNA in young women. In older women, β-adrenergic vasodilator mechanisms are diminished, and a direct relationship between MSNA and TPR is seen. In older men, the relationships among these variables are less clear cut, perhaps owing to age-related alterations in endothelial function. With ageing, the relationship between MSNA and blood pressure becomes positive, more so in women than in men. The finding that the physiological control of blood pressure is so different in men and women and that it varies with age suggests that future studies of mechanisms of hypertension will reveal corresponding differences among groups. (Received 28 April 2015; accepted after revision 2 July 2015; first published online 8 July 2015) Corresponding author M. J. Joyner: Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 555, USA. joyner.michael@mayo.edu Introduction This paper is a brief review of key observations about sex differences and blood pressure regulation in humans. It is based largely on the studies we have conducted, starting in the early 2000s, and attempts to integrate our observations from integrative physiological studies in DOI: /EP085146

2 3 M. J. Joyner and others Exp Physiol (2016) pp humans with epidemiological observations (Charkoudian et al. 2005, 2006; Hart et al. 2009a, 2011, 2012; Carter et al. 2013; Barnes et al. 2014). It is also a summary of a presentation that took place at the 2015 Experimental Biology meeting during a symposium on sex differences and cardiovascular control. The key issues summarized in the paper include the folllowing. (i) Health-related blood pressure issues differ between women and men. These differences vary depending on age. (ii) From a physiological perspective, it is important to consider these differences in the context of mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). Any major sex -related differences in blood pressure regulation are likely to be reflected in differences in the relationships among these variables. (iii) Sex-specific conditions, including the menstrual cycle, pregnancy, oral contraceptives and menopause, can have additional impacts on these relationships. With this introduction as a background, we will attempt to tell an integrative physiology story related to the issues highlighted above. Blood pressure, sex and age There are two major sex-related differences in human blood pressure regulation that are seen clinically. First, orthostatic hypotension and fainting are much more common in young women than in young men. By their early 20s, survey research indicates that almost % of young women report at least one episode of orthostatic intolerance or fainting, whereas only 25% of young men report similar symptoms (Ganzeboom et al. 2003). Additionally, clinically documented hypotensive disorders of blood pressure regulation are far more common in women than in men(ali et al. 2000). In contrast to this observation are the age-related increases in blood pressure that occur in both sexes (National Center for Health Statistics 2010). In young women, blood pressure is typically lower than in young men, even in groups of healthy normotensive people. Rates of hypertension are also much lower in young women. In men, blood pressure starts to drift up on a population basis during the third decade of life, and the incidence of hypertension climbs steadily to % in roughly the seventh decade of life. In contrast, in women, blood pressure rises with age much more slowly until the fourth or fifth decade in life, i.e. around the time of menopause. Then the rise in pressure acceleratessothatbytheageof65oryears,morewomen are hypertensive than men, and rates of hypertension in women continue to rise with ageing. It should be noted that these trends are for Western societies marked by low levels of physical activity, high levels of social stress, high levels of salt intake and epidemic levels of overweight and obesity. In some cultures, blood pressure does not increase with ageing at all (Hollenberg et al. 1997). Is there an integrative physiology story? When we think about blood pressure, we always think in terms of Ohm s Law for electrical circuits as applied to the circulation, which can be summarized as follows: MAP = CO TPR. Blood pressure is easy to measure, and while cardiac output is more difficult to measure it can also be assessed. This means that in physiological studies focused on the circulation as a whole, vascular resistance is always calculated (i.e. TPR = MAP/CO). In this context, the activity of efferent sympathetic vasoconstrictor nerves that release noradrenaline is an important determinant of vascular resistance in many conditions. Using this simple rubric, we have measured blood pressure, cardiac output, peripheral sympathetic nerve activity and blood vessel physiology in younger and older women and men in order to gain a better understanding of how sex and age affect the interactions among MAP, CO and TPR in healthy normotensive humans. Microneurography and efferent sympathetic outflow Microneurography is a technique that can be used to measure and record electrical activity of peripheral nerves in humans. The technique was originally developed to measure the activity of motor nerves and the large afferent and efferent innervation of skeletal muscles. By the late 19s, however, it was appreciated that microneurography could also be used to record multiunit sympathetic nervous system (SNS) activity in humans (Vallbo et al. 2004; Wallin & Charkoudian, 2007). One of the first observations made, primarily in young healthy males, was that baseline sympathetic nerve activity to skeletal muscles (muscle sympathetic nerve activity, MSNA) could vary widely (perhaps five- to 10-fold) in normotensive subjects with similar arterial pressures (Sundlöf & Wallin, 1977). Additionally, MSNA measurements were highly repeatable fromdaytoday.thisapparentparadox,wherepeoplewith higher vasoconstrictor neural activity could have blood pressures similar to those with much lower neural activity, suggested that there was dissociation between peripheral sympathetic activity and blood pressure. Over the years, a large number of normotensive young (<40 years old) and older male and female subjects have been studied using microneurography, as well as subjects with a range of pathophysiological conditions that might influence the autonomic nervous system. In general, for both men and women <40 years of age, MSNA can vary five- to -old at rest. In these people, as noted above, there is also little or no relationship between MSNA and blood pressure. The interindividual variability seen in younger people is also seen in those >40 years of age, but in the older group there is a modest relationship between MSNA and blood pressure that is slightly more robust for females than males (Narkiewicz et al. 2005; Hart et al. 2012). Figure1is

3 Exp Physiol (2016) pp Sex differences and human blood pressure 351 a schematic diagram showing these patterns. Additionally, when groups of normotensive and hypertensive subjects are compared, mean values of MSNA are approximately 10 20% higher in the hypertensive subjects (Anderson et al. 1989; Gudbjörnsdottir et al. 1996); however, as is the case for normotensive subjects, a wide range of baseline MSNA values are seen, and there is significant overlap in the distribution of values between groups of normotensive and hypertensive subjects. Why are humans with high SNS activity not hypertensive? This is the central question that led to our initial studies in the early 2000s. Our first experiments were on healthy normotensive young men (Charkoudian et al. 2005, 2006). We showed that in individuals with high levels of MSNA, cardiac output was lower and total peripheral resistance higher. Muscle sympathetic nerve activity was significantly related to TPR, and thus the two main factors determining arterial pressure balanced each other to maintain normal blood pressures across individuals with highly variable MSNA values. Figure 2 is an individual record from two of our early subjects. In one subject, MSNA is relatively high and cardiac output is low, whereas in the other subject the converse is true, and both have similar values for MAP. In this study, cardiac output was measured using acetylene uptake and arterial pressure was measured via a brachial artery catheter. In addition to these primary findings, we also found evidence that individuals with high nerve traffic were less responsive to the vasoconstrictor actions of adrenergic agonists. This decreased adrenergic vasoconstrictor responsiveness in people with higher nerve activity is likely to be another balancing factor contributing to the maintenance of normal blood pressures in those individuals. Of note, in older humans sympathetic activity is on average increased, perhaps as a result of changes in central sympathetic outflow and/or peripheral baroreceptor function. However, acute changes in sympathetic activity evoke smaller changes in blood pressure in older men and women compared with younger subjects, consistent with the idea of reduced vasoconstrictor responsiveness in those with high sympathetic activity (Vianna et al. 2012). We next attempted to determine whether the relationships we saw in young men were influenced by sex or age. In older men, we did not observe relationships between MSNA and CO or TPR, although as noted previously, older men do have a relationship betweenmsnaandmap(hartet al. 2009b). We believe these relationships were more variable in older men due to the additional complicating factor of changes in endothelial function in men as they age. Endothelial function declines with age but in a variable way, and this might disturb the relatively straightforward relationship between sympathetic activity and vascular resistance seen in younger males (Hart et al. 2014). MAP (mmhg) MAP (mmhg) 120 Males <40 years 120 Females <40 years Males 40 years 120 Females 40 years MSNA (bursts/min) MSNA (bursts/min) Figure 1. Relationships between muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) in men and women The top panels are for subjects <40 years old. The bottom panels are for subjects >40 years old. For the younger subjects, there was no relationship between MSNA and MAP, whereas for the older subjects the relationship became more positive, especially in the women. This conceptual figure was suggested by Narkiewicz et al. (2005) and Hart et al. (2012).

4 352 M. J. Joyner and others Exp Physiol (2016) pp When we began to study younger women, we were struck by the absence of relationships among MSNA, CO and TPR(Fig. 3; Hart et al. 2009b). Young women, like young men, showed no relationship between MSNA and arterial pressure (systolic, diastolic or mean), but they did not appear to balance the neural and haemodynamic factors contributing to MAP in the same way that young men did. Initially, we had expected that these relationships mightbeshiftedortheslopesmightbedecreasedin comparison to young men, but their near total absence in younger women was a surprise. These studies were led by Dr Emma Hart and have been summarized in several reviews (Joyner et al. 2015). With regard to potential mechanisms for these differences between men and women, we and others have shown that administration of noradrenaline via the brachial artery does not evoke substantial vasoconstriction in young healthy women. This is in contrast to young men, in whom robust, dose-dependent vasoconstriction is a reproducible observation. However, when the female forearm has been pretreated with the β-adrenergic blocking drug propranolol, noradrenaline evokes robust vasoconstriction similar to that seen in men (Hart et al. 2011). There are two important implications of these observations. One is that the relative absence of vasoconstriction in response to noradrenaline in young healthy women in a major vascular bed such as skeletal muscle might explain, in part, why the relationship between MSNA and TPR is blunted (or absent) in younger women. A second implication is that a decreased vasoconstriction in response to noradrenaline might also contribute to sex-specific differences in orthostatic tolerance and symptoms seen in younger women. During an orthostatic challenge, if any increased SNS activity evokes less vasoconstriction in young women, this could lead to a decreased ability to maintain arterial pressure during upright posture, which could then lead to orthostatic intolerance and fainting. The finding that vasoconstriction was augmented after treatment with propranolol suggests that α-adrenergic vasoconstriction is offset in young women via β-adrenergically mediated vasodilatation. When we carried out parallel studies in older (postmenopausal) women, we noted that there was a strong relationship between MSNA and TPR, as well as between MSNA and MAP in these women, along with robust forearm vasoconstriction to administration of noradrenaline via the brachial artery. There was no relationship between MSNA and CO in the older women (Hart et al. 2011). In other words, healthy older postmenopausal women appear to have lost whatever protective influence younger women may have in terms of β-adrenergic vasodilatation creating an offset to α-adrenergic vasoconstriction. When these haemodynamic observations are integrated with what is known about the effects of oestrogen on the cardiovascular system, it appears as if perimenopausal loss of oestrogen might contribute to both a rise in MSNA and loss of β-adrenergically mediated endothelial vasodilatation (Joyner et al. 2015). These observations may also explain why the relationship between MSNA and blood pressure becomes positive in older women and are likely to contribute to the increased incidence of hypertension in women after menopause. We followed up on these findings with a study in which we gave the ganglionic blocking drug trimetaphan to women. In younger women, the reduction in blood pressure was modest. In contrast, in older women, Subject 1 MSNA = 27 bursts/ hb; CO =7.6 l/min; MAP = 98 mmhg Subject 2 MSNA = 68 bursts/ hb; CO =4.4 l/min; MAP = 99 mmhg Figure 2. Individual record of MSNA [expressed as bursts per heart beats (hb)] in two young male subjects with similar values for MAP The subject in the top panel had low MSNA but high cardiac output, whereas the subject in the bottom panel had high MSNA and a lower cardiac output. These individual data highlight key concepts about the potential relationships among MSNA, cardiac output and blood pressure (N. Charkoudian, M. J. Joyner & B. G. Wallin, unpublished observations).

5 Exp Physiol (2016) pp Sex differences and human blood pressure 353 the drop in blood pressure was very marked and was proportionaltothehigherlevelsofmsnaseenintheolder group (Jones, et al. 2001; Barnes, et al. 2014). Collectively, these observations support the idea of a tight relationship between sympathetic activity and vascular resistance in this age group. Sex-specific conditions Studies using microneurography are complex, and many have relatively small sample sizes. To overcome this limitation, we have pooled our data with data from the laboratories of Jason Carter, Qi Fu and Chris Minson to evaluate influences of sex-specific conditions and of oral contraceptives on control mechanisms of MSNA and blood pressure. Using this approach, we quantified the changes in sex steroids between the mid-luteal and early follicular phases of the menstrual cycle and showed TPR (mmhg/i/min) CO (I/min) MSNA (bursts/ hb) MSNA (bursts/ hb) Men Women Men Women Figure 3. Schematic diagram showing the differences in blood pressure regulation in normotensive young men and women The bottom panel shows the relationship between MSNA [expressed as bursts per heart beats (hb)] and cardiac output (CO; in litres per minute) in normotensive young men and women. The top panel shows the relationship between MSNA and TPR (in millimetres of mercury per litre per minute) in normotensive young men and women. In both groups, there is no relationship between MSNA and blood pressure, but this lack of relationship results from completely different physiological mechanisms. This conceptual figure was suggested by Hart et al. (2012). that oestrogen or the ratio of oestrogen to progesterone has an inverse relationship with baseline levels of MSNA (Carter et al. 2013). Likewise, both the menstrual cycle and oral contraceptive use can affect baroreflex control of sympathetic activity, with an increase in baroreflex sensitivity seen during the mid-luteal phase of the menstrual cycle, whereas a decrease in MSNA baroreflex sensitivity is seen in the high-hormone phase of oral contraceptive use (Minson et al. 2000a,b). In a follow-up analysis from our collaborative group (Harvey et al. 2015), a large number of young healthy women with normal menstrual cycles were compared with a large number who used oral contraceptives. Although all women studied were normotensive, our recent analysis confirms the generally accepted idea that oral contraceptive use is associated with mild increases in blood pressure (Boldo & White, 2011); however, consistent with a number of reports, there is little evidence for any major changes in MSNA as a function of oral contraceptive use (Carter et al. 2010; Middlekauff et al. 2012). In pregnancy, MSNA increases in the first trimester and can remain elevated (Jarvis et al. 2012) throughout the pregnancy. This elevation occurs even when blood pressure remains normal and might be a response to the marked vasodilatation that occurs during pregnancy. One interesting hypothesis is that in various forms of hypertensive pregnancy, at least some of the pregnancy-induced vasodilatation is blunted or absent, permitting the increased sympathetic activity to predominate (vis-à-vis vasoconstriction) and cause blood pressure to rise. There is also emerging interest in the long-term effects of hypertensive disorders of pregnancy on blood pressure regulation later in life and how that might influence the basic relationships between mean arterial pressure, CO, TPR and MSNA that have been the foundation for the ideas summarized in this review (Collen et al. 2012). Summary Ageing affects blood pressure in a different manner in men and women. Young women typically have lower blood pressure and more hypotensive events or disorders. This may be related to the relative inability of their vascular sympathetic nerves to cause vasoconstriction. This relative insensitivity to sympathetic vasoconstriction is likely to result from augmented β-adrenergic vasodilator effects offsetting α-adrenergically mediated vasoconstriction in young women. As women age, their blood pressure catches up with men; after menopause and into the seventh and eighth decades of life, more women than men are hypertensive. This may result, in part, from the loss of oestrogen at menopause, causing an increase in sympathetic activity and an increase in adrenergic vasoconstrictor responsiveness.

6 354 M. J. Joyner and others Exp Physiol (2016) pp In younger women, the normal menstrual cycle, oral contraceptive use and pregnancy can have marked and transient effects on blood pressure and its determinants, including MSNA. These areas are only now coming into focus for detailed mechanistic studies in humans. Additionally, how these factors are affected or might contribute to hypertensive disorders during pregnancy and longer term risk for high blood pressure is an emerging topic of great interest. The finding that the physiological control of blood pressure is so different in men and women and that it varies with age raises the possibility that future studies of mechanisms of hypertension will reveal corresponding differences among groups. References Ali YS, Daamen N, Jacob G, Jordan J, Shannon JR, Biaggioni I & Robertson D (2000). Orthostatic intolerance: a disorder of young women. Obstet Gynecol Surv 55, Anderson EA, Sinkey CA, Lawton WJ & Mark AL (1989). 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7 Exp Physiol (2016) pp Sex differences and human blood pressure 355 Sundlöf G & Wallin BG (1977). The variability of muscle nerve sympathetic activity in resting recumbent man. JPhysiol 272, Vallbo AB, Hagbarth KE & Wallin BG (2004). Microneurography: how the technique developed and its role in the investigation of the sympathetic nervous system. JApplPhysiol96, Vianna LC, Hart EC, Fairfax ST, Charkoudian N, Joyner MJ & Fadel PJ (2012). Influence of age and sex on the pressor response following a spontaneous burst of muscle nerve activity. Am J Physiol Heart Circ Physiol 302, H2419 H2427. Wallin BG & Charkoudian N (2007). Sympathetic neural control of integrated cardiovascular function: insights from measurement of human sympathetic nerve activity. Muscle Nerve 36, Additional information Competing interests None declared. The opinions or assertions contained herein are the private views of the authors and should not be construed as official or reflecting the views of the Army or the Department of Defense. Author contributions All authors contributed to the writing and editing of this review. The original research conducted by the authors which underpins this review was a collaborative effort by all authors who all played key roles in the conceptualization, funding, data collection, analysis and writing of the work. Funding The collaborative studies of the authors on these topics were supported by NIH HL83947, NIH UL1RR0241 and the Caywood professorship. Acknowledgements We would like to thank our many collaborators, outstanding technical support staff and dedicated volunteer subjects for their contributions to this work.