Adaptations in autonomic nervous system regulation in normal and hypertensive pregnancy

VIRGINIA L BROOKS; QI FU; ZHIGANG SHI; CHERYL M HEESCH

doi:10.1016/B978-0-444-64239-4.00003-5

. Author manuscript; available in PMC: 2022 Jul 7.

Published in final edited form as: Handb Clin Neurol. 2020;171:57–84. doi: 10.1016/B978-0-444-64239-4.00003-5

Adaptations in autonomic nervous system regulation in normal and hypertensive pregnancy

VIRGINIA L BROOKS ^1,^*, QI FU ^2,³, ZHIGANG SHI ¹, CHERYL M HEESCH ⁴

PMCID: PMC9261029 NIHMSID: NIHMS1809919 PMID: 32736759

Abstract

There is an increase in basal sympathetic nerve activity (SNA) during normal pregnancy; this counteracts profound primary vasodilation. However, pregnancy also impairs baroreflex control of heart rate and SNA, contributing to increased mortality secondary to peripartum hemorrhage. Pregnancy-induced hypertensive disorders evoke even greater elevations in SNA, which likely contribute to the hypertension. Information concerning mechanisms is limited. In normal pregnancy, increased angiotensin II acts centrally to support elevated SNA. Hypothalamic sites, including the subfornical organ, paraventricular nucleus, and arcuate nucleus, are likely (but unproven) targets. Moreover, no definitive mechanisms for exaggerated sympathoexcitation in hypertensive pregnancy have been identified. In addition, normal pregnancy increases gamma aminobutyric acid inhibition of the rostral ventrolateral medulla (RVLM), a key brainstem site that transmits excitatory inputs to spinal sympathetic preganglionic neurons. Accumulated evidence supports a major role for locally increased production and actions of the neurosteroid allopregnanolone as one mechanism. A consequence is suppression of baroreflex function, but increased basal SNA indicates that excitatory influences predominate in the RVLM. However, many questions remain regarding other sites and factors that support increased SNA during normal pregnancy and, more importantly, the mechanisms underlying excessive sympathoexcitation in life-threatening hypertensive pregnancy disorders such as preeclampsia.

INTRODUCTION

Pregnancy is a fascinating state, especially because of the multitude of homeostatic changes that transpire to support the developing fetus. One such change is a surge in sympathetic nerve activity (SNA), which increases even further in pregnancy-induced hypertensive disorders such as preeclampsia. However, unfortunately, only limited information has been obtained about the mechanisms in both normal and hypertensive pregnancy. The purpose of this chapter is to summarize the current knowledge, with an eye toward stimulating further research.

LONGITUDINAL CHANGES IN HEMODYNAMICS AND HORMONES

Pregnancy induces rapidly developing and profound changes in cardiovascular function and hormonal levels to support the developing fetus (Fig. 3.1). The primary initial event is systemic vasodilation, which begins during the luteal phase of the menstrual cycle in women and thus is anticipatory of fetal and maternal needs. Considerable work from the Conrad lab and others indicates that relaxin, produced by the corpus luteum, is a major contributor to the early decrease in systemic vascular resistance, via increases in endothelial-derived nitric oxide and vasodilatory prostaglandins (Conrad, 2011; Leo et al., 2017). Simultaneously, the vasculature resists vasoconstriction induced by angiotensin II (AngII) and sympathetically released norepinephrine (Jarvis et al., 2012; Intapad et al., 2014; Fu, 2018; Reyes et al., 2018a; Spradley, 2019) to aid and abet primary vasodilation.

The dramatic early vasodilation (Chapman et al., 1997) decreases the effective arterial blood volume, which then rapidly stimulates fluid-retaining factors, such as the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (Jarvis et al., 2012; Tkachenko et al., 2014) (see below). Sodium retention ensues, despite concurrent increases in the glomerular filtration rate and renal blood flow (Tkachenko et al., 2014). This is accompanied by even greater thirst/drinking and vasopressin-mediated water retention, also due in part to arterial underfilling (nonosmotic stimulation of vasopressin release) and relaxin acting centrally, such that plasma osmolality is reset to a lower level (Conrad, 2011; Tkachenko et al., 2014). As a result, plasma volume increases rapidly (Tkachenko et al., 2014; de Haas et al., 2017). Cardiac output rises in parallel due in part to increased stroke volume (increased preload and decreased afterload), increased heart rate (HR), and eccentric cardiac hypertrophy (Meah et al., 2016; Fu, 2018), and the arterial pressure falls because the decrease in systemic vascular resistance exceeds the increase in cardiac output (Tkachenko et al., 2014; Meah et al., 2016; Fu, 2018). Thus, by the end of the first trimester in women, a hyperdynamic circulation, including increases in cardiac output, HR, and plasma volume, is clearly evident and driven largely by systemic vasodilation and an enlarged vascular container that triggers salt and water retention.

Many of these initial changes are maintained or progress throughout human pregnancy (Fig. 3.1). The decrease in systemic vascular resistance, while initially induced largely by corpus luteal products such as relaxin, may be further developed and sustained by additional factors, including placental hormones and the vasodilatory sex steroid estrogen (Conrad and Baker, 2013; Fu, 2018). Plasma volume expansion, driven by additional increments in AngII, aldosterone, and SNA, thus continues concurrently with a delayed but significant increase in red cell volume and therefore blood volume (Tkachenko et al., 2014; Vricella, 2017); cardiac output increases further until just before delivery, when slight decreases have been observed (Meah et al., 2016). As shown in Fig. 3.1, almost all hemodynamic and hormonal factors normalize rapidly after delivery (Hunter and Robson, 1992; Mabie et al., 1994; Gilson et al., 1997; Meah et al., 2016).

Rats have been studied frequently to address mechanistic hypotheses related to maternal adaptations to pregnancy, so we also include an overview of what is known about the longitudinal changes in hemodynamics and hormones in this species (Fig. 3.1). Implantation does not occur until 6 days following fertilization, nearly the end of the first trimester of the 21-day rat gestational period. Soon thereafter (~8 days of gestation), relaxin becomes detectable and, unlike in human pregnancy, rapidly rises to reach a peak just before delivery (Sherwood et al., 1980; Sherwood, 2004; Conrad, 2011). As in humans, this decreases systemic vascular resistance (Gilson et al., 1992; Conrad, 2011), which leads to increases in PRA (Fowler Jr. et al., 1981; Nadel et al., 1988), AngII, sodium and water retention (Atherton et al., 1982), plasma and blood volumes (Atherton et al., 1982; Nadel et al., 1988), cardiac output (Gilson et al., 1992; Slangen et al., 1996; Cadnapaphornchai et al., 2001), and HR (Brooks et al., 2010b). Decreases in MAP are evident midgestation, and MAP falls even more just before delivery (Fowler Jr. et al., 1981; Brooks et al., 2010b).

PREGNANCY INCREASES SNA

Numerous studies of the changes in indirect indices of SNA during human pregnancy have been published. While measurements of plasma norepinephrine levels have been inconsistent, this can be explained by the hyperdynamic circulation that can alter its volume of distribution and clearance (Fu, 2018). However, measurements of HR variability in pregnant women generally suggest a gradual increase in cardiac sympathetic activity, which begins early in gestation, and also a decrease in parasympathetic nerve activity (Lucini et al., 1999; Kuo et al., 2000; Avery et al., 2001; Rang et al., 2002; Kolovetsiou-Kreiner et al., 2018). Similar observations have been made in pregnant rats (Cohen et al., 1988). The greater decrease in HR following pharmacologic blockade of beta adrenergic receptors in pregnant animals further suggests that pregnancy increases cardiac sympathetic tone (Brooks et al., 1997; Lumbers and Yu, 1999).

Direct measurements of SNA have been more consistent. In women, increases in muscle SNA (MSNA) bursts (per minute and per 100 heart beats) have been detected early in pregnancy (5–6 weeks of gestation) (Jarvis et al., 2012; Hissen et al., 2017; Reyes et al., 2018a) (Fig. 3.2). This initial rise develops further during human gestation to reach a peak before delivery (Greenwood et al., 2001; Fischer et al., 2004; Usselman et al., 2015a; Reyes et al., 2018a; Schmidt et al., 2018) (Fig. 3.2). Subtle racial differences have been observed; the MSNA increase in pregnant Asian women is smaller than that seen in pregnant Caucasian women (Okada et al., 2015). Greenwood and colleagues detected an increase in single-unit MSNA per 100 heart beats in late pregnancy and suggested that this reflects enhanced central drive. Using action potential waveform detection analysis, Schmidt and colleagues also found that MSNA bursts and integrated activity were increased as was the total number of action potentials per minute or per 100 heart beats, in association with a reduced interspike interval. However, the number of single action potentials per burst was similar in pregnant and nonpregnant women (Schmidt et al., 2018). These authors speculated that the overall enhanced activity was due to decreased central baroreflex gating and decreased baroreflex gain.

Fig. 3.2. — Pregnancy induces a slowly developing sympathoexcitation in both women (left) and rats (right). Left: Data from Okada, Y., Best, S.A., Jarvis, S.S., et al., 2015. Asian women have attenuated sympathetic activation but enhanced renal–adrenal responses during pregnancy compared to Caucasian women. J Physiol 593, 1159–1168; Right: Shi and Brooks, unpublished data. Nonpregnant: n = 20; Gestation day 10 (P10):n = 6; Gestational day 20 (P20): n = 12.

In anesthetized late pregnant rats, the activity of sympathetic nerves innervating several organs increases, including splanchnic SNA (SSNA), lumbar SNA (LSNA) (Shi et al., 2015a), and cardiac SNA (Cohen et al., 1988). Elevations in renal SNA (RSNA) have also been reported (Masilamani and Heesch, 1997; Hines et al., 2007), albeit inconsistently (O’Hagan and Casey, 1998; Shi et al., 2015a). Nevertheless, despite insignificant changes in baseline RSNA, blockade of the arcuate nucleus (ArcN) decreased RSNA in late pregnant (but not virgin) rats (Shi et al., 2015a), suggesting that the increment in RSNA is relatively small and not always statistically detectable. Unlike in women, no longitudinal studies have been published, but preliminary observations suggest that pregnancy produces a progressive increase in LSNA in rats, as in women (Fig. 3.2).

Mechanisms of increased basal SNA during pregnancy

Brain sites and neurocircuitry underlying increased basal sympathoexcitation during pregnancy

Only limited information is available concerning the brain nuclei that drive the elevated SNA induced by pregnancy. Nevertheless, the hypothalamic paraventricular nucleus (PVN) is clearly one such site. In nonpregnant female and male rats, the PVN is not significantly involved in supporting ongoing sympathetic activity (Dampney et al., 2018), due largely to the substantial tonic inhibition conferred by multiple inputs, including gamma aminobutyric acid (GABA), nitric oxide, and neuropeptide Y (NPY). In contrast, nonspecific blockade of the PVN (with the GABA_A agonist muscimol) decreases LSNA in anesthetized pregnant (but not nonpregnant) rats, indicating that the PVN supports increased basal sympathetic activity during pregnancy (Shi et al., 2015a). One mechanism that may contribute to the elevated basal activity of PVN presympathetic neurons is a reduction in tonic inhibition. Indeed, while inhibition of PVN ionotropic GABA_A receptors (Dampney et al., 2018) or NPY Y1 and/or Y5 receptors (Cassaglia et al., 2014; Shi et al., 2017) increases SNA in males and nonpregnant females, reflecting this tonic inhibition, these blockers have no effect in pregnant animals; the tonic inhibition by GABA (Kvochina et al., 2009a; Page et al., 2011) and NPY (Shi et al., 2015a) inputs is decreased or lost. Moreover, pregnancy decreases the expression and activity of nitric oxide synthase in the PVN (Heesch et al., 2009). As PVN nitric oxide inhibits SNA by acting presynaptically to inhibit GABA release (Zhang and Patel, 1998), the parallel decreases in GABAergic tone and nitric oxide activity in pregnant rats may be linked.

Moreover, as PVN disinhibition via blockade of PVN GABA_A receptors or inhibitory neuromodulators, such as NPY and nitric oxide, unveils increased SNA drive in nonpregnant animals, PVN presympathetic neurons must also receive tonic excitatory inputs. Thus pregnancy may also elevate basal SNA via increased excitation of the PVN. One potential source of excitatory inputs is the subfornical organ (SFO), which may be activated by circulating hormones, such as AngII or relaxin (see later). Another site is the ArcN, since it projects heavily to the PVN, and ArcN blockade lowers LSNA in pregnant rats (Shi et al., 2015a). ArcN inhibitory NPY neurons and excitatory pro-opiomelanocortin (POMC) neurons, which release α-melanocyte stimulating hormone (α-MSH), converge onto PVN presympathetic neurons (Cassaglia et al., 2014). As suppression of tonic NPY inhibition is required before α-MSH can excite PVN presympathetic neurons (Shi et al., 2015b), and pregnancy decreases PVN NPY inhibition, we tested if α-MSH contributes to basal sympathetic tone. Indeed, blockade of PVN α-MSH MC3/4 receptors lowers SNA in pregnant but not nonpregnant rats (Shi et al., 2015a), indicating that ArcN POMC neurons are one source of excitation of PVN presympathetic neurons during pregnancy.

Thus current evidence supports a role for the PVN, SFO, and ArcN in the pregnancy-induced increases in basal SNA. We will now address possible factors that activate these sites.

Potential factors that activate central sympathetic regulatory regions during pregnancy

Gonadal steroids

Multiple studies of the variations in MSNA during the menstrual cycle have been conducted; however, the results are conflicting. To address this, four labs coalesced their data (Carter et al., 2013) to test the hypothesis that the inconsistent results can be explained by variable and nonparallel surges in estrogen (E2) and progesterone (P), the opposing effects of E2 (sympathoinhibitory) and P (sympathoexcitatory) on SNA (Charkoudian, 2001), and the different phases of the cycle that had been probed. Indeed, the changes in MSNA were best (negatively) correlated with the changes in E2 and the changes in the E2-to-P ratio. Thus it appears that the anticipatory increase in MSNA that has been detected during the mid-luteal phase is due to an increase in progesterone relative to estrogen.

Given that pregnancy elicits rather sizable increases in both E2 and P, the potential contribution of these hormones to the increases in MSNA warrants consideration. Reyes et al. reported a significant direct correlation between E2 and MSNA (Reyes et al., 2018b); however, since E2 is sympathoinhibitory, this may reflect estrogen-induced vasodilation, which indirectly evokes increases in MSNA. Others report no relationship between E2 and MSNA or a weak relationship between P and MSNA (P=0.08) (Jarvis et al., 2012). However, no published studies have examined if the increment in MSNA is directly related to a change in the P-to-E2 ratio during pregnancy. In contrast to this hypothesis, the P-to-E2 ratio decreases during pregnancy (Chapman et al., 1998; Okada et al., 2015). Moreover, a reanalysis of our data (Okada et al., 2015) revealed that the increment in MSNA is not related to the changes in E2 or the E2-to-P ratio. Nevertheless, again, a weak relationship between ΔMSNA and ΔP was observed (P=0.08). This relationship may suggest a contribution of P; however, the counteracting effects of high E2 levels and the parallel increases in the progesterone metabolite and neurosteroid allopregnanolone, which also inhibits SNA (see later), counters this suggestion. Therefore other factors must be involved.

Metabolic hormones: Insulin and leptin

Pregnancy increases the levels of a myriad other hormones, including those that contribute to metabolism and the production of nutrients necessary for fetal development and growth. Two such hormones are insulin and leptin, which also act centrally to increase SNA. Plasma leptin levels increase in pregnant women (Hardie et al., 1997; Sattar et al., 1998; Franco-Sena et al., 2015) and rats (Herrera et al., 2000; Seeber et al., 2002), secondary to both excess adiposity and uterine production and release of leptin. Pregnancy induces insulin resistance in women (Stanley et al., 1998; Lain and Catalano, 2007), rats (Leturque et al., 1984; Rossi et al., 1993; Munoz et al., 1995), and rabbits (Daubert et al., 2007). In women, insulin resistance eventually leads to increments in fasting plasma insulin levels by the end of gestation (Lain and Catalano, 2007; Perichart-Perera et al., 2017; Benaim et al., 2019). In experimental animals, insulin levels are elevated in nonfasted and glucose-challenged experimental animals (Munoz et al., 1995). However, pentobarbital anesthetized or fasted, conscious pregnant animals generally do not exhibit significant increases in plasma or brain insulin (Leturque et al., 1984; Daubert et al., 2007; Shi et al., 2019). Insulin and leptin act in the ArcN to increase SNA by suppressing tonic NPY inhibition and increasing α-MSH excitation in the PVN (Cassaglia et al., 2011, 2016; Ward et al., 2011; Shi and Brooks, 2015; Shi et al., 2015b), similarly to pregnancy. However, the sympathoexcitatory responses to intracerebroventricular (i.c.v.) insulin or leptin are completely eliminated in late pregnant rats, and blockade of ArcN insulin receptors (the site of action of insulin to increase SNA) fails to decrease LSNA (Shi et al., 2019). Collectively, these results indicate that neither hormone likely contributes to pregnancy-induced sympathoexcitation. Because sympathetic activation stimulates glucose uptake by muscle (Nonogaki, 2000), this central resistance to insulin and leptin, in parallel with systemic resistance, aids in the maintenance of sufficiently high glucose concentrations in plasma to ensure adequate delivery to the fetus.

Volume-retaining hormones (RAAS and vasopressin)

As shown in Fig. 3.1, the longitudinal profile of the increase in plasma volume and associated fluid-retaining hormones, such as the RAAS, are closely matched with the increases in SNA in both pregnant women and rats. Therefore a feasible hypothesis is that sympathoexcitatory hormones, such as AngII or aldosterone, contribute to pregnancy-induced sympathoexcitation. In support, the increase in MSNA in pregnant women has been found to be well correlated to the increases in direct renin and aldosterone (Jarvis et al., 2012). In women studied in the third trimester, MSNA was directly related to the increases in vasopressin (Charkoudian et al., 2017; Reyes et al., 2018b). As vasopressin is sympathoinhibitory, this relationship may indirectly reflect the actions of other volume-retaining hormones such as AngII or relaxin, both of which stimulate vasopressin secretion.

More direct evidence has been obtained in animal studies. Compared with nonpregnant females, pregnant animals are more dependent on AngII for maintenance of arterial pressure. Since the vasculature becomes resistant to AngII-induced vasoconstriction, this dependency likely includes a central mechanism. Indeed, Hines and Porter reported that while intravenous (i.v.) AngII increases blood pressure less in pregnant rats, the pressor response to i.c.v. AngII is greater, due in part to greater activation of the sympathetic nervous system (Hines and Porter, 1989). More importantly, O’Hagan et al. showed that either i.c.v. or combined i.c.v.+i.v. administration of losartan, an AT₁ receptor (AT1R) antagonist, shifted baroreflex relationships between arterial pressure and RSNA to the left more in pregnant compared with nonpregnant conscious rabbits (O’Hagan et al., 2001). As a result, RSNA was reduced at any given pressure after AT1R blockade in pregnant animals. However, the central site(s) of action of AngII to increase SNA are unclear. The SFO is a circumventricular organ devoid of a blood–brain barrier and a major site of action of circulating AngII. In pregnant rats, the pressor and sympathoexcitatory responses to nanoinjections of AngII into the SFO are markedly enhanced, and AT1R in the PVN are obligatory in this sympathoexcitatory pathway (Kvochina et al., 2009b). Pregnant rats also exhibit potentiated responses to nanoinjections of AngII into the PVN (Heesch et al., 2010) and ArcN (Shi and Brooks, unpublished observations). In parallel, AT1aR expression is increased in the SFO (Coldren et al., 2015), PVN (Heesch et al., 2010), and ArcN (Shi and Brooks, unpublished observation). Thus circulating AngII, through actions at the SFO, and also the brain RAS acting in the PVN and ArcN, may support elevated basal SNA during pregnancy, at least in experimental animals.

The sympathoexcitatory actions of AngII during pregnancy may be amplified by relaxin. Studies in both male (McKinley et al., 2004) and female rats (Coldren et al., 2015) have revealed that circulating relaxin increases SNA, through an AngII-dependent action in the SFO and subsequent activation of spinally projecting PVN-projecting neurons. Immunohistochemistry experiments revealed that relaxin receptor protein is present in the SFO of both nonpregnant and pregnant rats, and mRNA for relaxin in the SFO is not altered in pregnancy, raising the possibility that high circulating relaxin levels may contribute to pregnancy-induced sympathoexcitation. However, intracarotid artery relaxin infusion did not acutely activate the SFO or spinally projecting neurons in the PVN of term pregnant rats (Coldren et al., 2015). One possible explanation for lack of effect in pregnant rats could be downregulation of relaxin receptors due to chronic elevation of endogenous levels. However, different from most G-protein-coupled receptors, relaxin receptors are resistant to desensitization and responsiveness is maintained during long-term exposure to the agonist (Callander et al., 2009). For example, consistent with long-term actions of relaxin, overexpression of preprorelaxin in the region of the SFO in nonpregnant rats is associated with increased plasma vasopressin for at least 21 days (Silvertown et al., 2005), and endogenous relaxin contributes to central resetting of osmolality regulation throughout pregnancy (McKinley et al., 2004). Thus it is unlikely that CNS relaxin receptors become desensitized in pregnant rats. Alternatively, relaxin receptors in the SFO may be maximally occupied by high levels of endogenous relaxin, or downstream mechanisms, for example, upregulation of brain AT1R, may be already optimally activated by endogenous relaxin in term pregnant rats. Thus relaxin may be another hormone that acts centrally (in the SFO) to support increased SNA during pregnancy; however, additional experiments are required to substantiate this hypothesis.

PREGNANCY IMPAIRS BAROREFLEX CONTROL OF HR AND SNA

For the most part, hemodynamic and blood volume changes that occur during uncomplicated pregnancy (Fig. 3.1) are adaptive, contribute to optimal fetal development, and are well tolerated by pregnant women. However, one potentially deleterious occurrence is a profound decrease in the ability of the arterial baroreflex to compensate for hypotensive challenges. Compared with the nonpregnant state, pregnant women are more prone to orthostatic hypotension. Of greater concern is the fact that pregnancy is associated with a decreased ability to maintain cardiac output and peripheral resistance during blood loss (Clow et al., 2003). Substantial blood loss during delivery and the peripartum period, accompanied by severe hypotension, is a major contributor to maternal morbidity and mortality (Brooks et al., 2010a; Reyes et al., 2018a). Since the arterial baroreflex is an important feedback system for buffering changes in arterial pressure under a variety of physiologic challenges, numerous studies have focused on evaluating arterial baroreflex function in both normotensive and hypertensive pregnancy.

Early studies in anesthetized rabbits first noted that baroreflex-mediated peripheral vasoconstriction in response to arterial baroreceptor unloading (low carotid sinus pressure) was attenuated in pregnant compared with nonpregnant animals (Humphreys and Joels, 1974; Humphreys and Joels, 1982). Both animal and human studies have reported suppressed vascular responsiveness to alpha adrenergic agonists and decreased neurovascular transduction in pregnancy (Conrad and Russ, 1992; Jarvis et al., 2012; Fu, 2018; Reyes et al., 2018a; Spradley, 2019), which could contribute to attenuated baroreflex-mediated vasoconstriction. However, subsequent to the initial observations by Humphreys and Joels (1974, 1982) many studies have provided convincing evidence for an important neural component to pregnancy-associated suppression of baroreflex function.

The well-described brainstem pathway subserving arterial baroreflex function is shown in Fig. 3.3. In response to an increase in arterial pressure, the discharge of afferent fibers from peripheral baroreceptors is increased and second-order neurons in the nucleus tractus solitarii (NTS) are activated. Baroreceptor-sensitive NTS neurons project to and excite GABAergic interneurons in the caudal ventral lateral medulla (CVLM), which in turn project to and inhibit sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) (Dampney, 1994; Guyenet, 2006). Both presympathetic neurons in the RVLM and the arterial baroreceptors are active at baseline arterial blood pressure, which allows for reciprocal compensatory changes in efferent SNA to the heart and blood vessels in response to both increases (described earlier) and decreases in arterial blood pressure (baroreceptor unloading). Second-order neurons within the NTS also project to and excite cardiac vagal preganglionic neurons in the nucleus ambiguous, comprising the parasympathetic nervous system component for baroreflex control of HR (not shown).

Glutamate is the primary excitatory transmitter, and GABA is the primary inhibitory transmitter within the brain regions shown in Fig. 3.3. In addition to the baroreflex pathway through the CVLM, there are baroreflex-independent GABAergic projections primarily from the CVLM to the RVLM that inhibit sympathetic outflow and can influence overall reflex responses (Schreihofer and Guyenet, 2002; Guyenet, 2006).

In general, arterial baroreflex function in animals and humans adapts to changes in behavioral, psychologic, or physiologic conditions, such that the reflex continuously adjusts (resets) to accommodate the particular state and maintain appropriate buffering capacity of the reflex. For example, when baseline arterial pressure increases or decreases for periods as short as 5 min, both the baroreceptor and baroreflex function curves for control of SNA and HR shift toward the prevailing pressure, with no change in sensitivity to increments in arterial pressure. This parallel shift of arterial baroreflex function curves is termed peripheral pressure-dependent resetting and maintains buffering capacity over a broader range of baseline arterial pressures (Chapleau et al., 1989). Other examples of baroreflex resetting clearly involve a central nervous system (CNS) component. For example, during psychologic stress and exercise, “central command” from the cortex and forebrain contributes to resetting of the baroreflex (Dampney, 2016). In the case of exercise, afferent input from sensory receptors in the exercising muscle also plays a role. Arterial pressure, HR, and sympathetic outflow to nonexercising muscles increase progressively with increased exercise intensity, yet baroreflex sensitivity to increments in pressure is maintained due to a rightward shift of the curve toward elevated arterial pressure and an upward shift toward higher SNA (Ogoh et al., 2007; Mueller et al., 2017). Thus under a variety of states, the arterial baroreflex continues to regulate SNA but resets to accommodate the particular behavioral condition.

Studies in pregnant humans and experimental animals, using a variety of approaches, have documented depressed baroreflex control of multiple efferents, including HR, renal, splanchnic, and muscle SNA, and hormones such as vasopressin and ACTH/glucocorticoids (Fu and Levine, 2009; Brooks et al., 2010a; Reyes et al., 2018a; Shi et al., 2019). To evaluate the full range of arterial baroreflex responses, experiments in animal models infused vasoactive drugs to generate complete sigmoidal baroreflex relationships. Fig. 3.4 shows data from groups of conscious nonpregnant and pregnant rats demonstrating baroreflex control of HR (Brooks et al., 2010b) and RSNA (Masilamani and Heesch, 1997). To reduce variability in absolute nerve activity among animals, nerve activity for each animal is most often expressed as a percentage of the resting level (defined as 100%), and data is interpreted regarding the functional capacity of the baroreflex to compensate for perturbations around resting nerve activity. Three aspects of these curves are particularly affected in pregnancy: the baroreflex function curve is shifted to operate around the lower arterial pressure of pregnant rats; during hypotension the maximal increase above baseline for HR or SNA is blunted; and the sensitivity or gain (slope) of the curve around baseline arterial pressure is decreased. In general, responses to a hypertensive challenge appear to be well maintained or even augmented in pregnant animals (Fig. 3.4). Similar observations have been made for effects of pregnancy on baroreflex function curves in rabbits (O’Hagan et al., 2001; Daubert et al., 2007) and sheep (Lumbers and Yu, 1999). These data are consistent with previous reports in conscious rats (Conrad and Russ, 1992) and women (Leduc et al., 1991), indicating that bradycardia in response to i.v. vasoconstrictors is well maintained in term pregnancy. Pharmacologic blockade of the sympathetic or parasympathetic nervous systems has revealed that the sympathetic contribution to baroreflex-mediated tachycardia is particularly blunted in pregnant animals (Brooks et al., 1997; Lumbers and Yu, 1999).

Fig. 3.4. — Pregnancy impairs baroreflex control of heart rate (bpm = beats per min) and renal sympathetic nerve activity (RSNA) in conscious rats. Mean arterial pressure (MAP), heart rate, and RSNA were recorded over a range of arterial pressures obtained by infusions of phenylephrine or nitroprusside. Sigmoidal relationships between MAP and heart rate (top) or RSNA (bottom) were determined by fitting a four-parameter equation to data points, and curve parameters were statistically compared between late pregnant (P) and nonpregnant (NP) rats. The uppermost curve in each graph above represents data from NP rats. *Symbols on curves* labeled Base indicate baseline values of MAP, HR, and RSNA (100%). Major effects of pregnancy included increased baseline heart rate, decreased baseline arterial pressure, and decreased maximum heart rate and RSNA attained during hypotension (Max). In addition, pregnancy decreased the minimum RSNA achieved during hypertension (Min). Cardiac baroreflex gain was decreased and the slope (gain) of RSNA responses to decreases in arterial pressure was also decreased. * P < 0.05. Redrawn with permission from Brooks, V.L., Mulvaney, J.M., Azar, A.S., et al., 2010b. Pregnancy impairs baroreflex control of heart rate in rats: role of insulin sensitivity. Am J Physiol Regul Integr Comp Physiol 298, R419–R426; Masilamani, S., Heesch, C.M., 1997. Effects of pregnancy and progesterone metabolites on arterial baroreflex in conscious rats. Am J Physiol Regul Integr Comp Physiol 272, R924–R934.

As mentioned earlier, in reports from animal studies, SNA data is standardized (as a percentage of baseline or maximum nerve activity), and it is evident that pregnant animals exhibit less baroreflex excitatory reserve in response to hypotensive challenges (Crandall and Heesch, 1990; Brooks et al., 1995; Masilamani and Heesch, 1997; O’Hagan et al., 2001; Shi et al., 2019). However, standardization before comparisons does not take into account differences in baseline SNA between nonpregnant and pregnant animals. Therefore we replotted normalized data, from publications (Shi and Brooks, 2015; Shi et al., 2019) assessing baroreflex control of LSNA, SSNA, and RSNA in anesthetized pregnant and nonpregnant rats, as absolute SNA. As shown in Fig. 3.5, the basal levels of LSNA, RSNA, and SSNA are much closer to the maximal level elicited by baroreceptor unloading in pregnant rats. Moreover, the reduced baroreflex maximum seen with normalized data (Fig. 3.5) is likely due to the higher position of the baseline SNA on the curve since, if anything, the absolute level during hypotension is higher during pregnancy, at least for LSNA and SSNA. A study in women provides a similar interpretation. Passive postural changes from supine to head-up tilt were used to unload both low- (cardiopulmonary) and high-pressure (arterial) baroreceptors (Okada et al., 2015). Head-up tilt progressively increased absolute MSNA (bursts per minute), which was elevated at all postures in both early and late pregnant women, compared with nonpregnant controls (Fig. 3.6A). Expressed as change from supine values, the increase in MSNA due to tilt was attenuated in late pregnancy, likely due to high baseline (supine) values, closer to the baroreflex maximum (Fig. 3.6B).

Fig. 3.5. — Pregnancy increases basal SNA (in rats) closer to the baroreflex maximum. Comparison of baroreflex control of LSNA, SSNA, and RSNA expressed as raw SNA (results from individual experiments, each shown as different symbols; n=3–4 per group) and as % control [grouped data; n=8–10 (LSNA), n=4–5 (SSNA), n=5 (RSNA) in each group]. In the top two rows, baseline MAP and SNA are illustrated as *closed black symbols*. In the bottom row, points±SEM are the mean sigmoidal baroreflex parameters calculated as previously described (Shi and Brooks, 2015; Shi et al., 2019). Statistical comparisons (t-test) of the individual sigmoidal fit parameters between late pregnant (*top row*) and proestrus (*middle row*) revealed that in pregnant rats the baroreflex maximum for LSNA and SSNA was elevated (P < 0.05), the baroreflex minimum for LSNA and RSNA was suppressed (P < 0.05), and the baroreflex gain for LSNA and SSNA was increased (P < 0.05). In the bottom row, *P < 0.05, late pregnant (P20) lower than diestrus (Di) and proestrus (Pro); ^†P<0.05, proestrus (Pro) is higher than late pregnant (P20) and diestrus (Di). Data adapted from Shi, Z., Brooks, V.L., 2015. Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen. J Physiol 593, 1633–1647; Shi, Z., Hansen, K.M., Bullock, K.M., et al., 2019. Resistance to the sympathoexcitatory effects of insulin and leptin in late pregnant rats. J Physiol 597, 4087–4100.

Fig. 3.6. — Pregnancy increases basal MSNA (in women) closer to the maximum elicited by head-up tilt. Data adapted from Okada, Y., Best, S.A., Jarvis, S.S., et al., 2015. Asian women have attenuated sympathetic activation but enhanced renal–adrenal responses during pregnancy compared to Caucasian women. J Physiol 593, 1159–1168.

Most studies evaluating pregnancy-induced changes in baroreflex function in women have used noninvasive methods, including assessment of HR and blood pressure variability (spectral analysis) or spontaneous baroreflex sensitivity, and are restricted to the segment of baroreflex relationships close to basal values (Rang et al., 2002; Reyes et al., 2018a). Spectral analyses in both the time and frequency domains provide indirect indices related to the relative contributions of the sympathetic and parasympathetic nervous system, and most studies suggest that pregnancy is associated with a relative increase in sympathetic influences (Rang et al., 2002). Spontaneous cardiac baroreflex sensitivity is determined by identifying brief baroreflex-mediated ramps in which spontaneous fluctuations in systolic pressure are associated with simultaneous increases or decreases in pulse interval, reflecting primarily rapid reflex changes in parasympathetic nerve activity to the heart. Using these indirect methods, most (Voss et al., 2000; Silver et al., 2001; Kolovetsiou-Kreiner et al., 2018), but not all (Usselman et al., 2015a), studies in women, and also in experimental animals (Avery et al., 2001; Brooks et al., 2010b), suggest that pregnancy also depresses the parasympathetic component of cardiac baroreflex function. In addition, Usselman et al. (2015a) reported that late pregnancy was associated with decreased spontaneous baroreflex sensitivity for control of efferent MSNA in women. However, a limitation of evaluating spontaneous baroreflex gain based on natural fluctuations in arterial pressure and SNA around baseline is that the elevated baseline MSNA observed in pregnant women is also closer to the baroreflex maximum (Fig. 3.6). Thus, again, the reduced gain may reflect the falling slope of the relationship as it approaches the baroreflex maximum.

As discussed earlier, most experimental evidence suggests that baroreflex function is altered in late pregnancy and attenuated baroreflex compensation is especially evident during baroreceptor unloading (Figs. 3.4 and 3.6), where responses are dependent on removal of barosensitive GABAergic input to the RVLM (Fig. 3.3). Alterations of baroreflex function in pregnancy could be due to changes in afferent baroreceptor input or any number of CNS adaptions that might affect final sympathetic outflow. To test the integrity of efferent sympathetic pathways, responses to excitatory stimuli that do not rely on disinhibition of the RVLM to increase SNA, such as the exercise pressor reflex (isometric hand grip test) or the cold pressor test, have been evaluated in women (Rang et al., 2002). Responses to these tests appear to be preserved in pregnancy. The exercise pressor reflex is initiated by increased discharge in afferent fibers from exercising muscle that project to and activate presympathetic pathways in the brain, ultimately leading to increased glutamatergic excitation of the RVLM (Mueller et al., 2017). Increases in HR and BP following hand grip exercise are not different between pregnant and nonpregnant women (Rang et al., 2002). Extreme cold applied to a limb (cold pressor test) activates excitatory pain pathways, including synapses in the spinal cord and hypothalamic sites, and glutamatergic excitation of the RVLM contributes to the resultant sympathoexcitation (Nakamura et al., 2008). Elevations in MSNA during a cold pressor test are either unchanged (Schobel et al., 1996) or augmented (Usselman et al., 2015b) in term pregnant compared with nonpregnant women. Thus it appears that pregnancy differentially suppresses responses to baroreflex-mediated disinhibition while direct excitation of the RVLM is preserved.

Potential mechanisms for attenuated baroreflex function in pregnancy

Afferent limb

Studies in anesthetized rats in which discharge of the aortic depressor nerve was evaluated in response to brief incremental increases and decreases in arterial pressure revealed that the baroreceptor discharge curve was reset to operate around the lower baseline arterial pressure of pregnancy (peripheral pressure-dependent resetting). However, the change in afferent baroreceptor discharge in response to increments in pressure was preserved, so that baroreceptor sensitivity or gain was not different between nonpregnant and near term pregnant rats (Hines, 2000; Laiprasert et al., 2001). Thus preservation of arterial baroreceptor afferent gain around the prevailing arterial pressure suggests that the decrease in baroreflex sensitivity, and specifically attenuated increases in SNA during hypotension, that occurs during pregnancy must be due, to a large extent, to changes within the brain.

Descending pathways

Descending projections from higher brain centers have the potential to impact arterial baroreflex function by modulating neuronal activity at the brainstem sites. In this regard, hypothalamic nuclei, such as the PVN, have reciprocal connections with the major brainstem nuclei that comprise the medullary baroreflex pathway (Guyenet, 2006; Card and Sved, 2011; Dampney et al., 2018). As discussed earlier, adaptations at the level of the SFO, PVN, and ArcN in the hypothalamus may contribute to increased baseline SNA in pregnant rats in part via suppression of tonic GABA and NPY inhibition. However, while in nonpregnant female rats blockade of GABA_A receptors in the PVN augments arterial baroreflex-mediated increases in HR in response to hypotension and maximum cardiac baroreflex gain is increased, in late pregnant rats disinhibition of the PVN only slightly improved cardiac baroreflex function (Page et al., 2011). These data suggest that there is less (not more) GABAergic restraint of the baroreflex in pregnancy and that GABAergic mechanisms in the PVN do not play a major role in the attenuation of baroreflex-mediated sympathoexcitation in pregnancy (Page et al., 2011). The circulating hormones insulin and leptin have CNS sympathoexcitatory effects (Shi et al., 2019), and, as discussed earlier, both are elevated in pregnancy (Kirwan et al., 2002; Trujillo et al., 2011). In nonpregnant rats (Pricher et al., 2008; Cassaglia et al., 2011; Li et al., 2013) and humans (Young et al., 2010), i.c.v. or i.v. insulin or leptin augment baroreflex-mediated tachycardia and sympathoexcitation during hypotension. However, late pregnant rats become resistant to the effects of i.c.v. insulin and leptin, such that baseline SNA is unchanged and baroreflex control of LSNA remains suppressed compared with nonpregnant controls (Shi et al., 2019). Whether a decrease in brain insulin or leptin concentrations or actions elicits parallel decreases in SNA baroreflex function is unknown. Nevertheless, i.c.v. infusion of insulin improved HR baroreflex gain (Azar and Brooks, 2011; Shi et al., 2019), although other baroreflex parameters were not altered, suggesting only a small contribution of reduced insulin action in the brain. Thus although hypothalamic mechanisms clearly alter control of SNA in nonpregnant rats, studies to date suggest that descending inputs from the hypothalamus are not major contributors to attenuated arterial baroreflex-mediated sympathoexcitation in pregnancy. Studies evaluating potential mechanisms related to the medullary baroreflex pathway are described next.

Medullary baroreflex pathway

To determine potential sites within the medullary baroreflex pathway that may be altered by pregnancy, Curtis et al. (1999) evaluated expression of Fos protein as a marker for neuronal activation in the brainstem of term pregnant compared with nonpregnant rats. In conscious rats, a sustained decrease in arterial blood pressure, to a level that would unload arterial baroreceptors and result in maximum baroreflex-mediated sympathoexcitation, resulted in increased Fos expression in the NTS, CVLM, and RVLM in both groups. However, only in the RVLM was the increase in Fos expression less in pregnant compared with nonpregnant rats. Interestingly, while both noncatecholaminergic and catecholaminergic (C1) cells in the RVLM contribute to sympathetic outflow (Schreihofer and Guyenet, 2000; Guyenet, 2006), the effects of pregnancy to suppress activation of RVLM neurons during hypotension was specific to the noncatecholaminergic neuronal phenotype in this region (Curtis et al., 1999). Since the RVLM provides excitatory input to sympathetic preganglionic neurons in the spinal cord, these results suggest that alterations at the level of the RVLM likely contribute to the attenuated baroreflex-mediated increases in SNA in pregnant rats (Fig. 3.3).

Increased inhibition in the RVLM

Determining the endogenous factors that result in decreased activation of presympathetic neurons in the RVLM of pregnant animals during hypotension presents a challenge, as pregnancy is associated with changes in a multitude of humoral and inflammatory factors, which could potentially influence excitability of presympathetic neurons in this region (Brooks et al., 2010a). As discussed earlier, one explanation for impaired responses in the RVLM is that the ongoing level of activity is closer to the maximum baroreflex-induced level. In addition, inhibitory influences may be increased. Before discussing potential factors, it is important to consider that sympathoexcitation due to baroreceptor unloading (decreased arterial pressure) is mediated by withdrawal of baseline GABAergic tone within the medullary baroreflex pathway (disinhibition) (Guyenet, 2006). The RVLM receives a substantial baroreflex-independent GABAergic input, a large portion of which originates in the CVLM (Schreihofer and Guyenet, 2002) (Fig. 3.3), although other GABAergic influences, including GABA intemeurons within the RVLM, may contribute (Schreihofer and Guyenet, 2002; Guyenet, 2006). Thus although the effect of pregnancy is manifested as blunted baroreflex-mediated increases in HR and SNA, it is possible that mechanisms unrelated to the traditional arterial baroreflex pathway could contribute to attenuated sympathoexcitation during hypotension.

Since the final sympathetic outflow emanating from the RVLM at any given time is determined by the balance of excitatory and inhibitory influences, either decreased baseline excitatory drive to barosensitive neurons or increased baseline baroreflex-independent inhibition could contribute to the observation of decreased activation of the RVLM at low arterial pressure in pregnant rats (Curtis et al., 1999). To test the hypothesis that the RVLM of pregnant rats is under greater tonic baroreflex-independent GABAergic inhibition, responses to bilateral blockade of GABA_A receptors in the RVLM were tested in anesthetized pregnant and nonpregnant rats in which the arterial baroreceptors had been surgically denervated. Blockade of GABA_A receptors in the RVLM with nanoinjection of bicuculline produced greater increases in mean arterial pressure and RSNA in pregnant compared with nonpregnant rats (Fig. 3.7) (Kvochina et al., 2007). Thus it appears that pregnancy is associated with augmented tonic GABAergic inhibition of the RVLM, and in the absence of this GABAergic tone, underlying excitatory influences are greater in pregnant rats. Endogenous AngII within the RVLM is excitatory (Allen et al., 2009), and prior blockade of AngII AT1Rs in the RVLM decreased responses to RVLM bicuculline in both groups. However, augmented responses to bicuculline persisted in pregnant rats (Fig. 3.7). Thus underlying excitatory influences in addition to AngII must contribute to observed differences in responses to RVLM GABA_A blockade between pregnant and nonpregnant rats.

Fig. 3.7. — Baroreflex-independent GABA_A inhibition of the rostral ventrolateral medulla (RVLM) is increased in late pregnant rats. In sinoaortic denervated rats, increases in mean arterial pressure (Δ MAP) and renal sympathetic nerve activity (Δ RSNA) in response to bilateral blockade of GABA_A receptors (bicuculline, Bic) in the RVLM was greater in P compared with NP rats. Prior blockade of AngII AT₁ receptors (L158,809; AT1X) in the RVLM attenuated responses to Bic, but differences between NP and P rats persisted. *P≤0.05, greater than in NP rats. ^†P≤0.05, main effect of AT1X. Modified with permission from Kvochina, L., Hasser, E.M., Heesch, C.M., 2007. Pregnancy increases baroreflex independent GABAergic inhibition of the RVLM in rats. Am J Physiol Regul Integr Comp Physiol 293, R2295–R2305.

Potential role of neurosteroid metabolite of progesterone

With regard to the mechanisms for increased GABA_A influence in the RVLM, it is possible that, independent of arterial baroreflex inputs, GABA release in the RVLM is greater in pregnant animals. However, neither the source of drive for nonbaroreflex GABAergic inputs to the RVLM nor the potential signal that might increase that input during pregnancy has been elucidated. Another possibility, which would not require increased GABAergic input to the RVLM, would be an increase in positive modulation and/or upregulation of GABA_A receptors within the RVLM so that the effectiveness of existing GABAergic inputs would be amplified in pregnancy. In vitro studies have found that the major metabolite of progesterone, 3α-hydroxy-dihydroprogesterone (3α-OH-DHP, also called allopregnanolone), binds stereospecifically to a unique site on the GABA_A receptor complex and serves as a potent endogenous positive modulator of CNS GABA_A receptors (Mody, 2005). In addition, longer-term exposure to 3α-OH-DHP preferentially increases expression of the GABA_A receptor δ subunit (Sanna et al., 2009). Tonic GABAergic inhibition is mediated mainly by extrasynaptic GABA_A receptors containing the δ subunit, which is the most important receptor subunit in conferring high sensitivity to 3α-OH-DHP in native GABA_A receptors (Mody, 2005; Belelli et al., 2006; Biggio et al., 2009; Maguire and Mody, 2009). Thus the major metabolite of progesterone has both rapid nongenomic effects and longer-term genomic effects, which would potentiate GABAergic inhibition.

Along with progesterone, plasma levels of the neurosteroid metabolite 3α-OH-DHP increase during pregnancy in women (Pennell et al., 2015) and rats (Biggio et al., 2009). 3α-OH-DHP is highly lipid soluble and thus circulating levels have access to the CNS. In addition, synthetic enzymes for 3α-OH-DHP are present within the brain, and it can be synthesized from circulating progesterone or de novo from cholesterol (Stoffel-Wagner, 2001). While circulating levels of 3α-OH-DHP increase in parallel with progesterone, 3α-OH-DHP levels in the brain continue to increase throughout pregnancy after progesterone levels have peaked (Concas et al., 1998). In fact, in certain brain regions, levels of 3α-OH-DHP are several fold higher than circulating levels, and local regulation of the synthetic enzymes for converting progesterone to 3α-OH-DHP within the brain appears to be a major factor in determining brain region, and even cell type specific, actions of this neurosteroid (Belelli and Lambert, 2005). Enzymes responsible for synthesis of 3α-OH-DHP from progesterone, 5α-reductase and 3α-OH steroid oxidoreductase, are present in the medulla (Khanna et al., 1995; Li et al., 1997), and ovarian hormones that are elevated in pregnancy can regulate 3α-OH-DHP synthesis in brain tissue (Mitev et al., 2003). Importantly, messenger RNA for 5α-reductase, the rate-limiting enzyme for synthesis of 3α-OH-DHP, is increased in the RVLM of term pregnant rats (Heesch and Burcks, 2009).

It has been proposed that elevated levels of 3α-OH-DHP in the brain in pregnancy ameliorate responses to stress (Brunton et al., 2014). In women, inadequate elevation of this neurosteroid (and/or the rapid decline postpartum) may contribute to perinatal depressive disorders (Brunton et al., 2014; MacKenzie and Maguire, 2014). In support of a role for the neurosteroid metabolite of progesterone in regulation of SNA, initial experiments demonstrated that i.v. administration of 3α-OH-DHP to either anesthetized (Heesch and Rogers, 1995) or conscious nonpregnant female rats (Masilamani and Heesch, 1997) suppressed arterial baroreflex-mediated sympathoexcitation, while having no effect on afferent baroreceptor discharge (Laiprasert et al., 2001). In these experiments, i.v. administered 3α-OH-DHP would have access to multiple CNS sites. Additional experiments assessed baroreflex function before and after nanoinjections of 3α-OH-DHP into major nuclei in the medullary baroreflex pathway. Nanoinjection of 3α-OH-DHP, but not the inactive isomer 3β-OH-DHP, into the RVLM decreased maximum sympathoexcitation due to baroreceptor unloading (Heesch, 2011) (Fig. 3.8), whereas nanoinjections into the NTS and CVLM were without effect (Brooks et al., 2010a). Thus, similar to the effects of pregnancy to specifically suppress activation of neurons in the RVLM during hypotension (Curtis et al., 1999), acute effects of the neurosteroid metabolite of progesterone to suppress baroreflex-mediated increases in SNA also appear to be specific to the RVLM.

Fig. 3.8. — In the RVLM the progesterone metabolite 3α-OH-DHP, but not the inactive isomer 3β-OH-DHP, attenuates arterial baroreflex sympathoexcitation. Baroreflex curves before (control) and 15 min after bilateral nanoinjection of either the α- or β-isomer of 3-OH-DHP into the RVLM of anesthetized rats were constructed using a four-parameter sigmoidal curve formula and the curve coefficients were compared. (A) Nanoinjection of the inactive isomer 3β-OH-DHP into the RVLM had no effect on arterial baroreflex function. (B) Within 15 min following bilateral nanoinjection of 3α-OH-DHP into the RVLM, baroreflex sympathoexcitation was attenuated (decreased maximum RSNA during hypotension). RSNA, renal sympathetic nerve activity; MAP, mean arterial pressure; filled symbols represent resting MAP for each curve; *compared with control curve. Adapted from Heesch, C.M., 2011. Neurosteroid modulation of arterial baroreflex function in the rostral ventrolateral medulla. Auton Neurosci 161, 28–33 with permission.

However, well maintained or slightly potentiated baroreflex-mediated sympathoinhibition in response to a hypertensive challenge has been observed in pregnant rats (Crandall and Heesch, 1990; Masilamani and Heesch, 1997; Shi et al., 2019) (Figs. 3.4 and 3.5). Since baroreflex-mediated sympathoinhibition is due to incremental increases in GABAergic input to the RVLM, positive modulation of GABA_A receptors by 3α-OH-DHP at the level of the RVLM would be consistent with enhanced baroreflex-mediated sympathoinhibition. Indeed, 3α-OH-DHP (but not 3β-OH-DHP), administered either intravenously or directly into the RVLM of nonpregnant female rats, decreased the pressure threshold for baroreflex-mediated inhibition of single-unit neuronal discharge in spinally projecting RVLM neurons (Laiprasert et al., 1998). These results suggest that sensitivity of RVLM neurons to endogenously released GABA is increased acutely by 3α-OH-DHP.

Taken together, experiments in nonpregnant female rats provide convincing evidence that exogenous administration of 3α-OH-DHP, the neurosteroid metabolite of progesterone, mimics the effects of pregnancy to suppress baroreflex-mediated sympathoexcitation during hypotension, while sympathoinhibition in response to increased blood pressure is preserved. In addition, the effects of circulating 3α-OH-DHP are likely through an action in the RVLM, since local administration of the neurosteroid into the RVLM, but not other brain regions, produced results similar to i.v. administration. The remaining question was whether elevated endogenous levels of this neurosteroid metabolite of progesterone in pregnancy contribute to attenuated baroreflex-mediated sympathoexcitation. If so, chronic inhibition of 3α-OH-DHP synthesis should restore sympathoexcitation during hypotension in pregnant rats. During the last trimester of pregnancy the rate-limiting enzyme for synthesis of 3α-OH-DHP, 5-alpha reductase, was inhibited by daily subcutaneous injections of finasteride, while control rats received subcutaneous saline. Similar to previous studies (Fig. 3.4), the major effect of pregnancy was suppression of maximum baroreflex-mediated sympathoexcitation, and this effect was reversed by chronic finasteride treatment (Phaup et al., 2013) (Fig. 3.9). Taken together, these studies suggest that, likely due to an action in the RVLM, increased endogenous 3α-OH-DHP contributes to the observed effects of pregnancy on baroreflex function.

Fig. 3.9. — Chronic blockade of 3α-OH-DHP synthesis with the 5α-reductase inhibitor finasteride restores baroreflex-mediated sympathoexcitation in conscious pregnant rats. Baroreflex function curves were constructed (similar to Fig. 3.6) in four groups: nonpregnant (NP) and late pregnant (P) rats treated during the last trimester of pregnancy with either saline (Sal) or finasteride (Fin) (n=5 each group). Maximum RSNA during hypotension is shown. In Sal-treated rats, pregnancy reduced baroreflex-mediated sympathoexcitation (*). Finasteride did not change baroreflex function in NP rats, but in P rats maximum RSNA during hypotension was restored to levels not different from those achieved in NP rats. ^†Pregnant rats: Fin > Sal, P < 0.05. Data from Phaup, J.G., Hasser, E.M., Heesch, C.M., 2013. The neurosteroid metabolite of progesterone, 3α-OH-dihydroprogesterone (3α-OH-DHP), is required for attenuated baroreflex mediated sympathoexcitation in pregnancy. FASEB J 27, 1118.38.

Potential mechanisms by which pregnancy increases basal SNA and induces sympathoexcitation, yet impairs responses to baroreceptor unloading

The review of literature earlier in the chapter indicates that multiple neural and humoral adaptations during pregnancy likely contribute to observed changes in control of sympathetic outflow. Although many questions remain, experimental evidence to date suggests that mechanisms responsible for maintaining elevated baseline SNA and direct activation of RVLM neurons and those responsible for attenuated baroreflex-mediated sympathoexcitation in pregnancy involve different CNS modalities. One possibility is that, separate from increases in SNA due to disinhibition of the RVLM through the arterial baroreflex, sympathoexcitatory pathways that do not include the RVLM could contribute to directly induced increases in SNA. In addition to excitatory projections to the RVLM, several brain regions, including the PVN, dorsal medial hypothalamus (DMH), and A5 catecholaminergic neurons in the pons, have monosynaptic glutamatergic projections directly to preganglionic neurons in the spinal cord and have been implicated in increased SNA under a variety of conditions (Guyenet, 2006; Card and Sved, 2011). Although there is a paucity of information on a role of these pathways in pregnancy, the PVN contributes to elevated baseline SNA in pregnant rats (Shi et al., 2015a), and it is plausible that a direct PVN to spinal cord pathway could be involved. Importantly, whether the RVLM contributes to or supports the increased basal SNA during pregnancy has not been tested directly. Second, the explanation may be related to different roles of presympathetic cell phenotypes within the RVLM. A series of experiments in male rats evaluated effects of selective lesion of spinally projecting catecholaminergic neurons and found that in C1-lesioned rats, the remaining noncatecholaminergic spinally projecting neurons in the RVLM maintained basal sympathetic tone and, although slightly attenuated, arterial baroreflex function was preserved. In contrast, active sympathoexcitation due to stimulation of the arterial chemoreflex or electrical stimulation of the RVLM was greatly reduced in the absence of the RVLM C1 neurons (Guyenet et al., 2001). Again, little information is available regarding pregnancy. However, during a hypotensive challenge, decreased activation of RVLM neurons in pregnant rats was specific to the noncatecholaminergic neuronal phenotype (Curtis et al., 1999). Noncatecholaminergic cells in the RVLM predominate in arterial baroreflex responses, and their activation during hypotension is limited in pregnancy, presumably related to tonic GABAergic inhibition due to modulation by the progesterone metabolite 3α-OH-DHP. In women, direct sympathoexcitation initiated by the exercise pressor reflex and the cold pressor test are not attenuated by pregnancy, and it is tempting to speculate that, similar to the prominent role of RVLM C1 neurons in direct sympathoexcitation in animals, responses requiring direct activation of the RVLM may primarily involve C1 cells in humans as well. A third possibility to consider is that absolute baseline SNA is elevated in pregnancy. While noncatecholaminergic neurons in the RVLM are sufficient to maintain baseline SNA in normal male rats (Guyenet et al., 2001), it is possible that in pregnancy both RVLM C1 and non-C1 neurons assume a greater role. If so, greater activation of C1 neurons in the RVLM could contribute to both increased baseline SNA and augmented responses to stimuli such as the cold pressor test (Usselman et al., 2015b), but a parallel elevation in non-C1 activity would bring SNA closer to the baroreflex maximum (which is suppressed by 3α-OH-DHP).

Other reflexes altered in pregnancy

Atrial volume reflex

In addition to the arterial baroreflex, there are other important reflexes that contribute to homeostatic control and are altered in pregnancy. In particular, stretch receptors in the right atrium have a critical role in blood volume regulation. Activation of these receptors results in a rather selective reflex inhibition of RSNA (Lovick et al., 1993; Yang and Coote, 2003). The central pathways mediating this reflex have not been fully delineated but include afferent projections from stretch receptors in the atria to the NTS and a critical synapse in the PVN (Lovick et al., 1993; Yang and Coote, 2003). At the level of the PVN, GABAergic intemeurons are activated and result in inhibition of other PVN neurons that directly or indirectly regulate renal sympathetic outflow (Deng and Kaufman, 1995; Yang and Coote, 2003). Similar to the arterial baroreflex, reflex responses to atrial stretch are blunted by pregnancy (Kaufman and Deng, 1993; Deng and Kaufman, 1995; Hines and Mifflin, 1995; Hines and Hodgson, 2000). However, different from arterial baroreceptor afferent input that is well maintained in pregnancy, in response to atrial stretch, discharge of the high-frequency subgroup of cardiac vagal afferent fibers is greatly reduced (Deng and Kaufman, 1995; Hines and Hodgson, 2000; Storey and Kaufman, 2004) and activation of neurons in the PVN is blunted (Deng and Kaufman, 1995). Thus depressed function of the atrial volume reflex may contribute to maintenance of the expanded blood volume in pregnancy. Interestingly, acute i.v. administration of the progesterone metabolite 3α-OH-DHP to nonpregnant female rats decreased activation of the PVN during atrial distension, mimicking the effects of pregnancy (Storey and Kaufman, 2004).

Arterial chemoreflex

Resting ventilation and responsiveness to hypoxia are increased in pregnant women (Moore et al., 1986; Usselman et al., 2015a). Experiments in cats verified increased ventilatory responses to hypoxia and further demonstrated that sensitivity of the carotid body chemoreceptors to incremental hypoxia was augmented in pregnancy (Hannhart et al., 1989). In male rats, hypoxic stimulation of carotid body chemoreceptors increases afferent discharge in the carotid sinus nerve and not only mediates increased ventilation but also increases efferent SNA (Guyenet, 2006). Although efferent SNA in response to hypoxia has not been evaluated in pregnant women or animals, it is possible that augmented chemoreflex function in pregnancy could contribute to the effects of pregnancy on control of SNA.

PREECLAMPSIA ELICITS FURTHER INCREASES IN SNA

Preeclampsia is clinically defined as new onset of hypertension with proteinuria and/or end-organ dysfunction after the 20th week of gestation in a previously normotensive woman (Davey and MacGillivray, 1988; Roberts et al., 2003). According to the latest definition, new-onset thrombocytopenia, renal insufficiency, neurologic complications, liver involvement, and fetal growth restriction may substitute for new-onset proteinuria (Tranquilli et al., 2014). This disorder affects approximately 5% of all pregnancies worldwide (Sibai et al., 2005; Hemandez-Diaz et al., 2009), and it is one of the leading causes of maternal and fetal morbidity and mortality (Lyall and Greer, 1996; Granger et al., 2001a, b; Panchal et al., 2001; Roberts et al., 2003). Despite the critical importance of the problem, therapy for preeclampsia has not changed substantially in over 50 years (Noris et al., 2005; Frishman et al., 2006). There is no definite cure other than delivery (Steegers et al., 2010). The primary reason for the lack of progress in therapy is the failure to identify key underlying mechanisms.

Preeclampsia and sympathetic overactivity

One global theory that has been proposed to explain the morbid nature of preeclampsia is that a hyperadrenergic state may be involved in the pathophysiology of the disorder (Schobel et al., 1996; Greenwood et al., 1998, 2003). In support of this notion, previous microneurographic studies have demonstrated greater resting MSNA in preeclamptic women compared with normotensive pregnant women toward the end of their gestation when clinical signs and symptoms of the complication most commonly become manifest (Schobel et al., 1996; Greenwood et al., 1998, 2001, 2003; Fischer et al., 2004). It is suggested that the increases in peripheral vascular resistance and blood pressure that characterize preeclampsia are mediated, at least in part, by a substantial increase in MSNA (Schobel et al., 1996). Indeed, animal work has indicated that reduced uterine perfusion pressure (RUPP), causing placental ischemia-induced hypertension (a rat model of human preeclampsia), involves adrenergic receptor signaling to promote increases in blood pressure (Spradley et al., 2018). Moreover, the sympatholytic therapy with methyldopa in women with preeclampsia has been found to decrease blood pressure through a reduction in central sympathetic outflow (Roberts and Redman, 1993). Sympathetic activity and blood pressure decrease in parallel after delivery in preeclamptic women, which is further suggestive of a neurogenic component in preeclampsia (Schobel et al., 1996).

The key question that must be addressed is whether sympathetic overactivity can be detected early in pregnancy, or whether it occurs only at term when maternal symptoms of preeclampsia most commonly become manifest. A prospective longitudinal study showed that throughout early (within 8 weeks of gestation) and late (between 32 and 36 weeks) pregnancy, as well as postpartum (6–10 weeks after delivery), resting MSNA was markedly augmented in women who developed hypertension at term (Badrov et al., 2019). These results indicate sympathetic overactivity may be a biomarker for predicting the development of preeclampsia and other gestational hypertensive disorders. However, some researchers have proposed that preeclampsia manifests only when both sympathetic overactivity and impaired vasodilatory function occur (Fischer et al., 2004). Whether this is true or not remains to be determined. Interestingly, the magnitude of sympathetic overactivity recorded as multiunit MSNA during late pregnancy was found to be similar in women with preeclampsia and in those with gestational hypertension, but single-unit MSNA was lower in preeclamptic women, suggesting the central mechanisms for sympathetic overactivity underlying these two conditions may be different (Greenwood et al., 2003).

Potential mechanisms for sympathetic overactivity in preeclampsia

The pathophysiologic mechanisms for sympathetic overactivity in preeclampsia are unknown. While there is nothing definitive or proven, the following possibilities may be considered: these include, but are not limited to, impaired sympathetic baroreflex function, overactivation of the RAAS, increased maternal AngII type I receptor agonistic autoantibody (AT₁R-AA), inflammation, activation of the endothelin system, and dysregulation of the natriuretic peptide system (Fig. 3.10).

Fig. 3.10. — Proposed pathophysiologic mechanisms for sympathetic overactivity in preeclampsia. Aldo, aldosterone; Ang-(1–7), angiotensin-(1–7); AngII, angiotensin II; AT₁R-AA, angiotensin II type I receptor agonistic autoantibody; BRS, baroreflex sensitivity; ET-1, endothelin-1; HPA, the hypothalamic–pituitary–adrenal axis; PIGF, placental growth factor; RAAS, renin–angiotensin℃aldosterone system; ROS, reactive oxygen species; RSA, renin–angiotensin system; sFlt-1, soluble fins-like tyrosine kinase 1; VEGF, vascular endothelial growth factor.

The sympathetic baroreflex

Sympathetic overactivity in preeclampsia could be attributed to an impairment of baroreflex function (e.g., reduced sympathetic baroreflex sensitivity), leading to a decrease in baroreflex-mediated inhibitory restraint on central sympathetic outflow (Ekholm et al., 1994; Schobel et al., 1996). Surprisingly, there is little information available about the sympathetic baroreflex even during normal (uncomplicated) pregnancy in humans. One cross-sectional study found that sympathetic baroreflex sensitivity was reduced in normotensive pregnant women during the third trimester of gestation relative to healthy nonpregnant women despite the fact that blood pressure was similar between the groups (Usselman et al., 2015a). In contrast, a longitudinal case report involving a series of repeated measures over time showed that although sympathetic baroreflex sensitivity was variable throughout gestation, the majority of the values indicated a greater sensitivity in normal pregnancy compared with prepregnancy level (Hissen et al., 2017). These preliminary observations need to be confirmed in more pregnant women.

Animal research demonstrated that baroreflex control of RSNA was reset to a higher blood pressure level while the sensitivity of the sympathetic baroreflex (the slope of the baroreflex curve) was not different between pregnant rats with RUPP compared with normal pregnant rats (Hines et al., 2007) (Fig. 3.11). Whether this is true even in humans is unknown. However, MSNA responses to physiologic stimulations such as the Valsalva maneuver, a cold pressor test, and handgrip exercise were found to be similar in women with preeclampsia vs women with normotensive pregnancies (Schobel et al., 1996; Greenwood et al., 1998). These results indicate that baroreflex control of SNA may be intact in preeclampsia. Future studies should consider direct measurement of sympathetic baroreflex function in preeclamptic women.

Fig. 3.11. — The sympathetic baroreflex curves illustrating the relationship between mean arterial pressure and renal sympathetic nerve activity in nonpregnant virgin rats, normal pregnant sham-operated rats, and pregnant rats with reduced uterine perfusion. *Filled circles* represent the resting mean arterial pressure for each group. Adapted with permission from Hines, T., Beauchamp, D., Rice, C., 2007. Baroreflex control of sympathetic nerve activity in hypertensive pregnant rats with reduced uterine perfusion. Hypertens Pregnancy 26, 303–314.

RAAS

Normal pregnancy is associated with activation of the RAAS, which allows an aldosterone-dependent blood volume expansion (Verdonk et al., 2014). Upregulations of AngII and aldosterone concentrations elicited by the RAAS activation were found to increase MSNA in non-pregnant and pregnant individuals (Matsukawa et al., 1991; Kontak et al., 2010; Jarvis et al., 2012). However, women with preeclampsia display suppression of the RAAS and a reduction in aldosterone concentration (Brown et al., 1994, 1997; Verdonk et al., 2014), indicating the RAAS is not a contributing factor for sympathetic overactivity. These findings also suggest that the RAAS may not be the cause of hypertension in preeclampsia, but rather that its suppression may be the consequence of increased blood pressure (Powe et al., 2011; Saleh et al., 2016). Other possible mechanisms for the suppressed RAAS in preeclampsia may include, but are not limited to, increased levels of atrial natriuretic peptide (ANP), a decrease in vascular endothelial growth factor (VEGF), and an increase in endothelin-1 (ET-1) (Gennari-Moser et al., 2013; Verdonk et al., 2014, 2015; Volpe et al., 2014). It is likely that the suppressed RAAS is counter-intuitive in preeclampsia, given the reduced circulating volume in this disorder (Saleh et al., 2016).

Ang-(1–7) is a bioactive component of the RAAS, which has depressor, vasodilatory, and antihypertensive actions (Brosnihan et al., 2003; Valdes et al., 2006; Yamaleyeva et al., 2014). Animal studies have shown that augmentation of central Ang-(1–7) inhibits sympathetic outflow (Gironacci et al., 2004; Kar et al., 2011; Yu et al., 2019). The plasma level of Ang-(1–7) was found to increase by 51% in normotensive pregnant women, but it was significantly decreased in preeclamptic women (Merrill et al., 2002; Chen et al., 2019). Thus the decrease in Ang-(1–7) might contribute, in part, to sympathetic overactivity in preeclampsia.

AT₁R-AA

Preeclampsia could be accompanied by the presence of a maternal circulating AT₁R-AA (Wallukat et al., 1999; Siddiqui et al., 2010). A meta-analysis has concluded that AT₁R-AA positivity may be a valuable indicator for poorer prognosis in preeclampsia (Lei et al., 2016). In contrast, some studies found no difference in AT₁R-AA levels throughout gestation in both women with preeclampsia and women with normotensive pregnancies (Aggarwal et al., 2017). The reasons behind these contradictory results are unclear. More research is needed to confirm the findings of Aggarwal et al. (2017).

AT₁R-AA is functionally similar to AngII, and the latter could increase SNA through the AT₁Rs in the CNS (Stein et al., 1984; Dechend et al., 2000, 2004, 2005, 2006; Ruzicka et al., 2013). Yet, there has been no evidence showing a direct central effect of AT₁R-AA on sympathetic activity in animals or humans. Nonetheless, AT₁R-AA might cause sympathetic overactivity through other possible mechanisms or indirect pathways. For instance, it was found that AT₁R-AA increased the production of reactive oxygen species and decreased the bioavailability of nitric oxide through activation of the AT1Rs in the peripheral vasculature and the CNS (Dechend et al., 2003; Ariza et al., 2007; Parrish et al., 2011; Brewer et al., 2013), which might lead to overactivation of the sympathetic nervous system (Puzserova and Bernatova, 2016; Yan et al., 2017; Haspula and Clark, 2018). In addition, AT₁R-AA was reported to upregulate soluble fms-like tyrosine kinase 1 (sFlt-1) and inactivate VEGF (Zhou et al., 2008), both of which might result in an increase in ET-1 (LaMarca et al., 2009). Previous studies have indicated a sympathoexcitatory effect of endogenous ET-1 in humans (Bruno et al., 2011). AT₁R-AA is associated with increased AngII sensitivity (Wallukat et al., 1999, 2003; Herse et al., 2009; LaMarca et al., 2009; Parrish et al., 2011), leading to augmentation of vasoconstrictor responsiveness.

Inflammation

Preeclampsia is associated with increased proinflammatory, relative to antiinflammatory, cytokines (Catarino et al., 2012; Kucuk et al., 2012; Southcombe et al., 2015; Kalagiri et al., 2016; Cornelius et al., 2019; Zak and Soucek, 2019). Studies in RUPP rats strongly implicate inflammatory processes in the pathogenesis of preeclampsia. For example, adoptive transfer of proinflammatory immune cells into normal pregnant rats replicates many of the features of preeclampsia, including an elevation in proinflammatory cytokines (Harmon et al., 2016; Cornelius et al., 2019). In rats, proinflammatory cytokines act within the SFO and hypothalamus to cause centrally mediated sympathetic overactivity by activating the brain renin–angiotensin system and the hypothalamic–pituitary–adrenal axis in hypertension and other cardiovascular abnormalities (Kang et al., 2008; Wei et al., 2015, 2018; Yu et al., 2017, 2018; Haspula and Clark, 2018). Whether sympathetic overactivity in preeclamptic women is attributed to the increases in proinflammatory cytokines needs to be investigated.

The endothelin system

The endothelin system plays an important role in cardiovascular homeostasis through its direct vascular effects, as well as neural regulation of vasomotor sympathetic tone (Mosqueda-Garcia et al., 1993). ET-1 is a vasoconstrictor and mitogenic peptide produced by endothelial cells (Bruno et al., 2011). Animal research suggests that ET-1 can stimulate the sympathetic nervous system by activation of the subtype A receptor (Gulati et al., 1997; Rossi et al., 1997, 2008; Mortensen, 1999; Nakamura et al., 1999; Rossi and Maliszewska-Scislo, 2008). It also acts in carotid bodies and cervical superior and nodose ganglia, causing changes in the baroreflex control of SNA (Mortensen, 1999). Microneurographic studies in (nonpregnant) humans found that endogenous ET-1 had a sympathoexcitatory effect, especially in individuals with hypertension (Bruno et al., 2011).

Compared with women with normotensive pregnancies, those with preeclampsia were found to have a two- to threefold rise of circulating ET-1; in addition, there was a positive correlation between the severity of preeclampsia and the level of ET-1 (Bernardi et al., 2008; Aggarwal et al., 2012; Verdonk et al., 2015; Saleh et al., 2016). However, so far, there has been no direct evidence showing the impact of ET-1 on SNA in preeclamptic women. Verdonk et al. suggested that ET-1 is not only an independent determinant of both the blood pressure increase and proteinuria in preeclampsia but also a renin suppressor (Verdonk et al., 2015).

The natriuretic peptide system

The natriuretic peptide system, along with the sympathetic nervous system, has been recognized as a key neural–humoral system to maintain overall cardiovascular homeostasis (Volpe, 2014). In general, the beneficial physiologic actions of the natriuretic peptide system are counter-regulatory to those of the sympathetic nervous system (Volpe et al., 1987, 1988; Luchner and Schunkert, 2004). Natriuretic peptides interfere with autonomic and baroreflex control of the circulation, leading to sympathetic inhibition and/or parasympathetic activation (Volpe et al., 1987, 1988; Floras, 1990; Luchner and Schunkert, 2004).

As preeclampsia is associated with sympathetic overactivity, a decrease in maternal natriuretic peptide level would be expected in preeclamptic women. Surprisingly, many studies have shown increased plasma levels of ANP and brain natriuretic peptide (BNP) in preeclampsia (Itoh et al., 1993; Furuhashi et al., 1994; Stepan et al., 1999; Borghi et al., 2000; Tihtonen et al., 2007; Ringholm et al., 2011; Giannubilo et al., 2017), which may be attributed to the strain on the heart caused by high afterload rather than the function of the heart expressed as stroke index or cardiac index (Tihtonen et al., 2007). It is suggested that ANP and BNP may be rather a sequel to preeclamptic pathophysiologic changes and not play an important role as the etiological factor of preeclampsia (Furuhashi et al., 1994). It is possible that increased maternal ANP and BNP levels are a compensatory response to sympathetic overactivity and augmented vasoconstriction and may contribute to the suppressed RAAS in preeclampsia.

Research has demonstrated that the placenta released neprilysin, a widely expressed membrane-bound metalloprotease that binds and cleaves a variety of peptides, including vasodilators, natriuretics, and diuretics, is increased in preeclampsia (Gill et al., 2019), presumably due to the increases in ANP and BNP levels.

Corin is a transmembrane protease discovered in the heart where it converts pro-ANP to active ANP (Yan et al., 1999; Li et al., 2017). Its expression has also been detected in the pregnant uterus, which appears to play an important role in promoting trophoblast invasion and spiral artery remodeling (Cui et al., 2012). New research implies that corin may be involved in the pathogenesis of preeclampsia and other hypertensive disorders in pregnancy (Cui et al., 2012; Kaitu’u-Lino et al., 2013; Khalil et al., 2015; Liu et al., 2015; Miyazaki et al., 2016; Gu et al., 2018; Badrov et al., 2019). It was found that uterine Corin messenger RNA and protein levels were significantly lower, while plasma corin content was considerably higher in preeclamptic women compared with non-pregnant or normotensive pregnant women (Cui et al., 2012). It is possible that increased corin content in the blood, which is probably derived from the heart, is a compensatory response to the decreased corin expression in the uterus and/or to the increase in blood pressure in women with preeclampsia. A prospective longitudinal study showed that the change in circulating blood corin from early to late pregnancy was significantly greater in women who developed hypertension at term compared with those who had normotensive pregnancies (Badrov et al., 2019). More importantly, changes in corin from early to late pregnancy were related to blood pressure in late pregnancy, while MSNA in early pregnancy was related to changes in corin from early to late pregnancy (Badrov et al., 2019) (Fig. 3.12). It may be that the greater increase in maternal corin content in women who had hypertension at term is an adaptive response to the further increase in sympathetic activity and oncoming high blood pressure. Conversely, the greater increase in corin might contribute, at least in part, to sympathetic overactivity and, thereby, the development of preeclampsia.

Fig. 3.12. — Relationship between mean arterial pressure in late pregnancy and the change in corin from early to late pregnancy (A), and between the change in corin and muscle sympathetic nerve activity in early pregnancy (B), in low-risk normal pregnancy (LR-NP), high-risk normal pregnancy (HR-NP), and women who developed gestational hypertensive disorders (GHD). Adapted with permission from Badrov, M.B., Park, S. Y., Yoo, J.K., et al., 2019. Role of corin in blood pressure regulation in normotensive and hypertensive pregnancy. Hypertension 73, 432–439.

SUMMARY AND FUTURE DIRECTIONS

Normal pregnancy increases basal SNA, which is homeostatically appropriate, but impairs baroreflex control of HR and SNA, which can be harmful. Pregnancy-induced hypertensive disorders evoke even greater elevations in SNA, which likely contribute to the hypertensive state. Only limited information is available concerning the mechanisms. At term, the PVN and ArcN are two hypothalamic nuclei that support the basal sympathoexcitation. In normal pregnancy, increased AngII, by binding to AT1R, acts centrally to support elevated basal SNA. The SFO, ArcN, and PVN are likely (but unproven) targets of the activated RAAS. However, no definitive mechanisms for exaggerated sympathoexcitation that occurs with pregnancy-induced hypertensive disorders have been identified. In addition, normal pregnancy clearly induces increased GABAergic inhibition of the RVLM, and accumulated evidence supports a major role for the locally increased production and actions of 3α-OH-DHP as one mechanism. A consequence is suppression of baroreflex function. The ultimate level of basal SNA is determined by the integration of all excitatory and inhibitory inputs; the clearly apparent increases in SNA suggest that excitatory influences predominate in the RVLM, but this possibility requires direct experimentation.

Thus while some progress has been made in our understanding of the mechanisms by which normal and hypertensive pregnancy alters SNA, HR, and control of SNA and HR, even more remains to be established. This is a challenging quest because the homeostatic changes in normal pregnancy, and the pathophysiologic impact of preeclampsia, are complex and also because the study of pregnant women often precludes direct experimentation. Nevertheless, the following are future areas of research:

The degree of basal sympathoexcitation is greater in normal and hypertensive pregnancy than many other physiologic and pathophysiologic states, suggesting that factors besides the RAAS contribute. Other potential hormonal or nonhormonal factors that have not been directly investigated include aldosterone, progesterone, inflammation (cytokines), and endothelin.
Similarly, the high SNA suggests that additional brain sites may contribute, such as the DMH and other CVOs.
The study of rodent preeclampsia models, such as the RUPP rat or mouse, may suggest testable hypotheses for hypertensive pregnancy-induced sympathoexcitation in women, especially given the advent of sophisticated approaches for select activation or inhibition of specific brain cell types, such as optogenetics, chemogenetics, and GCaMP6.
Experiments in rats have demonstrated profound effects of the neurosteroid metabolite of progesterone, 3α-OH-DHP, on control of RSNA. However, its effects on SNA in other circulatory beds remain to be evaluated. Even less is known about a potential role for 3α-OH-DHP in modulation of SNA in human pregnancy. Given its effects to dampen responses to stress, evaluation of 3α-OH-DHP levels and MSNA in studies in pregnant women could provide important insights.

ACKNOWLEDGMENTS

We gratefully acknowledge the technical assistance of Jennifer Wong and J. Glenn Phaup. This work was supported in part by NIH grants HL088552 (vlb), HL128181 (vlb), HL088184 (qf), HL142605 (qf), HL36245 (cmh), HL098602 (cmh), and AHA grants 13GRNT16990064 (qf) and 15POST23040042 (zs).

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PERMALINK

Adaptations in autonomic nervous system regulation in normal and hypertensive pregnancy

VIRGINIA L BROOKS

QI FU

ZHIGANG SHI

CHERYL M HEESCH

Abstract

INTRODUCTION

LONGITUDINAL CHANGES IN HEMODYNAMICS AND HORMONES

Fig. 3.1.

PREGNANCY INCREASES SNA

Fig. 3.2.

Mechanisms of increased basal SNA during pregnancy

Brain sites and neurocircuitry underlying increased basal sympathoexcitation during pregnancy

Potential factors that activate central sympathetic regulatory regions during pregnancy

Gonadal steroids

Metabolic hormones: Insulin and leptin

Volume-retaining hormones (RAAS and vasopressin)

PREGNANCY IMPAIRS BAROREFLEX CONTROL OF HR AND SNA

Fig. 3.3.

Fig. 3.4.

Fig. 3.5.

Fig. 3.6.

Potential mechanisms for attenuated baroreflex function in pregnancy

Afferent limb

Descending pathways

Medullary baroreflex pathway

Increased inhibition in the RVLM

Fig. 3.7.

Potential role of neurosteroid metabolite of progesterone

Fig. 3.8.

Fig. 3.9.

Potential mechanisms by which pregnancy increases basal SNA and induces sympathoexcitation, yet impairs responses to baroreceptor unloading

Other reflexes altered in pregnancy

Atrial volume reflex

Arterial chemoreflex

PREECLAMPSIA ELICITS FURTHER INCREASES IN SNA

Preeclampsia and sympathetic overactivity

Potential mechanisms for sympathetic overactivity in preeclampsia

Fig. 3.10.

The sympathetic baroreflex

Fig. 3.11.

RAAS

AT1R-AA

Inflammation

The endothelin system

The natriuretic peptide system

Fig. 3.12.

SUMMARY AND FUTURE DIRECTIONS

ACKNOWLEDGMENTS

References

ACTIONS

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