Priscila A. Cassaglia

Sympathetic nerve activity in the superior cervical ganglia increases in response to imposed increases in arterial pressure

Sympathetic vasoconstriction of cerebral vessels has been proposed to be a protective mechanism for the brain, limiting cerebral perfusion and microcirculatory pressure during transient increases in arterial pressure. To furnish direct neural evidence for this proposition, we aimed to develop a method for recording cerebral sympathetic nerve activity (SNA) from the superior cervical ganglion (SCG). We hypothesized that SNA recorded from the SCG increases during imposed hypertension, but not during hypotension. Lambs (n = 11) were anesthetized (alpha-chloralose, 20 mg.kg(-1).h(-1)) and ventilated. SNA was measured using 25-microm tungsten microelectrodes inserted into the SCG. Arterial blood pressure (AP) was pharmacologically raised (adrenaline, phenylephrine, or ANG II, 1-50 microg/kg iv), mechanically raised (intravascular balloon in the thoracic aorta), or lowered (sodium nitroprusside, 1-50 microg/kg iv). In response to adrenaline (n = 10), mean AP increased 135 +/- 10% from baseline (mean +/- SE), and the RMS value of SNA (Square Root of the Mean of the Squares, SNA(RMS)) increased 255 +/- 120%. In response to mechanically induced hypertension, mean AP increased 43 +/- 3%, and SNA(RMS) increased 53 +/- 13%. Generally, (9 of 10 animals), SNA(RMS) did not increase, as AP was lowered with sodium nitroprusside. Using a new model for direct recording of cerebral SNA from the SCG, we have demonstrated that SNA increases in response to large induced rises, but not falls, in AP. These findings furnish direct support for the proposed protective role for sympathetic nerves in the cerebral circulation.

Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats

Non‐technical summary  Though the pancreatic hormone insulin is known to act in the brain to increase sympathetic nerve activity and baroreflex control of sympathetic nerve activity, its specific site of action had yet to be identified. We show that a region in the hypothalamus, the arcuate nucleus, is the site at which insulins effects are initiated. This new information may lead to a greater understanding of the role of insulin in the brain in adverse cardiovascular complications, like hypertension and heart attacks, which are associated with insulin‐resistant states, such as obesity and diabetes.

Leptin Acts in the Forebrain to Differentially Influence Baroreflex Control of Lumbar, Renal, and Splanchnic Sympathetic Nerve Activity and Heart Rate

Although leptin is known to increase sympathetic nerve activity (SNA), we tested the hypothesis that leptin also enhances baroreflex control of SNA and heart rate (HR). Using &agr;-chloralose anesthetized male rats, mean arterial pressure (MAP), HR, lumbar SNA (LSNA), splanchnic SNA (SSNA), and renal SNA (RSNA) were recorded before and for 2 hours after lateral cerebroventricular leptin or artificial cerebrospinal fluid administration. Baroreflex function was assessed using a 4-parameter sigmoidal fit of HR and SNA responses to slow ramp (3–5 minutes) changes in MAP, induced by intravenous infusion of nitroprusside and phenylephrine. Leptin (3 &mgr;g) increased (P<0.05) basal LSNA, SSNA, RSNA, HR, and MAP, and the LSNA, SSNA, RSNA, and HR baroreflex maxima. Leptin also increased gain of baroreflex control of LSNA and RSNA, but not of SSNA or HR. The elevations in HR were eliminated by pretreatment with methscopalamine, to block parasympathetic nerve activity; however, after cardiac sympathetic blockade with atenolol, leptin still increased basal HR and MAP and the HR baroreflex maximum and minimum. Leptin (1.5 &mgr;g) also increased LSNA and enhanced LSNA baroreflex gain and maximum, but did not alter MAP, HR, or the HR baroreflex. Lateral cerebroventricular artificial cerebrospinal fluid had no effects. Finally, to test whether leptin acts in the brain stem, leptin (3 &mgr;g) was infused into the 4th ventricle; however, no significant changes were observed. In conclusion, leptin acts in the forebrain to differentially influence baroreflex control of LSNA, RSNA, SSNA, and HR, with the latter action mediated via suppression of parasympathetic nerve activity.

Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation

Neuropeptide Y (NPY) acts in the brain to decrease sympathetic nerve activity (SNA); however, the specific site is unknown. We identify the paraventricular nucleus of the hypothalamus (PVN) as a site of action, since nanoinjection of NPY into the PVN dose‐dependently decreases SNA, whereas PVN injection of NPY Y1 and Y5 receptor antagonists increases SNA. NPY may directly inhibit PVN presympathetic neurons, since these neurons express Y1 receptors and, in patch‐clamp experiments, are inhibited by NPY. Our data also indicate that identified PVN presympathetic neurons that are inhibited by NPY are also excited by α‐melanocyte‐stimulating hormone. These results identify endogenous PVN NPY as a novel and potent inhibitory neuromodulator that may contribute to changes in SNA that occur in states associated with altered energy balance, such as obesity and pregnancy.

Baroreflex Function in Females: Changes With the Reproductive Cycle and Pregnancy

This review briefly describes the changes in baroreflex function that occur during female reproductive life, specifically during the reproductive cycle and pregnancy. The sensitivity or gain of baroreflex control of heart rate and sympathetic activity fluctuates during the reproductive cycle, reaching a peak when gonadal hormone levels increase, during the follicular phase in women and proestrus in rats. The increase in baroreflex sensitivity (BRS) is likely mediated by estrogen because ovariectomy in rats eliminates the BRS increase, the cyclic profile of changes in BRS mirror the changes in estrogen, and estrogen acts in the brainstem to increase BRS. In contrast, pregnancy depresses both BRS and the maximal level of sympathetic activity and heart rate evoked by severe hypotension. The decrease in BRS may be mediated by a reduction in the actions of insulin in the arcuate nucleus to support the baroreflex. In addition, increased levels of the neurosteroid progesterone metabolite 3α-OH-DHP act downstream in the rostral ventrolateral medulla to suppress maximal baroreflex increases in sympathetic activity. Consequently, these changes in baroreflex function impair blood pressure regulation in the presence of hypotensive challenges such as orthostasis and hemorrhage, a common event during delivery. As a result, peripartum hemorrhage is a major cause of human maternal death.

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

It is well established that GABAergic inputs to the paraventricular nucleus of the hypothalamus (PVN) tonically suppress heart rate and the activity of several sympathetic nerves. However, whether GABA similarly inhibits PVN control of baroreflex function has not been previously investigated. To test this hypothesis, it was determined whether microinjection of the GABA(A) antagonist, bicuculline, into the PVN enhances the baroreflex in anesthetized female virgin rats. In addition, because GABAergic inhibition of PVN preautonomic neurons is decreased during pregnancy, it was also determined whether the effects of PVN bicuculline administration on baroreflex function were less in pregnant animals. In virgin rats, PVN microinjection of bicuculline increased (P < 0.05) baroreflex gain and maximum levels of heart rate (gain, from 1.6 ± 0.6 to 3.8 ± 1.3 bpm/mmHg; maximum, from 406 ± 18 to 475 ± 14 bpm) and of lumbar sympathetic nerve activity (gain from 2.6 ± 0.7 to 4.8 ± 1.6%/mmHg; maximum, 149 ± 32 to 273 ± 48%), indicating that PVN GABA normally suppresses baroreflex function. Pregnancy decreased heart rate baroreflex gain (pregnant, 0.9 ± 0.3 bpm/mmHg; virgin, 1.9 ± 0.2 bpm/mmHg; P < 0.05). Following PVN bicuculline administration in pregnant rats, smaller (P < 0.01) increments in baroreflex gain (pregnant, 0.6 ± 0.1 bpm/mmHg; virgin, 2.4 ± 0.9 bpm/mmHg) and maximum (pregnant, 33 ± 7 bpm; virgin, 75 ± 12 bpm; P < 0.05) were produced. Collectively, these data suggest that the PVN normally inhibits the baroreflex via tonic GABAergic inputs and that this inhibition is less during pregnancy.

Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats: Roles of Neuropeptide Y and α-Melanocyte–Stimulating Hormone

Pregnancy increases sympathetic nerve activity (SNA), but the mechanisms are unknown. Here, we investigated the contributions of the hypothalamic paraventricular and arcuate nuclei in &agr;-chloralose–anesthetized pregnant and nonpregnant rats. Baseline arterial pressure (AP) was lower, and heart rate (HR), lumbar sympathetic activity, and splanchnic SNA were higher in pregnant rats compared with nonpregnant rats. Inhibition of the paraventricular nucleus via bilateral muscimol nanoinjections decreased AP and HR more in pregnant rats than in nonpregnant rats and decreased lumbar SNA only in pregnant rats. Similarly, after arcuate muscimol nanoninjections, the decreases in AP, HR, and lumbar, renal, and splanchnic sympathetic nerve activities were greater in pregnant rats than in nonpregnant rats. Major arcuate neuronal groups that project to the paraventricular nucleus express inhibitory neuropeptide Y (NPY) and excitatory &agr;-melanocyte–stimulating hormone. Inhibition of paraventricular melanocortin 3/4 receptors with SHU9119 also decreased AP, HR, and lumbar SNA in pregnant rats but not in nonpregnant rats. Conversely, paraventricular nucleus NPY expression was reduced in pregnant animals, and although blockade of paraventricular NPY Y1 receptors increased AP, HR, and lumbar sympathetic activity in nonpregnant rats, it had no effects in pregnant rats. Yet, the sympathoinhibitory, depressor, and bradycardic effects of paraventricular NPY nanoinjections were similar between groups. In conclusion, the paraventricular and arcuate nuclei contribute to increased basal SNA during pregnancy, likely due in part to decreased tonic NPY inhibition and increased tonic &agr;-melanocyte–stimulating hormone excitation of presympathetic neurons in the paraventricular nucleus.

Insulin increases sympathetic nerve activity in part by suppression of tonic inhibitory neuropeptide Y inputs into the paraventricular nucleus in female rats.

Following binding to receptors in the arcuate nucleus (ArcN), insulin increases sympathetic nerve activity (SNA) and baroreflex control of SNA via a pathway that includes the paraventricular nucleus of the hypothalamus (PVN). Previous studies in males indicate that the sympathoexcitatory response is mediated by α-melanocyte stimulating hormone (α-MSH), which binds to PVN melanocortin type 3/4 receptors (MC3/4R). The present study was conducted in α-chloralose-anesthetized female rats to test the hypothesis that suppression of inhibitory neuropeptide Y (NPY) inputs to the PVN is also involved. In support of this, blockade of PVN NPY Y1 receptors with BIBO 3304 (NPY1x), ArcN insulin nanoinjections, and PVN NPY1x followed by ArcN insulin each increased lumbar SNA (LSNA) and its baroreflex regulation similarly. Moreover, prior PVN injections of NPY blocked the sympathoexcitatory effects of ArcN insulin. Finally, PVN nanoinjections of the MC3/4R inhibitor SHU9119 prevented both the acute (15 min) and longer, more slowly developing (60 min), increases in LSNA in response to ArcN insulin. In conclusion, in females, ArcN insulin increases LSNA, in part, by suppressing tonic PVN NPY inhibition, which unmasks excitatory α-MSH drive of LSNA. Moreover, the steadily increasing rise in LSNA induced by ArcN insulin is also dependent on PVN MC3/4R.

Autonomic Control During Pregnancy

Publisher Summary This chapter discusses how pregnancy activates the sympathetic nervous system and pregnancy impairs the baroreceptor reflex. In parallel to increases in fluid-retaining hormones, alterations in the autonomic nervous system accompany normal pregnancy. While pregnancy induces sympathoexcitation, simultaneously, basal parasympathetic tone decreases. Baroreflex dysfunction has been documented in several species besides humans, including rabbits, rats, goats, sheep, and dogs. While pregnancy could depress the function of any or all anatomical links within the baroreflex pathway, current evidence indicates that brain control is particularly impaired. Insulin resistance is a normal adaption of pregnancy that, by increasing circulating glucose levels, serves to enhance glucose availability into the fetus. Preeclampsia is a potentially fatal hypertensive disorder of pregnancy that is initiated by reduced placental perfusion. Increased sympathetic tone may contribute to the hypertension, since basal muscle sympathetic nerve activity is clearly increased above the levels observed in normal pregnant women. The changes in basal autonomic tone may counteract to some degree the profound vasodilation that is a hallmark of normal pregnancy.

Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats

Pregnancy increases sympathetic nerve activity (SNA), but the mechanisms are unknown. Here, we investigated the contributions of the hypothalamic paraventricular and arcuate nuclei in &agr;-chloralose–anesthetized pregnant and nonpregnant rats. Baseline arterial pressure (AP) was lower, and heart rate (HR), lumbar sympathetic activity, and splanchnic SNA were higher in pregnant rats compared with nonpregnant rats. Inhibition of the paraventricular nucleus via bilateral muscimol nanoinjections decreased AP and HR more in pregnant rats than in nonpregnant rats and decreased lumbar SNA only in pregnant rats. Similarly, after arcuate muscimol nanoninjections, the decreases in AP, HR, and lumbar, renal, and splanchnic sympathetic nerve activities were greater in pregnant rats than in nonpregnant rats. Major arcuate neuronal groups that project to the paraventricular nucleus express inhibitory neuropeptide Y (NPY) and excitatory &agr;-melanocyte–stimulating hormone. Inhibition of paraventricular melanocortin 3/4 receptors with SHU9119 also decreased AP, HR, and lumbar SNA in pregnant rats but not in nonpregnant rats. Conversely, paraventricular nucleus NPY expression was reduced in pregnant animals, and although blockade of paraventricular NPY Y1 receptors increased AP, HR, and lumbar sympathetic activity in nonpregnant rats, it had no effects in pregnant rats. Yet, the sympathoinhibitory, depressor, and bradycardic effects of paraventricular NPY nanoinjections were similar between groups. In conclusion, the paraventricular and arcuate nuclei contribute to increased basal SNA during pregnancy, likely due in part to decreased tonic NPY inhibition and increased tonic &agr;-melanocyte–stimulating hormone excitation of presympathetic neurons in the paraventricular nucleus.