Sympathetic Cardiovascular Responses Research Articles

Orexinergic neurons contribute to autonomic cardiovascular regulation for locomotor exercise.

While the hypothalamic orexinergic nervous system is established as having a pivotal role in the long-term regulation of various organismic functions, including wakefulness, metabolism and hypertensive states, whether this system contributes to the rapid autonomic cardiovascular regulation during physical activity remains elusive. This study aimed to elucidate the role of the orexinergic nervous system in transmitting volitional motor signals, i.e. central command, to drive somatomotor and sympathetic cardiovascular responses. We first found that this system is activated by voluntary locomotor exercise as evidenced by an increased expression of Fos, a marker of neural activation, in the orexinergic neurons of Sprague-Dawley rats engaged in spontaneous wheel running. Next, using transgenic Orexin-Cre rats for optogenetic manipulation of orexinergic neurons, we found that optogenetic excitation of orexinergic neurons caused sympathoexcitation on a subsecond timescale under anaesthesia. In freely moving conscious rats, this excitatory stimulation rapidly elicited exploration-like behaviours, predominantly locomotor activity, along with pressor and tachycardiac responses. Meanwhile, optogenetic inhibition of orexinergic neurons during spontaneous wheel running immediately suppressed locomotor activities and blood pressure elevation without affecting basal cardiovascular homeostasis. Taken together, these findings demonstrate the essential role of the orexinergic nervous system in the central circuitry that transmits central command signals for locomotor exercise. This study not only offers insights into the brain circuit mechanisms precisely regulating autonomic cardiovascular systems during voluntary exercise but also likely contributes to our understanding of brain mechanisms underlying abnormal cardiovascular adjustments to exercise in pathological conditions, such as hypertension. KEY POINTS: The hypothalamic orexinergic nervous system plays various roles in the long-term regulation of autonomic and endocrine functions, as well as motivated behaviours. We present a novel, rapid role of the orexinergic nervous system, revealing its significance as a crucial substrate in the brain circuit mechanisms that coordinate somatomotor and autonomic cardiovascular controls for locomotor exercise. Our data demonstrate that orexinergic neurons relay volitional motor signals, playing a necessary and sufficient role in the autonomic cardiovascular regulation required for locomotor exercise in rats. The findings contribute to our understanding of how the brain precisely regulates autonomic cardiovascular systems during voluntary exercise, providing insights into the central neural mechanisms that enhance physical performance moment-by-moment during exercise.

A brainstem monosynaptic excitatory pathway that drives locomotor activities and sympathetic cardiovascular responses

Exercise including locomotion requires appropriate autonomic cardiovascular adjustments to meet the metabolic demands of contracting muscles, yet the functional brain architecture underlying these adjustments remains unknown. Here, we demonstrate brainstem circuitry that plays an essential role in relaying volitional motor signals, i.e., central command, to drive locomotor activities and sympathetic cardiovascular responses. Mesencephalic locomotor neurons in rats transmit central command-driven excitatory signals onto the rostral ventrolateral medulla at least partially via glutamatergic processes, to activate both somatomotor and sympathetic nervous systems. Optogenetic excitation of this monosynaptic pathway elicits locomotor and cardiovascular responses as seen during running exercise, whereas pathway inhibition suppresses the locomotor activities and blood pressure elevation during voluntary running without affecting basal cardiovascular homeostasis. These results demonstrate an important subcortical pathway that transmits central command signals, providing a key insight into the central circuit mechanism required for the physiological conditioning essential to maximize exercise performance.

The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow

Heart failure (HF) is associated with activation of various neurohumoral factors including the renin–angiotensin–aldosterone and sympathetic nervous systems. In HF patients, elevated sympathetic nerve activity (SNA) is reflected by increased whole body, as well as regional (e.g. cardiac and renal) noradrenaline spillover (Kaye et al. 1994; Petersson et al. 2005), and increased sympathetic nerve discharge (Leimbach et al. 1986). Importantly, the degree of sympathoexcitation predicts mortality in HF patients (Petersson et al. 2005). Consequently, an immense amount of research effort has been directed towards the identification of mechanisms and circuitry underlying elevated SNA in HF. Neurons of the hypothalamic paraventricular nucleus (PVH) regulate SNA in a variety of physiological conditions and pathophysiological states through mono- and polysynaptic projections to the medulla and spinal cord (Guyenet, 2006). Evidence from studies, largely conducted in anaesthetized rodents, suggests HF activates PVH neurons through a reduction in GABAergic function (Patel, 2000). A critical question is the extent to which PVH neurons contribute to elevated SNA in HF. In this issue of The Journal of Physiology, Ramchandra and colleagues (2013) provide novel data utilizing chronic SNA recordings in conscious sheep to address this important question. Interruption of PVH neurotransmission by radiofrequency ablation or neuronal inhibition by microinjection of glycine or the GABAA agonist muscimol failed to lower cardiac and/or renal SNA in both control and HF sheep. Furthermore, blockade of PVH GABAA receptors with injection of bicuculline increased cardiac SNA, mean arterial blood pressure and heart rate in control but not HF sheep. The absence of sympathetic-cardiovascular responses to GABAA receptor activation or blockade in HF versus control sheep confirms a reduced GABAergic function in the PVH. More importantly, these findings challenge the general notion that PVH neurons contribute to sympathoexcitation in HF. Several issues may explain the discrepancies between the present and past studies: (1) differences between anaesthetized versus conscious animals, (2) differences in the central nervous system circuitry/mechanisms between HF models (i.e. coronary ligation versus ventricular pacing), and (3) the possibility that PVH neurons contribute to the development, but not maintenance, of elevated SNA in HF. A second intriguing finding is the differential contribution of PVH neurons to cardiac and renal sympathoinhibitory responses to volume expansion. In conscious sheep, PVH inhibition with injection of the GABAA agonist muscimol reversed the renal, but not the cardiac, sympathoinhibition during intravenous infusion of gelofusine. At least two critical questions arise from these findings. First, PVH neurons abundantly express the vesicular glutamate transporter but are not GABAergic (e.g. GAD67 positive) (Stocker et al. 2006). If volume expansion reduces the discharge of spinally projecting PVH neurons (Lovick & Coote, 1988), why does further inhibition using muscimol reverse the sympathoinhibition? Second, how do PVH neurons differentially regulate SNA to various end organs? The notion that PVH neurons can selectively increase SNA to one organ but not to another has been reported previously (Deering & Coote, 2000; Ward et al. 2011). Therefore, are there distinct populations of PVH neurons that regulate renal versus cardiac versus muscle SNA? Do these neurons receive different anatomical and neurochemical inputs? Previous studies have utilized transneuronal viruses to map the neuronal circuitry associated with a specific end-organ, but limited data exist to demonstrate whether PVH and other central nuclei contain overlapping or distinct populations of neurons to permit differential regulation of SNA. The findings of Ramchandra and colleagues (2013) provide evidence against a role of PVH neurons in elevating SNA in HF but emphasize the ability of PVH neurons to differentially control sympathetic outflow to distinct end-organs. The present findings highlight our limited understanding of how many CNS structures are anatomically and neurochemically connected to coordinate sympathetic outflow to a variety of organs.

Abstract 414: Intrinsic Osmosensitivity of Neurons in the Organum Vasculosum of the Lamina Termialis is Mediated by Benzamil-Sensitive Channels

Neurons of the Organum Vasculosum of the Lamina Terminalis (OVLT) play a pivotal role in body fluid homeostasis and blood pressure regulation. Lesion of OVLT neurons severely disrupts drinking, antidiuretic hormone secretion, and sympathetic-cardiovascular responses to acute sodium loads. Importantly, OVLT lesions also lower blood pressure in several models of salt-sensitive hypertension. Similarly, intracerebroventricular administration of the non-voltage dependent channel blocker benzamil attenuates sympathetic-cardiovascular responses to acute sodium loads and salt-sensitive hypertension. Therefore, the purpose of the present study was two-fold: 1) to establish OVLT neurons are sensitive to physiological changes in osmolality, and 2) to identify whether benzamil-sensitive channels mediate the osmosensitivity of OVLT neurons. Whole-cell patch-clamp recordings were performed in OVLT neuronal slices of male Sprague-Dawley rats (250-350g). 71% (17/24) of OVLT neurons responded to increased bath osmolality by addition of mannitol (5-20 mOsm/L). There were no differences in basic electrophysiological properties (ie, input resistance, membrane capacitance, etc) between responsive and non-responsive neurons. Increases in bath osmoality produced dose-dependent decreases in membrane potential (5 mOsm: 5.0±0.63 mV, 10 mOsm: 6.1±1.24 mV, 15 mOsm: 12.4±2.1; n=5, P<0.05) and increases in firing rates (5 mOsm: 208±32%, 10 mOsm: 246±55%, 15 mOsm: 274±101%, 20 mOsm: 496±53%; n=5, P<0.05). Bath application of benzamil (0.5 uM) significantly attenuated the membrane depolarization (0.2±0.7 vs 5.3±0.4 mV) and increased firing rate (98±6% vs 219±20%) during a 10mOsm/L increase in bath osmolality. These findings suggest OVLT neurons are sensitive to physiological changes in osmolality, and the intrinsic sensitivity of OVLT neurons are mediated by benzamil-sensitive channels.

Brain angiotensin AT1 receptors as specific regulators of cardiovascular reactivity to acute psychoemotional stress

1. Cardiovascular reactivity, an abrupt rise in blood pressure (BP) and heart rate in response to psychoemotional stress, is a risk factor for heart disease. Pharmacological and molecular genetic studies suggest that brain angiotensin (Ang) II and AT(1) receptors are required for the normal expression of sympathetic cardiovascular responses to various psychological stressors. Moreover, overactivity of the brain AngII system may contribute to enhanced cardiovascular reactivity in hypertension. 2. Conversely, brain AT(1) receptors appear to be less important for the regulation of sympathetic cardiovascular responses to a range of stressors involving an immediate physiological threat (physical stressors) in animal models. 3. Apart from threatening events, appetitive stimuli can induce a distinct, central nervous system-mediated rise in BP. However, evidence indicates that brain AT(1) receptors are not essential for the regulation of cardiovascular arousal associated with positively motivated behaviour, such as anticipation and the consumption of palatable food. The role of central AT(1) receptors in regulating cardiovascular activation elicited by other types of appetitive stimuli remains to be determined. 4. Emerging evidence also indicates that brain AT(1) receptors play a limited role in the regulation of cardiovascular responses to non-emotional natural daily activities, sleep and exercise. 5. Collectively, these findings suggest that, with respect to cardiovascular arousal, central AT(1) receptors may be involved primarily in the regulation of the defence response. Therefore, these receptors could be a potential therapeutic target for selective attenuation of BP hyperreactivity to aversive stressors, without altering physiologically important cardiovascular adjustments to normal daily activities, sleep and exercise.

COLD PRESSOR TEST DEMONSTRATES RESIDUAL SYMPATHETIC CARDIOVASCULAR ACTIVATION IN FAMILIAL DYSAUTONOMIA

In familial dysautonomia (1713), i.e. Riley‐Day‐syndrome, sympathetic cardiovascular function, as well as afferent temperature and pain mediating neurons, are significantly reduced. Thus, it was questioned if cold pressor test (CPT), which normally enhances sympathetic outflow and induces peripheral vasoconstriction by the activation of thermo‐ and nociceptive system activation, could be used to assess sympathetic function in FD. To evaluate whether CPT can be used to assess sympathetic activation in FD, we performed CPT in 15 FD patients and IS controls. After a 35‐min resting period, participants immersed their right hand and arm up to the elbow into 0‐1°C cold water while we monitored heart rate (HR), respiration, beat‐to‐beat radial artery blood pressure (BP), and laser Doppler skin blood flow (SBF) at the right index finger pulp. From these measurements, heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low and high frequency (LF, HF) power spectra of the electrocardiogram (ECG). All participants perceived cold stimulation and indicated discomfort. In controls, SBF decreased and HR and BP increased rapidly upon CPT. After 60 s, SBF indicated secondary vasodilatation in six controls, BP rise attenuated and HR returned to baseline in all controls. In the patients, SBF remained unchanged, HR and BP increased significantly, but after 50‐60 s of CPT and changes were lower than in controls (p*LT0.05). RMSSD and CV decreased and LF increased significantly only in the controls. We conclude that CPT activates sympathetic HR and BP modulation despite impaired pain and temperature perception in FD patients. BP increase in the presence of almost unchanged SBF might be due to HR increase and to nociceptive arousal and emotionally induced catecholamine release as seen in emotional crises of FD patients. CPT assesses sympathetic cardiovascular responses independently from baroreflex function, which is compromised in FD.

Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia

In familial dysautonomia (FD), i.e. Riley–Day-syndrome, sympathetic cardiovascular function, as well as afferent temperature and pain mediating neurons, are significantly reduced. Thus, it was questioned if cold pressor test (CPT), which normally enhances sympathetic outflow and induces peripheral vasoconstriction by the activation of thermo- and nociceptive system activation, could be used to assess sympathetic function in FD. To evaluate whether CPT can be used to assess sympathetic activation in FD, we performed CPT in 15 FD patients and 18 controls. After a 35-min resting period, participants immersed their right hand and arm up to the elbow into 0–1 °C cold water while we monitored heart rate (HR), respiration, beat-to-beat radial artery blood pressure (BP), and laser Doppler skin blood flow (SBF) at the right index finger pulp. From these measurements, heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low and high frequency (LF, HF) power spectra of the electrocardiogram (ECG). All participants perceived cold stimulation and indicated discomfort. In controls, SBF decreased and HR and BP increased rapidly upon CPT. After 60 s, SBF indicated secondary vasodilatation in six controls, BP rise attenuated and HR returned to baseline in all controls. In the patients, SBF remained unchanged, HR and BP increased significantly, but after 50–60 s of CPT and changes were lower than in controls ( p<0.05). RMSSD and CV decreased and LF increased significantly only in the controls. We conclude that CPT activates sympathetic HR and BP modulation despite impaired pain and temperature perception in FD patients. BP increase in the presence of almost unchanged SBF might be due to HR increase and to nociceptive arousal and emotionally induced catecholamine release as seen in emotional crises of FD patients. CPT assesses sympathetic cardiovascular responses independently from baroreflex function, which is compromised in FD.

Chronic administration of oxprenolol and metoprolol attenuate sympathetic cardiovascular responses only in non-adrenalectomized pithed rats.

1. Oxprenolol and metoprolol (30 mg kg-1) were injected intraperitoneally (i.p.) for 1 day (acute treatment) and 6 weeks (chronic treatment) to Sprague-Dawley rats. 2. Increases of mean blood pressure and heart rate to noradrenaline (0.1-10 micrograms kg-1) and to electrical stimulation (0.5 msec, supramax V, 0.25-5 Hz) of the entire sympathetic outflow were measured in non-adrenalectomized (acute and chronic) and adrenalectomized (chronic) pithed rats. 3. Acute beta-adrenoceptor antagonist administration was without effect on mean blood pressure and heart rate increases to noradrenaline and electrical stimulation. 4. Chronic administration with oxprenolol significantly diminished the stimulation-induced increases of mean blood pressure and heart rate in non-adrenalectomized pithed rats. 5. Increases in heart rate, elicited by stimulation of the entire sympathetic outflow in non-adrenalectomized but not in adrenalectomized pithed rats, were decreased by metoprolol treatment. Both treatments were without effect on noradrenaline responses. 6. These results indicate that chronic beta-adrenoceptor antagonist treatment is associated with a reduction in the cardiovascular responses to sympathetic nerve-stimulation. However, this mechanism only operates when adrenomedullary adrenaline is present to facilitate the noradrenaline release through activation of presynaptic beta 2-adrenoceptors.

Effects of some antipsychotic drugs on cardiovascular catecholamine receptors in the rat.

1. Experiments were performed to determine the activity of four antipsychotic drugs on several catecholamine receptors that control the sympathetic cardiovascular responses in rats. 2. Chlorpromazine, thioridazine (0.03 and 0.1 mg kg-1) and haloperidol (0.3 and 1 mg kg-1) inhibited methoxamine-induced diastolic blood pressure increases in the pithed rat, whereas sulpiride (1 and 3 mg kg-1) was without effect. 3. Only sulpiride (3 mg kg-1) antagonized the pressor responses induced by xylazine. 4. Xylazine inhibited the heart rate increase induced by electrical stimulation of the spinal cord (C7-Th1) in the pithed rat. This effect was partially prevented by sulpiride (1 and 3 mg kg-1) and chlorpromazine (0.3 mg kg-1). A higher dose of chlorpromazine (1 mg kg-1) abolished the inhibitory effect of xylazine. 5. Apomorphine infusion inhibited the pressor responses induced by electrical stimulation (Th5-L4) in pithed rats. This effect was reversed by sulpiride (0.01, 0.03 and 0.1 mg kg-1) and partially antagonized by haloperidol (0.1 mg kg-1). 6. The depressor response to fenoldopam in anaesthetized rats was only inhibited by the higher dose of chlorpromazine and thioridazine (3 mg kg-1). 7. Our results suggest that, in the peripheral nervous system of the rat, haloperidol and sulpiride act as antagonists of DA2 receptors while chlorpromazine and thioridazine antagonized DA1 receptors. Furthermore, thioridazine and haloperidol show alpha 1-adrenoreceptor antagonist properties, whereas sulpiride antagonizes alpha 2-adrenoreceptors. Chlorpromazine shows mixed alpha 1/alpha 2-adrenoreceptor antagonism.

Pharmacology of agents acting on the renin-angiotensin system.

The renin-angiotensin system is the most important hormonal system in the control of blood pressure. It can be blocked at several steps in its reaction pathway. Angiotensin-converting enzyme, or kininase II, is responsible for catalysing the formation of vasoconstrictor angiotensin II as well as for the breakdown of the vasodilator bradykinin. With the advent of specific orally active angiotensin-converting enzyme inhibitors (captopril and enalapril) a practical and effective means of blocking angiotensin formation is now clinically available. ACE inhibitors are effective long-term therapy in patients with essential hypertension. They are particularly useful in the treatment of severe accelerated drug-resistant hypertension and renovascular hypertension, and the agents of choice for afterload reduction in severe congestive cardiac failure. They have several pharmacological advantages, important in anaesthetic practice, over other hypotensive agents. They have no central nervous or autonomic nervous system effects. Thus, patients being treated with ACE inhibitors retain normal sympathetic cardiovascular responses.