Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a ß-adrenoceptor blocker (propranolol) to determine the role of ß-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min-1 , P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min-1 , P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min-1 , P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min-1  mmHg-1 , P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on ß-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by ß-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by ß-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

The sympathetic nervous system in heart failure with preserved ejection fraction.

The sympathetic nervous system (SNS) is a major mediator of cardiovascular physiology during exercise in healthy people. However, its role in heart failure with preserved ejection fraction (HFpEF), where exercise intolerance is a cardinal symptom, has remained relatively unexplored. The present review summarizes and critically explores the currently limited data on SNS changes in HFpEF patients with a particular emphasis on caveats of the data and the implications for its subsequent interpretation. While direct measurements of SNS activity in HFpEF patients is scarce, modest increases in resting levels of muscle sympathetic nerve activity are apparent, although this may be due to the co-morbidities associated with the syndrome rather than HFpEF per se. In addition, despite some evidence for dysfunctional sympathetic signaling in the heart, there is no clear evidence for elevated cardiac sympathetic nerve activity. The lack of a compelling prognostic benefit with use of ß-blockers in HFpEF patients also suggests a lack of sympathetic hyperactivity to the heart. Similarly, while renal and splanchnic denervation studies have been performed in HFpEF patients, there is no concrete evidence that the sympathetic nerves innervating these organs exhibit heightened activity. Taken together, the totality of data suggests limited evidence for elevated sympathetic nerve activity in HFpEF and that any SNS perturbations that do occur are not universal to all HFpEF patients. Finally, how the SNS responds during exertion in HFpEF patients remains unknown and requires urgent investigation.

Neural control of coronary artery blood flow by non-adrenergic and non-cholinergic mechanisms.

NEW FINDINGS: What is the topic of this review? How non-adrenergic, non-cholinergic neural mechanisms regulate coronary artery blood flow. What advances does it highlight? The main coronary arteries dynamically adapt to maintain adequate blood flow to the working myocardium. There is growing evidence for an important role of non-classic neurotransmitters in regulating coronary blood flow. This review highlights current evidence for non-adrenergic, non-cholinergic control of coronary artery blood flow and our understanding of the dynamics of this system. ABSTRACT: Blood flow through the coronary vasculature is essential to maintain myocardial function. As the metabolic demand of the heart increases, so does blood flow through the coronary arteries in a dynamic and adaptive manner. Several mechanisms, including local metabolic factors, mechanical forces and autonomic neural control, regulate coronary artery blood flow. To date, neural control has predominantly focused on the classical neurotransmitters of noradrenaline and acetylcholine. However, autonomic nerves, sympathetic, parasympathetic and sensory, release a variety of neurotransmitters that can directly affect the coronary vasculature. Reduced or altered coronary blood flow and autonomic imbalance are hallmarks of most cardiovascular diseases. Understanding the role of autonomic non-adrenergic, non-cholinergic cotransmitters in coronary blood flow regulation is fundamental to furthering our understanding of this vital system and developing novel targeted therapies.

Activation of the carotid body increases directly recorded cardiac sympathetic nerve activity and coronary blood flow in conscious sheep.

Activation of the carotid body (CB) using intracarotid potassium cyanide (KCN) injection increases coronary blood flow (CoBF). This increase in CoBF is considered to be mediated by co-activation of both the sympathetic and parasympathetic nerves to the heart. However, whether cardiac sympathetic nerve activity (cardiac SNA) actually increases during CB activation has not been determined previously. We hypothesized that activation of the CB would increase directly recorded cardiac SNA, which would cause coronary vasodilatation. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA and diaphragmatic electromyography (dEMG), flow probes to record CoBF and cardiac output, and a catheter to record arterial pressure. Intracarotid KCN injection was used to activate the CB. To eliminate the contribution of metabolic demand on coronary flow, the heart was paced at a constant rate during CB chemoreflex stimulation. Intracarotid KCN injection resulted in a significant increase in directly recorded cardiac SNA frequency (from 24 ± 2 to 40 ± 4 bursts/min; P < 0.05) as well as a dose-dependent increase in mean arterial pressure (79 ± 15 to 88 ± 14 mmHg; P < 0.01) and CoBF (75 ± 37 vs. 86 ± 42 mL/min; P < 0.05). The increase in CoBF and coronary vascular conductance to intracarotid KCN injection was abolished after propranolol infusion, suggesting that the increased cardiac SNA mediates coronary vasodilatation. The pressor response to activation of the CB was abolished by pretreatment with intravenous atropine, but there was no change in the coronary flow response. Our results indicate that CB activation increases directly recorded cardiac SNA, which mediates vasodilatation of the coronary vasculature.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin-angiotensin-aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.

Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure.

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α1-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%-40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min-1·mmHg-1) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α1-adrenoceptor stimulation.

Mechanisms underlying the increased cardiac norepinephrine spillover in heart failure.

Patients with heart failure (HF) have increased levels of cardiac norepinephrine (NE) spillover, which is an independent predictor of mortality. We hypothesized that this increase in NE spillover in HF depends not only on increases in sympathetic nerve activity (SNA) but also on changes in the mechanisms controlling NE release and reuptake. Such changes would lead to differences between the increases in directly recorded SNA and NE spillover to the heart in HF. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA (CSNA). In addition, arterial pressure and cardiac NE spillover were determined. In HF, the levels of both CSNA (102 ± 8 vs. 45 ± 8 bursts/min, P < 0.05) and cardiac NE spillover (21.6 ± 3.8 vs. 3.9 ± 0.8 pmol/min, P < 0.05) were significantly higher than in normal control animals. In HF, baroreflex control of cardiac NE spillover was impaired, and when CSNA was abolished by increasing arterial pressure, there was no reduction in cardiac NE spillover. A decrease in cardiac filling pressures in the HF group led to a significant increase in CSNA, but it significantly decreased cardiac NE spillover. In HF, the levels of cardiac NE spillover were enhanced above those expected from the high level of SNA, suggesting that changes in mechanisms controlling NE release and reuptake further increase the high level of NE at the heart, which will act to enhance the deleterious effects of increased CSNA in HF. NEW & NOTEWORTHY This is the first study, to our knowledge, to compare direct recordings of cardiac sympathetic nerve activity with simultaneously measured cardiac norepinephrine (NE) spillover. Our results indicate that in heart failure, increased cardiac sympathetic nerve activity is a major contributor to the increased NE spillover. In addition, there is enhanced NE spillover for the levels of synaptic nerve activity.

Cardiorespiratory interactions in humans and animals: rhythms for life.

The cardiorespiratory system exhibits oscillations from a range of sources. One of the most studied oscillations is heart rate variability, which is thought to be beneficial and can serve as an index of a healthy cardiovascular system. Heart rate variability is dampened in many diseases including depression, autoimmune diseases, hypertension, and heart failure. Thus, understanding the interactions that lead to heart rate variability, and its physiological role, could help with prevention, diagnosis, and treatment of cardiovascular diseases. In this review, we consider three types of cardiorespiratory interactions: respiratory sinus arrhythmia (variability in heart rate at the frequency of breathing), cardioventilatory coupling (synchronization between the heart beat and the onset of inspiration), and respiratory stroke volume synchronization (the constant phase difference between the right and the left stroke volumes over one respiratory cycle). While the exact physiological role of these oscillations continues to be debated, the redundancies in the mechanisms responsible for its generation and its strong evolutionary conservation point to the importance of cardiorespiratory interactions. The putative mechanisms driving cardiorespiratory oscillations as well as the physiological significance of these oscillations will be reviewed. We suggest that cardiorespiratory interactions have the capacity to both dampen the variability in systemic blood flow as well as improve the efficiency of work done by the heart while maintaining physiological levels of arterial CO2. Given that reduction in variability is a prognostic indicator of disease, we argue that restoration of this variability via pharmaceutical or device-based approaches may be beneficial in prolonging life.

Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis.

Increased cardiac sympathetic nerve activity (CSNA) is a key feature of heart failure (HF) and is associated with poor outcome. There is evidence that central angiotensinergic mechanisms contribute to the increased CSNA in HF, but the central sites involved are unknown. In an ovine, rapid pacing model of HF, we investigated the contribution of the lamina terminalis and area postrema to the increased CSNA and also the responses to fourth ventricular infusion of the angiotensin type 1 receptor antagonist losartan. Ablation of the area postrema or sham lesion (n = 6/group), placement of lamina terminalis lesion electrodes (n = 5), and insertion of a cannula into the fourth ventricle (n = 6) were performed when ejection fraction was ~ 50%. When ejection fraction was < 40%, recording electrodes were implanted, and after 3 days, resting CSNA and baroreflex control of CSNA were measured before and following lesion of the lamina terminalis, in groups with lesion or sham lesion of the area postrema and before and following infusion of losartan (1.0 mg/h for 5 h) into the fourth ventricle. In conscious sheep with HF, lesion of the lamina terminalis did not significantly change CSNA (91 ± 2 vs. 86 ± 3 bursts/100 heart beats), whereas CSNA was reduced in the group with lesion of the area postrema (89 ± 3 to 45 ± 10 bursts/100 heart beats, P < 0.01) and following fourth ventricular infusion of losartan (89 ± 3 to 48 ± 8 bursts/100 heartbeats, P < 0.01). These findings indicate that the area postrema and brainstem angiotensinergic mechanisms may play an important role in determining the increased CSNA in HF.

Intracranial pressure influences the level of sympathetic tone.

Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the "cost" of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system. A direct link between decreases in cerebral perfusion pressure and sympathetic tone generation in a conscious large animal has not been shown. We hypothesized that there is a novel control pathway between physiological levels of intracranial pressure (ICP) and blood pressure via the sympathetic nervous system. Intracerebroventricular infusion of saline produced a ramped increase in ICP of up to 20 mmHg over a 30-min infusion period (baseline 4.0 ± 1.1 mmHg). The ICP increase was matched by an increase in mean arterial pressure such that cerebral perfusion pressure remained constant. Direct recordings of renal sympathetic nerve activity indicated that sympathetic drive increased with increasing ICP. Ganglionic blockade, by hexamethonium, preventing sympathetic transmission, abolished the increase in arterial pressure in response to increased ICP and was associated with a significant decrease in cerebral perfusion pressure. This is the first study to show that physiological elevations in ICP regulate renal sympathetic activity in conscious animals. We have demonstrated a novel physiological mechanism linking ICP levels with sympathetic discharge via a possible novel intracranial baroreflex.

Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure.

Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg(-1)·h(-1)) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep (n = 6) and sheep with pacing-induced HF (n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.

Reinnervation following catheter-based radio-frequency renal denervation.

NEW FINDINGS: What is the topic of this review? Does catheter-based renal denervation effectively denervate the afferent and efferent renal nerves and does reinnervation occur? What advances does it highlight? Following catheter-based renal denervation, the afferent and efferent responses to electrical stimulation were abolished, renal sympathetic nerve activity was absent, and levels of renal noradrenaline and immunohistochemistry for tyrosine hydroxylase and calcitonin gene-related peptide were significantly reduced. By 11 months after renal denervation, both the functional responses and anatomical markers of afferent and efferent renal nerves had returned to normal, indicating reinnervation. Renal denervation reduces blood pressure in animals with experimental hypertension and, recently, catheter-based renal denervation was shown to cause a prolonged decrease in blood pressure in patients with resistant hypertension. The randomized, sham-controlled Symplicity HTN-3 trial failed to meet its primary efficacy end-point, but there is evidence that renal denervation was incomplete in many patients. Currently, there is little information regarding the effectiveness of catheter-based renal denervation and the extent of reinnervation. We assessed the effectiveness of renal nerve denervation with the Symplicity Flex catheter and the functional and anatomical reinnervation at 5.5 and 11 months postdenervation. In anaesthetized, non-denervated sheep, there was a high level of renal sympathetic nerve activity, and electrical stimulation of the renal nerve increased blood pressure and reduced heart rate (afferent response) and caused renal vasoconstriction and reduced renal blood flow (efferent response). Immediately after renal denervation, renal sympathetic nerve activity and the responses to electrical stimulation were absent, indicating effective denervation. By 11 months after denervation, renal sympathetic nerve activity was present and the responses to electrical stimulation were normal, indicating reinnervation. Anatomical measures of renal innervation by sympathetic efferent nerves (tissue noradrenaline and tyrosine hydroxylase) and afferent sensory nerves (calcitonin gene-related peptide) demonstrated large decreases at 1 week postdenervation, but normal levels at 11 months postdenervation. In summary, catheter-based renal denervation is effective, but reinnervation occurs. Studies of central and renal changes postdenervation are required to understand the causes of the prolonged hypotensive response to catheter-based renal denervation in human hypertension.

The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity.

The lack of noninvasive approaches to measure cardiac sympathetic nerve activity (CSNA) has driven the development of indirect estimates such as the low-frequency (LF) power of heart rate variability (HRV). Recently, it has been suggested that LF HRV can be used to estimate the baroreflex modulation of heart period (HP) rather than cardiac sympathetic tone. To test this hypothesis, we measured CSNA, HP, blood pressure (BP), and baroreflex sensitivity (BRS) of HP, estimated with the modified Oxford technique, in conscious sheep with pacing-induced heart failure and in healthy control sheep. We found that CSNA was higher and systolic BP and HP were lower in sheep with heart failure than in control sheep. Cross-correlation analysis showed that in each group, the beat-to-beat changes in HP correlated with those in CSNA and in BP, but LF HRV did not correlate significantly with either CSNA or BRS. However, when control sheep and sheep with heart failure were considered together, CSNA correlated negatively with HP and BRS. There was also a negative correlation between CSNA and BRS in control sheep when considered alone. In conclusion, we demonstrate that in conscious sheep, LF HRV is neither a robust index of CSNA nor of BRS and is outperformed by HP and BRS in tracking CSNA. These results do not support the use of LF HRV as a noninvasive estimate of either CSNA or baroreflex function, but they highlight a link between CSNA and BRS.

Effects of renal denervation on regional hemodynamics and kidney function in experimental hyperdynamic sepsis.

OBJECTIVE: To determine the influence of the renal sympathetic nerves on the pathogenesis of septic acute kidney injury. DESIGN: Interventional control study to determine the effects of renal denervation in ovine hyperdynamic sepsis. SETTING: Research Institute. SUBJECTS: Twenty-four adult Merino ewes. INTERVENTIONS: The effects of infusion of angiotensin II and norepinephrine and induction of hyperdynamic sepsis by administration of live Escherichia coli were examined in control sheep and in sheep at 2 weeks after bilateral renal denervation (n = 10/group). MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamics and renal function were measured in conscious sheep instrumented with flow probes on the pulmonary and renal arteries. Angiotensin II, but not norepinephrine, had a greater pressor effect in denervated animals. Sepsis increased cardiac output by 60%, renal blood flow by 35%, and arterial lactate by approximately four-fold. The denervated compared with the control group had a greater degree of hypotension during sepsis (68 vs 81 mm Hg; p = 0.003) and a reduction in the early polyuric response (from 496 to 160 mL at 2-8 hr of sepsis; p < 0.001). Creatinine clearance decreased similarly in both groups. CONCLUSIONS: In experimental hyperdynamic sepsis, renal denervation was associated with greater hypotension and a loss of the initial diuresis, but no significant change in creatinine clearance. In sepsis, the renal nerves help support arterial pressure and determine the initial diuretic response, but septic acute kidney injury developed similarly in the innervated and denervated groups.

Central exogenous nitric oxide decreases cardiac sympathetic drive and improves baroreflex control of heart rate in ovine heart failure.

Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympathoexcitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from downregulation of neuronal NO synthase (nNOS). Therefore, we investigated the effects of increasing the levels of NO in the brain, or selectively in the paraventricular nucleus of the hypothalamus (PVN), on cardiac sympathetic nerve activity (CSNA) and baroreflex control of CSNA and heart rate in ovine pacing-induced HF. The resting level of CSNA was significantly higher in the HF than in the normal group, but the resting level of RSNA was unchanged. Intracerebroventricular infusion of the NO donor sodium nitroprusside (SNP; 500 µg · ml(-1)· h(-1)) in conscious normal sheep and sheep in HF inhibited CSNA and restored baroreflex control of heart rate, but there was no change in RSNA. Microinjection of SNP into the PVN did not cause a similar cardiac sympathoinhibition in either group, although the number of nNOS-positive cells was decreased in the PVN of sheep in HF. Reduction of endogenous NO with intracerebroventricular infusion of N(ω)-nitro-l-arginine methyl ester decreased CSNA in normal but not in HF sheep and caused no change in RSNA in either group. These findings indicate that endogenous NO in the brain provides tonic excitatory drive to increase resting CSNA in the normal state, but not in HF. In contrast, exogenously administered NO inhibited CSNA in both the normal and HF groups via an action on sites other than the PVN.

Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney.

Hypertonic NaCl infused into the carotid arteries increases mean arterial pressure (MAP) and changes sympathetic nerve activity (SNA) via cerebral mechanisms. We hypothesized that elevated sodium levels in the blood supply to the brain would induce differential responses in renal and cardiac SNA via sensors located outside the blood-brain barrier. To investigate this hypothesis, we measured renal and cardiac SNA simultaneously in conscious sheep during intracarotid infusions of NaCl (1.2 M), sorbitol (2.4 M), or urea (2.4 M) at 1 ml/min for 4 min into each carotid. Intracarotid NaCl significantly increased MAP (91 ± 2 to 97 ± 3 mmHg, P < 0.05) without changing heart rate (HR). Intracarotid NaCl was associated with no change in cardiac SNA (11 ± 5.0%), but a significant inhibition of renal SNA (-32.5 ± 6.4%, P < 0.05). Neither intracarotid sorbitol nor urea changed MAP, HR, central venous pressure, cardiac SNA, and renal SNA. The changes in MAP and renal SNA were completely abolished by microinjection of the GABA agonist muscimol (5 mM, 500 nl each side) into the paraventricular nucleus of the hypothalamus (PVN). Infusion of intracarotid NaCl for 20 min stimulated a larger increase in water intake (1,100 ± 75 ml) than intracarotid sorbitol (683 ± 125 ml) or intracarotid urea (0 ml). These results demonstrate that acute increases in blood sodium levels cause a decrease in renal SNA, but no change in cardiac SNA in conscious sheep. These effects are mediated by cerebral sensors located outside the blood-brain barrier that are more responsive to changes in sodium concentration than osmolality. The renal sympathoinhibitory effects of sodium are mediated via a pathway that synapses in the PVN.

Role of prostaglandins in determining the increased cardiac sympathetic nerve activity in ovine sepsis.

Effective treatment of sepsis remains a significant challenge in intensive care units. During sepsis, there is widespread activation of the sympathetic nervous system, which is thought to have both beneficial and detrimental effects. The sympathoexcitation is thought to be partly due to the developing hypotension, but may also be a response to the inflammatory mediators released. Thus, we investigated whether intracarotid infusion of prostaglandin E2 (PGE2) induced similar cardiovascular changes to those caused by intravenous infusion of Escherichia coli in sheep and whether inhibition of prostaglandin synthesis, with the nonselective cyclooxygenase inhibitor indomethacin, administered at 2 and 8 h after the onset of sepsis, reduced sympathetic nerve activity (SNA), and heart rate (HR). Studies were performed in conscious sheep instrumented to measure mean arterial pressure (MAP), HR, cardiac SNA (CSNA), and renal SNA (RSNA). Intracarotid infusion of PGE2 (50 ng·kg(-1)·min(-1)) increased temperature, CSNA, and HR, but not MAP or RSNA. Sepsis, induced by infusion of E. coli, increased CSNA, but caused an initial, transient inhibition of RSNA. At 2 h of sepsis, indomethacin (1.25 mg/kg bolus) increased MAP and caused reflex decreases in HR and CSNA. After 8 h of sepsis, indomethacin did not alter MAP, but reduced CSNA and HR, without altering baroreflex control. These findings indicate an important role for prostaglandins in mediating the increase in CSNA and HR during the development of hyperdynamic sepsis, whereas prostaglandins do not have a major role in determining the early changes in RSNA.

Tonic arterial chemoreceptor activity contributes to cardiac sympathetic activation in mild ovine heart failure.

Heart failure (HF) is associated with a large increase in cardiac sympathetic nerve activity (CSNA), which has detrimental effects on the heart and promotes arrhythmias and sudden death. There is increasing evidence that arterial chemoreceptor activation plays an important role in stimulating renal sympathetic nerve activity (RSNA) and muscle sympathetic nerve activity in HF. Given that sympathetic nerve activity to individual organs is differentially controlled, we investigated whether tonic arterial chemoreceptor activation contributes to the increased CSNA in HF. We recorded CSNA and RSNA in conscious normal sheep and in sheep with mild HF induced by rapid ventricular pacing (ejection fraction <40%). Tonic arterial chemoreceptor function was evaluated by supplementing room air with 100% intranasal oxygen (2-3 l min(-1)) for 20 min, thereby deactivating chemoreceptors. The effects of hyperoxia on resting levels and baroreflex control of heart rate, CSNA and RSNA were determined. In HF, chemoreceptor deactivation induced by hyperoxia significantly reduced CSNA [90 ± 2 versus 75 ± 5 bursts (100 heart beats)(-1), P < 0.05, n = 10; room air versus hyperoxia] and heart rate (96 ± 4 versus 85 ± 4 beats min(-1), P < 0.001, n = 12). There was no change in RSNA burst incidence [93 ± 4 versus 92 ± 4 bursts (100 heart beats)(-1), n = 7], although due to the bradycardia the RSNA burst frequency was decreased (90 ± 8 versus 77 ± 7 bursts min(-1), P < 0.001). In normal sheep, chemoreceptor deactivation reduced heart rate without a significant effect on CSNA or RSNA. In summary, deactivation of peripheral chemoreceptors during HF reduced the elevated levels of CSNA, indicating that tonic arterial chemoreceptor activation plays a critical role in stimulating the elevated CSNA in HF.

The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep.

The paraventricular nucleus of the hypothalamus (PVN) plays a major role in central cardiovascular and volume control, and has been implicated in controlling sympathetic nerve activity (SNA) during volume expansion and in heart failure (HF). The objectives were to determine the role of the PVN on cardiac and renal SNA (CSNA and RSNA) in conscious normal sheep and sheep with pacing-induced heart failure. In normovolaemic sheep in the normal state and in HF, bilateral microinjection of the GABA agonist muscimol (2 mm, 500 nl), had no effects on resting mean arterial pressure (MAP), heart rate (HR), CSNA or RSNA. In addition, neither chemical inhibition of the PVN using the inhibitory amino acid glycine (0.5 m, 500 nl), nor electrolytic lesion of the PVN reduced the elevated level of CSNA in HF. Dysinhibition of the PVN with bilateral microinjection of bicuculline (1 mm, 500 nl) in normal sheep increased MAP, HR and CSNA, but decreased RSNA, whereas in HF bicuculline had no effects on MAP, HR or CSNA, but inhibited RSNA. During volume expansion in normal sheep, muscimol reversed the inhibition of RSNA, but not of CSNA. In summary, removal of endogenous GABAergic inhibition to the PVN indicated that CSNA is normally under inhibitory control. Although this inhibition was absent in HF, the responses to pharmacological inhibition, or lesion of the PVN, indicates that it does not drive the increased CSNA in HF. These findings indicate the PVN has a greater influence on RSNA than CSNA in the resting state in normal and HF sheep, and during volume expansion in normal sheep.