Cardiac Sympathetic Afferents Research Articles

Transient receptor potential vanilloid 1-expressing cardiac afferent nerves may contribute to cardiac hypertrophy in accompany with an increased expression of brain-derived neurotrophic factor within nucleus tractus solitarius in a pressure overload model

ABSTRACT Introduction Increased sympathetic output contributes to cardiac hypertrophy. Sympathoexcitation is induced by activating the cardiac sympathetic afferent nerves through transient receptor potential vanilloid 1 (TRPV1) in cardiac afferent endings. Brainstem nucleus tractus solitarius (NTS) receives the sensory cardiac afferent inputs. Brain-derived neurotrophic factor (BDNF) is released within NTS from sensory neurons in an activity-dependent manner. Additionally, BDNF in NTS tonically regulates sympathetic activity. Therefore, we hypothesized that TRPV1-expressing cardiac afferent nerves contribute to cardiac hypertrophy in accompany with an increased BDNF expression in NTS. Methods and Results Abdominal aortic banding (AB) or sham operation was conducted in wild-type C57BL/6 J (WT-AB) and TRPV1 knockout mice (TRPV1 KO-AB). At 8 weeks post-operation, echocardiographic left ventricular wall thickness and heart weight/body weight ratio were significantly greater in WT-AB than WT-Sham mice, and these hypertrophic indexes were attenuated in TRPV1 KO-AB mice. Among the groups, left ventricular fractional shortening was not different. The protein levels of TRPV1 in heart and BDNF in NTS were significantly increased in WT-AB compared to WT-Sham mice, whereas BDNF expression in NTS was not increased by AB in TRPV1-KO mice. Chemical ablation of TRPV1-expressing cardiac afferents attenuated the AB-induced cardiac hypertrophy and increase in BDNF in NTS. Sympathetic activity analyzed using heart rate variability, and sympathoexcitatory responses to the stimulation of cardiac afferents were increased in WT-AB compared to WT-Sham mice. Conclusion TRPV1-expressing cardiac afferent nerves may contribute to pressure overload-induced cardiac hypertrophy in accompany with the increased BDNF within NTS.

Chronic ablation of TRPV1-sensitive skeletal muscle afferents attenuates the muscle metaboreflex.

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Activation of Bradykinin‐Sensitive Pericardial Afferents Increases Splanchnic Nerve Activity

Sympathetic drive plays a key role in control of cardiovascular function. The heart performs an important sensory function via a variety of cardiac receptors that modulate sympathetic drive. Bradykinin‐sensitive sympathetic afferent nerves from the heart can trigger marked increases in efferent sympathetic nerve activity to some cardiovascular targets such as the kidney. We reported previously that pericardial injection of bradykinin increased venous tone and cardiac output. The splanchnic vascular compartment plays an important role in control of venous return and cardiac output. This work tested the hypothesis that activation of bradykinin‐sensitive pericardial afferents increases postganglionic splanchnic sympathetic nerve activity.Sprague Dawley rats were anesthetized with a cocktail of alpha chloralose (80 mg/kg) and urethane (800 mg/kg). Catheters were placed in the femoral artery and vein to record arterial pressure (MAP) and heart rate (HR). A PE10 catheter was placed in the pericardial space for the injection of bradykinin (BK), an agent known to stimulate cardiac sympathetic afferents. The chest was closed and the rat allowed to breathe spontaneously. The splanchnic sympathetic nerve was isolated via a dorsal approach and placed on recording electrodes. After stabilization, the blood pressure, heart rate, and integrated splanchnic nerve activity (SPLNA) responses to pericardial injection of BK or vehicle were recorded. Responses were also recorded for intravenous injection of dimethylphenylpiperazinium (DMPP 150 ug/kg), a ganglionic stimulant, and a ganglion blocker (hexamethonium 20 mg/kg).Pericardial injection of saline vehicle had little effect (MAP: 0.1±0.4 mm Hg; HR: 1.2±1.4 bpm; SPLNA 1±2%). In contrast, intravenous injection of a ganglionic stimulant, DMPP, increased MAP (23±1 mm Hg) and SPLNA (95±46%). Pericardial injection of BK (10 ug/kg) increased MAP (21±3 mm Hg), HR (28±7 bpm) and SPLNA (93±37%). Ganglionic blockade with hexamethonium reduced SPLNA (−75±6%) and abolished the responses to pericardial injection of BK (MAP: −1±3 mm Hg; HR: −2±1 bpm; SPLNA: 7±30 %).We interpret these data to indicate that activation of bradykinin‐sensitive pericardial afferents increases postganglionic splanchnic sympathetic nerve activity. This finding is consistent with the view that activation of the cardiac sympathetic afferent reflex elicits a venoconstrictor response to increase venous return from the splanchnic vascular compartment.Support or Funding InformationSupported by NIH R01 HL136741‐03 (DM), R01 DK114663‐1 (HZ), and the Basic Biomedical Sciences program of the Sanford School of Medicine, University of South Dakota.

Changes in Splanchnic Hemodynamics Contribute to the Cardiovascular Responses Following Activation of Bradykinin‐Sensitive Pericardial Afferents

Sympathetic drive is a major controller of cardiovascular function. The heart performs an important sensory function via a variety of cardiac receptors that modulate cardiovascular responses by both neural and humoral reflexes. Bradykinin‐sensitive sympathetic afferent nerves from the heart can trigger marked increases in efferent sympathetic nerve activity to some cardiovascular target organs such as the kidney, arteries and veins. We reported previously that pericardial injection of bradykinin increased venous tone and cardiac output. The splanchnic vascular compartment plays an important role in control of venous return and cardiac output. This work tested the hypothesis that activation of bradykinin‐sensitive pericardial afferents modulates splanchnic hemodynamics.Sprague Dawley rats were anesthetized with a cocktail of alpha chloralose (80 mg/kg) and urethane (800 mg/kg). Catheters were placed in the femoral artery and vein to record arterial pressure (MAP) and heart rate (HR). A PE10 catheter was placed in the pericardial space for the injection of bradykinin (BK), an agent known to stimulate cardiac sympathetic afferents. The chest was closed and the rats allowed to breathe spontaneously. The portal vein and mesenteric artery were exposed via a midline laparotomy and fitted with transit time flow probes. After stabilization, the blood pressure, heart rate, portal venous flow (PF) and mesenteric flow (MF) responses to pericardial injection of BK or vehicle were recorded.Pericardial injection of saline vehicle had little effect (MAP: 2±2 mm Hg; HR: 13±6 bpm; PF: −5±1%; MF: −3±1%). In contrast, pericardial injection of BK (10 ug/kg) increased MAP (16±3 mm Hg) and HR (28±5 bpm). After an initial transient decrease, PF (10±2%) and MF (5±2%) were increased during the plateau phase of the MAP response (60–120 seconds).We interpret these data to indicate that activation of bradykinin‐sensitive pericardial afferents increases portal venous flow. This finding is consistent with the view that activation of the cardiac sympathetic afferent reflex elicits a venoconstrictor response to increase venous return from the splanchnic compartment.Support or Funding InformationSupported by NIH R01 HL136741‐03, and the Basic Biomedical Sciences program of the Sanford School of Medicine.

Role of opioid receptors in modulation of P2X receptor-mediated cardiac sympathoexcitatory reflex response

Myocardial ischemia evokes powerful reflex responses through activation of vagal and sympathetic afferents in the heart through the release of ischemic metabolites. We have demonstrated that extracellular ATP stimulates cardiac sympathetic afferents through P2 receptor-mediated mechanism, and that opioid peptides suppress these afferents’ activity. However, the roles of both P2 receptor and endogenous opioids in cardiac sympathoexcitatory reflex (CSR) responses remain unclear. We therefore hypothesized that activation of cardiac P2 receptor evokes CSR responses by stimulating cardiac sympathetic afferents and these CSR responses are modulated by endogenous opioids. We observed that intrapericardial injection of α,β-methylene ATP (α,β-meATP, P2X receptor agonist), but not ADP (P2Y receptor agonist), caused a graded increase in mean arterial pressure in rats with sinoaortic denervation and vagotomy. This effect of α,β-meATP was abolished by blockade of cardiac neural transmission with intrapericardial procaine treatment and eliminated by intrapericardial A-317491, a selective P2X2/3 and P2X3 receptor antagonist. Intrapericardial α,β-meATP also evoked CSR response in vagus-intact rats. Furthermore, the P2X receptor-mediated CSR responses were enhanced by intrapericardial naloxone, a specific opioid receptor antagonist. These data suggest that stimulation of cardiac P2X2/3 and P2X3, but not P2Y receptors, powerfully evokes CSR responses through activation of cardiac spinal afferents, and that endogenous opioids suppress the P2X receptor-mediated CSR responses.

Abstract P202: Targeting the Cardiac Sympathetic Afferent Reflex in Hypertrophic Cardiomyopathy

Sarcomere gene mutations cause hypertrophic cardiomyopathy (HCM). Hallmark features include cardiac hypertrophy, fibrosis, excessive cardiac sympathetic tone, and increased risk of arrhythmias and sudden death. The mechanism(s) of increased sympathetic tone is poorly understood. We hypothesized that cardiac spinal (sympathetic) afferents are sensitized by metabolites (e.g., H+) produced during myocyte energy depletion in HCM, resulting in an enhanced cardiac sympathetic afferent reflex (CSAR). We studied mice with cardiac-specific expression of mutated alpha-tropomyosin (Glu180Gly), an established model of HCM. The CSAR was assessed by measuring mean arterial pressure (MAP) and heart rate (HR) responses to epicardial application of the TRPV1 agonist capsaicin (2.5mM, 2μL) to the left ventricle in anesthetized, ventilated HCM (n=5) and wild-type (WT) littermate control (n=5) mice. Pressor and tachycardic responses to capsaicin were markedly enhanced in HCM mice (Table). Blocking the tonic influence of cardiac afferent activity by epicardial application of the local anesthetic lidocaine (2%) caused small, significant decreases in MAP in both groups of mice; but decreased HR markedly in HCM mice only (n=5) (Table). mRNA expression (qPCR) of acid-sensing ion channel 3 was increased by 2-fold in dorsal root ganglia (T1-T9) of HCM vs. WT mice (n=6 each, P<0.05), suggesting a mechanism for sensitization of cardiac sympathetic afferents in HCM. We conclude that the CSAR is enhanced in HCM mice and speculate that increased activity of cardiac ‘sympathetic’ afferent nerves contributes to increased sympathetic tone, arrhythmias and disease progression in HCM.

Activation of Bradykinin‐Sensitive Pericardial Afferents Increases Systemic Venous Tone and Cardiac Output

The venous system plays a critical role in blood pressure regulation by controlling venous return, cardiac filling, and cardiac output. Sympathetic drive is a major controller of venous function. However, outside of the arterial baroreflex, the mechanisms that regulate sympathetic drive to veins remain poorly defined in both physiological and disease conditions. The heart itself has an important sensory function via a variety of cardiac receptors that modulate cardiovascular function by neural and humoral reflexes. Bradykinin‐sensitive sympathetic afferent nerves from the heart can trigger marked increases in efferent sympathetic nerve activity to some cardiovascular target organs such as the kidney. This work tested the hypothesis that the activation of bradykinin‐sensitive cardiac afferents increases venous tone and cardiac output.Sprague Dawley rats were anesthetized with a cocktail of alpha chloralose (80 mg/kg) and urethane (800 mg/kg). Catheters were placed in the femoral artery and vein to record arterial and venous blood pressures. A PE 10 catheter was placed in the pericardial space for the injection of bradykinin (BK), an agent known to stimulate cardiac sympathetic afferents. In some rats, a balloon tipped catheter was placed in the right atrium to allow transient arrest of cardiac pumping for the estimation of mean circulatory filling pressure (MCFP), an estimate of systemic venous tone. In other rats, an electromagnetic flow probe was placed on the aortic arch for the direct measurement of cardiac output.In rats instrumented for the measurement of venous tone, pericardial injections of BK (0.4–20 μg/kg) were associated with dose‐related increases in mean arterial pressure (9±6 to 27±6 mm Hg) and MCFP (0.6±0.2 to 1.6±0.4 mm Hg). These responses were largely attenuated after ganglionic blockade. In rats instrumented for the measurement of cardiac output, pericardial injection of BK (10 μg/kg) increased mean arterial pressure (23±3 mm Hg) and cardiac output (16±2 ml/min).We interpret these data to indicate that activation of bradykinin‐sensitive pericardial afferents increases venous tone sufficiently to increase cardiac filling and cardiac output.Support or Funding InformationSupported by NIH R01 HL136741‐01 and the Basic Biomedical Sciences program of the Sanford School of Medicine, University of South Dakota.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states.

Cardiac sympathetic afferents are considered to be essential pathways for transmission of cardiac nociception to the central nervous system during myocardial ischaemia. However, a potential contribution of the CSAR control of cardiac dysfunction in both normal and chronic heart failure (CHF) states remains unknown. We found that activation of the CSAR evokes little increase in cardiac contractility with an exaggerated peripheral vasoconstriction in the CHF state. CSAR inhibition by epicardial lidocaine decreased cardiac contractility to a greater extent in CHF rats than sham rats. Furthermore, we also found that epicardial lidocaine paradoxically decreased left ventricular end-diastolic pressure (LVEDP) and left ventricular end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. Chronic ablation of the CSAR by epicardial application of the afferent neurotoxin, RTX, selectively lowered diastolic blood pressure CHF rats. The observation suggests that CSAR has a differential effect on cardiac function in normal and CHF states. CSAR activation in normal state causes significant increase in cardiac contractility and cardiac output. The enhanced 'cardiac sympathetic afferent reflex' (CSAR) critically contributes to the exaggerated global sympathetic tone in chronic heart failure (CHF). However, a potential contribution of the cardio-cardiac reflex control of cardiac function in both normal and CHF states remains unknown. In this study, we evaluated the effects of direct activation or inhibition of the CSAR on cardiac function by pressure-volume (P-V) loop analysis in ∼12-week sham-operated and myocardial infarcted (MI) rats. In sham rats, acute CSAR activation by epicardial application of bradykinin (BK) increased heart rate (HR), left ventricular systolic pressure (LVSP), the maximum first derivative of left ventricular pressure (dp/dtmax ), and the slope of the end-systolic P-V relationship (ESPVR), suggesting that acute CSAR activation in the normal state enhances myocardial contractility. CSAR activation also decreased left ventricular (LV) systolic and diastolic volumes with little effect on LV end-diastolic pressure (LVEDP) or the end-diastolic P-V relationship (EDPVR) in sham rats. Compared to sham, CHF rats exhibit a reduced increase in the slope of the ESPVR and dp/dtmax in response to BK, indicating a poor contractile response to CSAR activation. Interestingly, BK application in CHF rats increased cardiac systolic and diastolic volumes and further increased the elevated LVEDP, neither of which was seen in sham rats. Following CSAR inhibition by epicardial lidocaine, blood pressure, HR, LVSP, dp/dt, LVEDP and ESPVR decreased in CHF rats whereas lidocaine had little effect in sham rats, indicating that the CSAR is tonically active in CHF and contributes to cardiac dysfunction. Furthermore, we found that epicardial lidocaine paradoxically decreased LV end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. The decreased preload by lidocaine in CHF rats may be due to a reduction in peripheral vascular resistance since epicardial lidocaine significantly lowered peripheral (renal) sympathetic nerve activity in CHF rats but not in sham rats. Furthermore, chronic ablation of CSAR by epicardial application of a selective afferent neurotoxin, resiniferatoxin, selectively lowered diastolic blood pressure both at daytime and night-time with less effect on systolic blood pressure in CHF rats. Our data suggest that there is an imbalance between cardiac and peripheral responses to CSAR in CHF animals compared to sham-operated controls.

Abstract P311: Cardiac Sympathetic Afferents Does Not Initiate but Contributes to the Further Development of Hypertension in Spontaneous Hypertensive Rats

Sympatho-excitation plays a critical role in the pathogenesis of hypertension. However, it is unclear what factors initiate and maintain sympatho-excitation in hypertension. Our past studies have confirmed a critical role of cardiac sensory nerve endings that mediate a sympatho-excitatory reflex called the “cardiac sympathetic afferent reflex” (CSAR) in the setting of heart failure. However, whether/when the CSAR is activated and contributes to the development of hypertension remains unclear. To address this issue, we chronically abolished the CSAR by epidural application of a selective afferent neurotoxin, resiniferatoxin (RTX) at the level of the T1-T4 dorsal root ganglia (DRGs) by destroying TRPV1-expressing neuronal soma in 8-week and 16-w old spontaneous hypertensive rats (SHR). Conscious blood pressure was monitored before (baseline) and during 2 months post RTX using radio telemetry. As shown in Figure 1A, in early-hypertensive (8-w old) SHR rats, there was no difference in mean arterial pressure (MAP) between vehicle and RTX groups until 3 weeks post intervention. At that time, MAP in vehicle-treated SHR rats continued to increase whereas this increase was largely abolished in the RTX-treated group. In the established (16-w old) SHR rats (Figure 1B), treatment with RTX immediately reduced MAP by ~15 mmHg, which was maintained for the 2-month recording period. These data strongly suggest that although CSAR does not initiate hypertension at the early stage in SHR, it contributes to the further development of hypertension in the mid/late stages. These data support a potential novel therapy possibly involving cardiac afferents.

ElPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves.

The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway.

Activation of cardiac P2X receptors in hypertensive rats displays exaggerated sympathoexcitatory reflexes

The concurrence of hypertension and ischemia leads to increased morbidity and fatality in individuals compared to myocardial ischemia alone. Ischemic mediators activate cardiac sympathetic afferents and evoke cardiac sympathoexcitatory reflex (CSR) responses. Recent work has revealed that the ischemic mediator ATP stimulates ischemic‐sensitive cardiac sympathetic afferents mostly through activation of P2X receptors. However, little is known about these mediators in CSR responses of hypertensive animals. We therefore hypothesized that activation of P2X receptors in the cardiac sensory nerves exaggerates CSR responses in hypertensive compared to normotensive animals. Arterial pressure and renal sympathetic nerve activity in response to intrapericardial injection of the P2X receptor agonist α,β‐meATP (31 to 125 nmol) were recorded in four groups of rats (n=5/each group), two of which were hypertensive, including cold‐induced hypertension (CIH) and spontaneous hypertension (SHR). The other two groups included SD and WKY normotensive rats. A larger CSR was evoked in response to intrapericardial α,β‐meATP in hypertensive (CIH and SHR) rats vs. normotensive (SD and WKY) rats in a dose‐dependent manner. In all four groups, intrapericardial injection of vehicle produced no CSR response. These data suggest that cardiac sympathoexcitatory reflexes induced by activation of P2X receptors are exacerbated in hypertensive animals. (Funded by HL‐66217)

Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation.

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

Symbolic dynamics to discriminate healthy and ischaemic dilated cardiomyopathy populations: an application to the variability of heart period and QT interval

Myocardial ischaemia is hypothesized to stimulate the cardiac sympathetic excitatory afferents and, therefore, the spontaneous changes of heart period (approximated as the RR interval), and the QT interval in ischaemic dilated cardiomyopathy (IDC) patients might reflect this sympathetic activation. Symbolic analysis is a nonlinear and powerful tool for the extraction and classification of patterns in time-series analysis, which implies a transformation of the original series into symbols and the construction of patterns with the symbols. The aim of this work was to investigate whether symbolic transformations of RR and QT cardiac series can provide a better separation between IDC patients and healthy control (HC) subjects compared with traditional linear measures. The variability of these cardiac series was studied during daytime and night-time periods and also during the complete 24 h recording over windows of short data sequences of approximately 5 min. The IDC group was characterized by an increase in the occurrence rate of patterns without variations (0 V%) and a reduction in the occurrence rate of patterns with one variation (1 V%) and two variations (2 V%). Concerning the RR variability during the daytime, the highest number of patterns had 0 V%, whereas the rates of 1 V% and 2 V% were lower. During the night, 1 V% and 2 V% increased at the expense of diminishing 0 V%. Patterns with and without variations between consecutive symbols were able to increase the separation between the IDC and HC groups, allowing accuracies higher than 80%. With regard to entropy measures, an increase in RR regularity was associated with cardiac disease described by accuracy >70% in the RR series and by accuracy >60% in the QTc series. These results could be associated with an increase in the sympathetic tone in IDC patients.

Cardiac sympathetic afferent reflex and its implications for sympathetic activation in chronic heart failure and hypertension.

Persistent excessive sympathetic activation greatly contributes to the pathogenesis of chronic heart failure (CHF) and hypertension. Cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex with positive feedback characteristics. Humoral factors such as bradykinin, adenosine and reactive oxygen species produced in myocardium due to myocardial ischaemia stimulate cardiac sympathetic afferents and thereby reflexly increase sympathetic activity and blood pressure. The CSAR is enhanced in myocardial ischaemia, CHF and hypertension. The enhanced CSAR at least partially contributes to the sympathetic activation and pathogenesis of these diseases. Nucleus of the solitary tract (NTS), hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla are the most important central sites involved in the modulation and integration of the CSAR. Angiotensin II, AT1 receptors and NAD(P)H oxidase-derived superoxide anions pathway in the PVN are mainly responsible for the enhanced CSAR in CHF and hypertension. Central angiotensin-(1-7), nitric oxide, endothelin, intermedin, hydrogen peroxide and several other signal molecules are involved in regulating CSAR. Blockade of the CSAR shows beneficial effects in CHF and hypertension. This review focuses on the anatomical and physiological basis of the CSAR, the interaction of CSAR with baroreflex and chemoreflex, and the role of enhanced CSAR in the pathogenesis of CHF and hypertension.

Pro-inflammatory cytokines in paraventricular nucleus mediate the cardiac sympathetic afferent reflex in hypertension.

Our previous studies showed that pro-inflammatory cytokines (PIC) in the hypothalamic paraventricular nucleus (PVH) potentiated the cardiac sympathetic afferent reflex (CSAR) in normotensive rats. This study determined whether PIC in the PVH mediate enhanced CSAR and over-excited sympathetic activity in spontaneously hypertensive rats (SHR). CSAR was evaluated by renal sympathetic nerve activity (RSNA) response to epicardial application of bradykinin (BK). Inflammatory cytokine levels were measured with ELISA. In both SHR and normotensive Wistar-Kyoto (WKY) rats, PVH microinjection of PIC, tumour necrosis factor (TNF)-α or interleukin (IL)-1β, increased the baseline mean arterial blood pressure (MAP), RSNA and the CSAR, but anti-inflammatory cytokines (AIC), IL-4 or IL-13, only increased the baseline MAP. PVH pretreatment with PIC caused sub-response dose of angiotension (Ang) II to produce baseline RSNA and MAP elevation and the CSAR enhancement responses, but AIC (IL-4 or IL-13) did not. PVH microinjection of PIC induced greater changes in SHR than in normotensive WKY rats. In addition, stimulation of cardiac sympathetic afferents with epicardial application of BK increased PIC levels in the PVH in both SHR and WKY rats. Intrapericardial administration of resiniferatoxin (RTX) which abolished the CSAR decreased the PIC levels in the PVH to a lower level in SHR than in WKY rats. These results suggest that the increased PIC in the PVH in SHR mediated the increased sympathetic outflow and the enhanced CSAR, and that the augmented effect of Ang II in the PVH on sympathetic activity and the CSAR is also associated with PIC.

Activated pathway from the parabrachial nucleus to rostal ventrolateral medulla during stimulation of cardiac sympathetic afferents (686.8)

Our previous studies have shown that stimulation of cardiac sympathetic afferents activates pontine nuclei like the parabrachial nucleus (PBN) and locus coeruleus (LC) as well as rostral ventrolateral medulla (rVLM), a critical area that controls cardiac sympathoexcitatory responses. However, there is no information on direct influence of pontine nuclei on the rVLM during stimulation of cardiac sympathetic afferents. Thus, the present study evaluated neuronal activation of the pontine nuclei in response to stimulation of cardiac sympathetic afferents, with regard to their projections to the rVLM. Seven to ten days after unilateral microinjection of rodamine‐conjugated microspheres retrograde tracer (100 nl) into the rVLM, rats with bilateral cervical vagotomy were subjected to epicardial application of α, β‐meATP (1.1 to 6.5 mM, in 40 µl) or 0.9% normal saline for six times over 90 min. Repetitive increases in blood pressure were observed in the rats following repeated stimulation of the heart with α, β‐meATP, but not with normal saline. Perikarya containing the microsphere tracer were found in the PBN and, but not in the LC of both groups. Compared to three controls, c‐Fos immunoreactivity and neurons double‐labeled with c‐Fos, an immediate early gene and the tracer were more frequently found in the PBN, but not LC of rats with cardiac stimulation (n=5), particularly in the lateral PBN and Kölliker‐Fuse nucleus. These results suggest that PBN neurons responsive to cardiac sympathetic afferent stimulation frequently project directly to the rVLM, which is known to participate in processing of excitatory cardiovascular responses during stimulation of cardiac sympathetic afferents.Grant Funding Source: NIH grant HL‐66217

Relative contributions of the thalamus and the paraventricular nucleus of the hypothalamus to the cardiac sympathetic afferent reflex

The cardiac sympathetic afferent reflex (CSAR) is induced by stimulating the cardiac sympathetic afferents, which evokes increases in sympathetic outflow and arterial pressure. In the present study, we attempted to identify the contribution of thalamic and hypothalamic nuclei involved in the CSAR. First, we observed that there was an increase in the number of c-Fos-labeled cells in the paraventricular nucleus (PVN) (190 ± 18 vs. 101 ± 15; P < 0.05), the paraventricular nucleus of the thalamus (PVT) (239 ± 23 vs. 151 ± 15; P < 0.05), and the mediodorsal thalamic nucleus (MD) (92 ± 9 vs. 63 ± 6; P < 0.05) following epicardial application of bradykinin (BK) compared with the control group (P < 0.05). Second, using extracellular single-unit recording, we found 25% of spontaneously active neurons in the thalamus were stimulated by epicardial application of BK or capsaicin in intact rats. However, 24% of spontaneously active neurons in the thalamus were still stimulated by epicardial application of BK or capsaicin despite vagotomy and sinoaortic denervation. None of the neurons in the thalamus responded to baroreflex changes in arterial pressure, induced by intravenous injection of phenylephrine or sodium nitroprusside. The CSAR was inhibited by microinjection of muscimol or lidocaine into the PVN. However, it was not inhibited or blocked by microinjection of muscimol or lidocaine into the thalamus. Taken together, these data suggest that the thalamus, while activated, is not critical for autonomic adjustments in response to activation of the CSAR. On the other hand, the PVN is critically involved in the central pathway of the CSAR.

Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T₂-T₅) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32-3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin.

Autonomic modulation for chronic heart failure: a new kid on the block?

Autonomic modulation for chronic heart failure: a new kid on the block?

Hydrogen Sulfide in Paraventricular Nucleus Enhances Sympathetic Activity and Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats

BackgroundIntracerebroventricular infusion of NaHS, a hydrogen sulfide (H2S) donor, increased mean arterial pressure (MAP). This study was designed to determine the roles of H2S in the paraventricular nucleus (PVN) in modulating sympathetic activity and cardiac sympathetic afferent reflex (CSAR) in chronic heart failure (CHF).Methodology/Principal FindingsCHF was induced by left descending coronary artery ligation in rats. Renal sympathetic nerve activity (RSNA) and MAP were recorded under anesthesia. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. PVN microinjection of low doses of a H2S donor, GYY4137 (0.01 and 0.1 nmol), had no significant effects on RSNA, MAP and CSAR. High doses of GYY4137 (1, 2 and 4 nmol) increased baseline RSNA, MAP and heart rate (HR), and enhanced CSAR. The effects were greater in CHF rats than sham-operated rats. A cystathionine-β-synthase (CBS) inhibitor, hydroxylamine (HA) in PVN had no significant effect on the RSNA, MAP and CSAR. CBS activity and H2S level in the PVN were decreased in CHF rats. No significant difference in CBS level in PVN was found between sham-operated rats and CHF rats. Stimulation of cardiac sympathetic afferents with capsaicin decreased CBS activity and H2S level in the PVN in both sham-operated rats and CHF rats.ConclusionsExogenous H2S in PVN increases RSNA, MAP and HR, and enhances CSAR. The effects are greater in CHF rats than those in sham-operated rats. Endogenous H2S in PVN is not responsible for the sympathetic activation and enhanced CSAR in CHF rats.