Cardiac Sympathetic Stimulation Research Articles

Relation of plasma neuropeptide-Y with myocardial function and infarct severity in acute ST-elevation myocardial infarction

Abstract Background Acute myocardial infarction is associated with high levels of cardiac sympathetic stimulation, which leads to the release of the co-transmitter neuropeptide-Y (NPY). NPY acts as a potent vasoconstrictor and an association with increased risk for heart failure and microvascular dysfunction after acute ST-elevation myocardial infarction (STEMI) has been suggested. Purpose This study aims to comprehensively evaluate the association of plasma NPY with myocardial function and infarct severity, visualized by cardiac magnetic resonance (CMR) imaging, in STEMI patients revascularized by primary percutaneous coronary intervention (PCI). Methods In this observational study, we included 260 STEMI patients treated with primary PCI. Plasma NPY concentrations were measured by an immunoassay 24h after PCI from peripheral venous blood samples. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), infarct size (IS) and microvascular obstruction (MVO) were determined using CMR imaging 4 days and 4 months after PCI. Results Median plasma concentrations of NPY were 70 [interquartile range (IQR): 35-115] pg/ml. NPY levels above median were significantly associated with lower LVEF (48% vs. 52%, p=0.004), decreased GLS (-8.8% vs. -12.6%, p<0.001) and larger IS (17% vs. 13%, p=0.041) in the acute phase after infarction as well as in the chronic stage (LVEF: 50% vs. 52%, p=0.030, GLS: -10.5 vs. -12.9, p<0.001, IS: 13% vs. 10%, p=0.011). In addition, NPY levels were significantly related to presence of MVO (58% vs. 52%, p=0.041). Moreover, in multivariable linear regression analysis, NPY remained significantly associated with all investigated CMR parameters (LVEF: p<0.001, GLS: p<0.001, IS: p=0.003, MVO: p=0.042) independent of other established clinical variables including high-sensitivity cardiac troponin T, pre-interventional TIMI flow 0 and left anterior descending artery as culprit lesion location. Conclusion High plasma levels of NPY, measured 24h after STEMI, were independently associated with lower LVEF, decreased GLS, larger IS as well as presence of MVO, indicating plasma NPY as a valuable biomarker for optimized risk stratification.

Vasopressin and cardiovascular autonomic adjustment in chronic hypertensive pregnancy

Chronic hypertensive pregnancy (CHP) is a growing health issue with unknown etiology. Vasopressin (VP), a nonapeptide synthesized in paraventricular (PVN) and supraoptic nucleus (SON), is a well-known neuroendocrine and autonomic modulator of the cardiovascular system, related to hypertension development. We quantified gene expression of VP and its receptors, V1aR and V1bR, within the PVN and SON in CHP and normal pregnancy, and assessed levels of secreted plasma VP. Also, we evaluated autonomic cardiovascular adaptations to CHP using spectral indices of blood pressure (BPV) and heart rate (HRV) short-term variability, and spontaneous baroreflex sensitivity (BRS). Experiments were performed in female spontaneously hypertensive rats (SHRs) and in normotensive Wistar rats (WRs). Animals were equipped with a radiotelemetry probe for continuous hemodynamic recordings before and during pregnancy. BPV, HRV and BRS were assessed using spectral analysis and the sequence method, respectively. Plasma VP was determined by ELISA whilst VP, V1aR, and V1bR gene expression was analyzed by real-time-quantitative PCR (RT-qPCR). The results show that non-pregnant SHRs exhibit greater VP, V1aR, and V1bR gene expression in both PVN and SON respectively, compared to Wistar dams. Pregnancy decreased VP gene expression in the SON of SHRs but increased it in the PVN and SON of WRs. Pregnant SHRs exhibited a marked drop in plasma VP concentration associated with BP normalization. This triggered marked tachycardia, heart rate variability increase, and BRS increase in pregnant SHRs. It follows that regardless of BP normalization in late pregnancy, SHRs exhibit cardiovascular vulnerability and compensate by recruiting vagal mechanisms.Pregnant SHR dams have reduced expression of VP in SON associated with increased V1bR expression, lower plasma VP, normal BP during late pregnancy and marked signs of enhanced sympathetic cardiac stimulation (increased HR and LFHR variability) and recruitment of vagal mechanisms (enhancement of BRS and HFHR variability).

Elucidating the Molecular Mechanisms for Activation of the L-Type Calcium Channel in the Fight or Flight Response

In cardiac muscle sympathetic stimulation leads to an increase in heart rate and contraction as a result of increased calcium influx through the L-type Ca2+ channel (Cav1.2). This involves activation of the β-adrenergic receptor and an increase in cAMP dependent protein kinase A (PKA). It is unknown whether direct modification of Cav1.2 is responsible for altered channel function and as a result the mechanism has remained controversial. We searched for the functionally relevant site for PKA phosphorylation on the human cardiac L-type Ca2+ channel pore forming α1 subunit using a novel approach. Functional studies were performed on proteoliposomes containing human Cav1.2 channel protein and phosphatidylcholine lipid only. Using this approach channel function is studied in isolation from the auxiliary subunits of the channel complex and the regulatory pathways present in the cell. We confirm a direct effect of PKA on Cav1.2 channel function. Robust increases in frequency of channel openings were recorded after phosphorylation of the long and short N terminal isoforms and a protein kinase A anchoring protein (AKAP) was not required. Mutation of Ser1928 and potential PKA substrate serines in the cytoplasmic Repeat I-II and II-III linker regions did not attenuate the effect nor truncation of the C terminus. We find that direct phosphorylation of a single serine that lies in close proximity to the Repeat IV S6 region on Cav1.2 alters posttranslational folding and is necessary and sufficient for an increase in function responsible for the “Fight or Flight” response.

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.

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.

The kidney-heart connection during electrical storm: from bedside back to bench.

One of the most challenging clinical pre-sentations for cardiologists is the ‘electrical storm’ of incessant ventricular tachycardia (VT). This often occurs in patients with previous myocardial infarctions or non-ischaemic cardiomyopathies, who are already on the maximally tolerated doses of cardiac medications (including β-blockers). Such patients may have already been implanted with a cardiac defibrillator (ICD) and are therefore likely to receive multiple therapies from their device. The cardiologist corrects plasma electrolytes, administers additional antiarrhythmic drugs (such as amiodarone and lidocaine) and reprograms the ICD in an attempt to suppress the storm, but ultimately many patients will require general anaesthesia and emergency ablation of their VT. This is a perilous ‘last-ditch’ procedure with limited long-term success. It may, however, stabilize the patient long enough for consideration of heart transplantation. Case reports and small case series have highlighted novel procedures aimed at reducing cardiac sympathetic drive as possible adjunct therapies in such patients. This builds on over 50 years of intense research linking cardiac sympathetic drive to arrhythmogenicity (Shen & Zipes, 2014). Even sedation or general anaesthesia in itself can be antiarrhythmic, because sympathetic hyperactivity during the electrical storm can be reinforced by chest pain from VT and ICD shocks received whilst still conscious. Recent publications have advocated stellatectomy (Schwartz, 2014), thoracic epidural anaesthesia and renal sympathetic nerve denervation (Bradfield et al. 2014) as potential approaches. In this context, the paper by Huang et al. (2014) in this issue of Experimental Physiology is of particular interest. In anaesthetized dogs following renal sympathetic denervation or a sham procedure, Huang et al. (2014) performed catheter-based measurements of ventricular refractory period and action potential duration (APD) restitution at multiple epicardial sites. This is the first publication to my knowledge to characterize ventricular electrophysiological changes in response to renal denervation. Interestingly, the flattening in the slope of the APD restitution curve, prolongation of the refractory period and reduced ability to induce APD alternans mirrors previous reports of the action of selective cardiac sympathetic stimulation on these parameters. Moreover, renal denervation reduced the incidence of ventricular arrhythmias in the hour following ligation of the left anterior descending coronary artery. The paper by Huang et al. (2014) also follows the recently published failure of renal sympathetic nerve denervation to produce a significant reduction in blood pressure in patients with resistant hypertension when compared with a sham procedure in the Symplicity HTN-3 trial (Bhatt et al. 2014). There are a number of interesting methodological differences in the approach to renal denervation taken by Huang et al. (2014) compared with that used in Symplicity HTN-3. In human subjects, renal denervation is usually undertaken via an endovascular approach using a radiofrequency ablation catheter introduced via the femoral artery. Discrete lesions are made circumferentially in a spiral pattern along both renal arteries, but unfortunately there is no way of determining that successful denervation has been achieved during the procedure. Huang et al. (2014) performed epivascular ablation via small bilateral retroperitoneal flank incisions. Furthermore, they demonstrated as evidence of successful denervation that high-frequency electrical stimulation of the adventitia no longer caused hypertension following ablation. This is a useful and novel approach, and a similar clinical end-point of success in patients is clearly needed. The fact that afferent and efferent nerves innervate the kidney through a plexus surrounding the renal arteries has long been appreciated. Renal afferent nerves are able to stimulate the hypothalamus in response to renal hypoxia and ischaemia and thereby increase global sympathetic activity. Likewise, sympathetic efferent nerves cause renin release, sodium and water retention, and through angiotensin II, reinforce sympathetic drive both centrally and by increasing catecholamine release peripherally (Singh et al. 2014). Renal denervation as a method to reduce cardiac sympathetic drive therefore appears logical, although many questions regarding this approach remain unanswered. Can a reduction in cardiac sympathetic activity following renal denervation be measured directly? Do the electrophysiological changes in APD and refractory period observed in the normal canine heart also occur in ischaemic and non-ischaemic cardiomyopathy? How long do these electrophysiological changes persist for and what are the underlying mechanisms by which they occur? In the clinical case reports of renal denervation for electrical storm, patients were already maximally β-blocked. Is the antiarrhythmic action of this procedure therefore independent of β-receptors, and if so, which other receptors or sympathetic cotransmitters play a role? This promises to be an active area of research, which may help us to identify new antiarrhythmic targets as well as refine our approach to renal denervation in patients. Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/expphysiol;99/11/1451 None declared. N.H. is a British Heart Foundation CRE Intermediate Fellow at the University of Oxford.

Occurrence of Takotsubo cardiomyopathy and use of antidepressants

Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, is a peculiar reversible cardiovascular disease (CVD) that may mimic an acute coronary syndrome, often affecting postmenopausal women after a stressful event. The prevalence ranges between 1.7 and 2.2% inpatients admittedwith chest pain for suspected acute coronary syndrome [1,2]. Proposed pathophysiological mechanisms include: catecholamine cardiotoxicity, microvascular dysfunction and coronary artery spasm [3,4]. Major depression and comorbid anxiety disorders have been associated with elevated sympathetic activity and diminished reuptake of norepinephrine, which may be responsible for prolonged cardiac sympathetic stimulation [5]. As suggested by Ziegelstein et al. [6], the double impact effect of disproportional high catecholamine responses and increased cardiac sympathetic sensitivity may place depressed patients at higher risk for developing TTC when exposed to stressful situations. Several case reports [7–11] have suggested that the use of SSRIs (in both therapeutic and over dosage scenarios) is associated with TCC, potentially by increasing norepinephrine levels in neuronal tissue via reuptake inhibition. This retrospective descriptive study consisted of 78 patients who met the Modified Mayo criteria [12]: 1) akinesia or dyskinesia of the apical and/or midventricular segments of the left ventricle with regionalwallmotionabnormalities extendingbeyond thedistributionof a single epicardial vessel, 2) absence of obstructive coronary artery disease, 3) new electrocardiographic abnormalities, and 4) absence of pheochromocytomas/myocarditis. The diagnosis of depression and anxiety was made based on clinical criteria by a primary care physician or psychiatrist before being admitted to the hospital. The diagnosis of anxiety included generalized anxiety disorder, panic disorder, post-traumatic stress disorder and social phobia. Clinical outcomes were assessed during the hospital admission and within 6 months after the index event, as follows: in hospital death (all cause-mortality), inpatient acute heart failure (HF), length of stay, and left ventricular ejection fraction (LVEF) determined by 2-D echocardiogram. Chi-squared and paired t-tests were used to assess statistical differences in categorical and continuous variables, respectively. A twotailed P b 0.05 was considered statistical significant. Cox-proportional hazard model was constructed to evaluate mortality. All analyses were performed employing SPSS v 19.0, Chicago IL. This study was approved by the hospital’s institutional review board. Baseline characteristics of the studypopulation aswell as by SSRI use are reported in Tables 1 and 2 respectively. SSRIs use was strongly associatedwith all-causemortality during index hospital admission (OR 7.6; 95% CI 1.1–50.3; P= 0.016). Mean LVEF on admission in patients taking SSRIs was 36.3 ± 11.4% and for patients not taking SSRIs was 36.7 ± 11.0%. Repeated echocardiogram within 6-months revealed statistically significant recovery of LVEF in each group (P b 0.05 for both comparisons) with a relatively lower LVEF in patients taking SSRIs (Fig. 1, P = 0.01). (See Table 3.) Mean LVEF on admission for patients without depressionwas 36.4 ± 11.2% and for patients with depression was 37.2 ± 10.6%. Repeated LVEF within 6-months revealed statistically significant recovery of LVEF in each group (P b 0.05 for both comparisons), although patientswith depression had relatively lower LVEFcompared topatientswithoutdepression (Fig. 2, P=0.02). The survival curve (Fig. 3) showed that SSRIs patients had lower survival rate compared with patients not taking SSRIs (P=0.04). In this study, the prevalence of depression and anxiety (21% and 31%, respectively) was consistent with previous reports [4,13,14] which reported a prevalence ranging between 20 and 40%. Several authors

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

Sympathetic Nervous System Moves Toward Center Stage in Cardiovascular Medicine

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

Rate pressure product predicts cardiovascular risk in type 2 diabetics with cardiac autonomic neuropathy

Background: Unexplained sudden deaths due cardiac involvement are linked to autonomic neuropathy in diabetics but mechanisms remain unclear. Heart rate and pulse pressure etc have been used to predict cardiovascular risk. But the association of Rate Pressure Product remains unascertained. Objective: To predict cardiovascular risk in type 2 diabetic patients with cardiac autonomic neuropathy using a non-invasive indicator, rate pressure product. Materials and Methods: Case control study done on two groups of 20 each, age matched type 2 diabetics with/without cardiac autonomic neuropathy and matched with 20 controls of either sex (n=60). Rate Pressure Product was measured in response to cold pressor and hand grip test. Statistical analysis was done using SPSS software by paired and unpaired t test. Results: There was a significant increase in rate pressure product in controls and in patients without autonomic neuropathy after the tests (p0.001). The change in RPP (ΔRPP) was least in diabetics with autonomic neuropathy and significant in controls and non-neuropathy diabetics using unpaired t-test ( p< 0.05 ). Resting RPP was recorded highest in diabetic autonomic neuropathy patients. Conclusion: Heightened resting RPP and failure of Rate Pressure Product increment during cardiac sympathetic stimulation promotes aggravated ischemic episodes. This renders autonomic neuropathy diabetics vulnerable to adverse cardiovascular events leading to increased morbidity and mortality.

Augmentation of Left Ventricular Contractility by Cardiac Sympathetic Neural Stimulation

Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation. In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97+/-20 to 138+/-32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143+/-334 versus 1725+/-632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531+/-128 versus 888+/-331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3+/-0.8 versus 3.1+/-0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5+/-0.8 versus 4.4+/-0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by beta1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site. Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.

Muscarinic potassium channels play a significant role in the negative chronotropic response with or without background sympathetic tone

Although a larger decrease in the steady‐state heart rate (HR) in response to more potent tonic vagal stimulation (VS) is mediated by the muscarinic potassium (KACh) channels, the effect of background sympathetic tone on the contribution of the KACh channels to the negative chronotropic response remains to be elucidated. In anesthetized rabbits with sinoaortic denervation and vagotomy, we examined the HR response to stepwise vagal stimulation (VS) (5, 10, 15 and 20 Hz). A selective KACh channel blocker tertiapin attenuated the HR decrease to less than half of that observed under control condition. A concomitant tonic cardiac sympathetic stimulation (5 Hz) significantly augmented the HR reduction both in control (91±16 to 130±27 bpm, @20Hz VS, mean±SD, P&lt;0.01) and tertiapin (30±12 to 67±13 bpm, P&lt;0.01) condition. The contribution of KACh channels, assessed by the attenuation of the HR reduction, was 60±24 and 63±17 bpm in the absence and the presence of background sympathetic tone, respectively. In conclusion, muscarinic potassium channels play a significant role in the negative chronotropic response with or without background sympathetic tone.

Accentuated Antagonism in Vagal Heart Rate Control Mediated through Muscarinic Potassium Channels

Although muscarinic K(+) (K(ACh)) channels contribute to a rapid heart rate (HR) response to vagal stimulation, whether background sympathetic tone affects the HR control via the K(ACh)channels remains to be elucidated. In seven anesthetized rabbits with sinoaortic denervation and vagotomy, we estimated the dynamic transfer function of the HR response by using random binary vagal stimulation (0-10 Hz). Tertiapin, a selective K(ACh) channel blocker, decreased the dynamic gain (to 2.3+/- 0.9 beats.min(-1).Hz(-1), from 4.6+/- 1.1, P < 0.01, mean+/- SD) and the corner frequency (to 0.05+/- 0.01 Hz, from 0.26+/- 0.04, P < 0.01). Under 5 Hz tonic cardiac sympathetic stimulation (CSS), tertiapin decreased the dynamic gain (to 3.6+/- 1.0 beats.min(-1).Hz(-1), from 7.3+/- 1.1, P < 0.01) and the corner frequency (to 0.06+/- 0.02 Hz, from 0.23+/- 0.06, P < 0.01). Two-way analysis of variance indicated significant interaction between the tertiapin and CSS effects on the dynamic gain. In contrast, no significant interactions were observed between the tertiapin and CSS effects on the corner frequency and the lag time. In conclusion, although a cyclic AMP-dependent mechanism has been well established, an accentuated antagonism also occurred in the direct effect of ACh via the K(ACh) channels. The rapidity of the HR response obtained by the K(ACh) channel pathway was robust during the accentuated antagonism.

Cardiac sympathetic afferent stimulation inhibits the arterial baroreflex in heart failure at the level of the nucleus tractus solitarius by an angiotensin II mechanism

The enhanced cardiac sympathetic afferent reflex (CSAR) has been suggested to contribute to increased sympathetic outflow and blunted baroreflex via a central angiotensin II (Ang II) mechanism in chronic heart failure (CHF). This work was designed to determine the Ang II mechanism in the nucleus tractus solitarius (NTS) underlying the interaction between the baroreflex and the CSAR using extracellular recording in rats with CHF. CHF was produced by coronary artery ligation. Of 38 NTS cells tested for barosensitivity by elevation of arterial pressure, 28 were recorded in CHF rats and 10 were tested in sham rats. CSAR activation by epicardial application of capsaicin (0.4 μg) attenuated the barosensitivity of 12 NTS neurons by 86.2 ± 9.3% and this was significantly greater in CHF rats than in sham rats (65.7 ± 6.3%). In 8 cells from CHF rats, tonic inhibition of CSAR by epicardial lidocaine (6 μl) improved the barosensitivity of NTS neurons by 42.8 ± 5.9 %. In the remaining 8 cells from CHF rats, intravenous injection of the Ang II AT1 receptor antagonist losartan (2 mg/kg) not only sensitized the barosensitivity by 83.1 ± 7.2% but also reversed the inhibitory effect of CSAR activation on barosensitivity (−84.7 ± 9.6 vs. −12.5 ± 4.8 %). In conclusion, these data suggest that the NTS plays an important role in mediating the blunting of baroreflex by CSAR activation via an AT1 receptor dependent mechanism in CHF.

Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure

The following letters are in response to the Point:Counterpoint series “Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure” that appears in this issue. To the Editor: The Point:Counterpoint concerning the issue of

Pharmacological evidence that α 2A- and α 2C-adrenoceptors mediate the inhibition of cardioaccelerator sympathetic outflow in pithed rats

It has been suggested that the α 2-adrenoceptors mediating cardiac sympatho-inhibition in pithed rats closely resemble the pharmacological profile of the α 2A-adrenoceptor subtype. However, several lines of evidence suggest that more than one subtype may be involved. Thus, the present study has pharmacologically re-evaluated the receptor subtype(s) involved in the inhibitory effect of the α 2-adrenoceptor agonist, B-HT 933, on the tachycardic responses elicited by selective cardiac sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) in desipramine-pretreated pithed rats. I.v. continuous infusions of B-HT 933 (30 μg/kg min), which failed to modify the tachycardic responses to exogenous noradrenaline, inhibited those induced by preganglionic (C 7-T 1) stimulation of the cardiac sympathetic outflow at all frequencies of stimulation (0.03–3 Hz). This cardiac sympatho-inhibitory response to B-HT 933 was: (1) unaltered by saline (1 ml/kg) or the antagonists BRL44408 (100 μg/kg; α 2A) or imiloxan (3000 and 10,000 μg/kg; α 2B); (2) partially antagonized by BRL44408 (300 μg/kg) or MK912 (10 μg/kg; α 2C) given separately; and (3) completely antagonized by rauwolscine (300 μg/kg; α 2), MK912 (30 μg/kg) or the combination of BRL44408 (300 μg/kg) plus MK912 (10 μg/kg). Moreover, the above doses of antagonists, which are high enough to block their respective receptors, failed to block per se the tachycardic responses to sympathetic stimulation. These results suggest that the cardiac sympatho-inhibition induced by B-HT 933 in pithed rats is mainly mediated by stimulation of α 2A- and α 2C-adrenoceptors.

Differential effects of cardiac sympathetic afferent stimulation on neurons in the nucleus tractus solitarius

Activation of the cardiac “sympathetic afferent” reflex (CSAR) has been reported to depress the arterial baroreflex and enhance the arterial chemoreflex via a central mechanism. In the present study, we used single-unit extracellular recording techniques to examine the effects of stimulation of cardiac sympathetic afferents on baro- or chemosensitive neurons in the nucleus tractus solitarius (NTS) in anesthetized rats. Of 54 barosensitive NTS neurons tested for their response to epicardial application of capsaicin (0.4 μg), 38 were significantly ( P < 0.01) inhibited by 38% while 16 did not respond. Of 42 NTS chemosensitive neurons tested for their response to capsaicin, 33 were significantly ( P < 0.01) excited by 47% while 9 did not respond. In addition, of 12 both barosensitive and chemosensitive NTS neurons tested for capsaicin, 2 were excited, 7 were inhibited, and 3 did not respond. In conclusion, this study indicates that CSAR activation inhibited NTS barosensitive neurons and excited NTS chemosensitive neurons, suggesting that the NTS plays an important role in processing the interactions between these cardiovascular reflexes.

A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Influence of Endogenous Neuropeptide Y (NPY) on the Sympathetic-Parasympathetic Interaction in the Canine Heart

The purpose of this study was to examine the sympathetic-parasympathetic interactions on heart rate through release of neuropeptide Y (NPY) and its action on prejunctional NPY Y2 receptors on vagal and sympathetic nerve fibers. In other studies on various preparations and in various organs, attenuation of transmitter release has in fact been demonstrated through activation of the NPY Y2 receptor. In the present study on anesthetized dogs we examine, however, for the first time if vagal bradycardia is attenuated by endogenous NPY released during intense cardiac sympathetic stimulation. In addition, we explore if sympathetic transmitter release and heart rate, during moderate sympathetic stimulation, are affected through this receptor system. The significance of the NPY Y2 receptor was revealed by performing experiments before and after administration of its specific receptor antagonist BIIE0246. We found that attenuation of the bradycardia during vagal nerve stimulation was dose-dependently counteracted by BIIE0246 and that the tachycardia elicited by sympathetic stimulation remained unaffected after NPY Y2 receptor blockade. Thus, endogenous NPY appears to attenuate vagal bradycardia by stimulating prejunctional NPY Y2 receptors on cardiac vagal nerve terminals and, less efficiently, to attenuate transmitter release and tachycardia through a feedback loop on the cardiac sympathetic nerve fibers.

Phospholemman-Phosphorylation Mediates the β-Adrenergic Effects on Na/K Pump Function in Cardiac Myocytes

Cardiac sympathetic stimulation activates beta-adrenergic (beta-AR) receptors and protein kinase A (PKA) phosphorylation of proteins involved in myocyte Ca regulation. The Na/K-ATPase (NKA) is essential in regulating intracellular [Na] ([Na]i), which in turn affects [Ca]i via Na/Ca exchange. However, how PKA modifies NKA function is unknown. Phospholemman (PLM), a member of the FXYD family of proteins that interact with NKA in various tissues, is a major PKA substrate in heart. Here we tested the hypothesis that PLM phosphorylation is responsible for the PKA effects on cardiac NKA function using wild-type (WT) and PLM knockout (PLM-KO) mice. We measured NKA-mediated [Na]i decline and current (IPump) to assess beta-AR effects on NKA function in isolated myocytes. In WT myocytes, 1 micromol/L isoproterenol (ISO) increased PLM phosphorylation and stimulated NKA activity mainly by increasing its affinity for internal Na (Km decreased from 18.8+/-1.4 to 13.6+/-1.5 mmol/L), with no significant effect on the maximum pump rate. This led to a significant decrease in resting [Na]i (from 12.5+/-1.8 to 10.5+/-1.4 mmol/L). In PLM-KO mice under control conditions Km (14.2+/-1.5 mmol/L) was lower than in WT, but comparable to that for WT in the presence of ISO. Furthermore, ISO had no significant effect on NKA function in PLM-KO mice. ATPase activity in sarcolemmal vesicles also showed a lower Km(Na) in PLM-KO versus WT (12.9+/-0.9 versus 16.2+/-1.5). Thus, PLM inhibits NKA activity by decreasing its [Na]i affinity, and this inhibitory effect is relieved by PKA activation. We conclude that PLM modulates the NKA function in a manner similar to the way phospholamban affects the related SR Ca-ATPase (inhibition of transport substrate affinity, that is relieved by phosphorylation).