Attenuation of long-lasting effects of sympathetic stimulation after repeated stimulation

Neuropeptide Y (NPY) is stored with norepinephrine in sympathetic nerves throughout the cardiovascular system and is released during activation of the sympathetic nervous system in humans and other animals. After stimulation of the cardiac sympathetic nerves in anesthetized dogs, the action of the vagus nerve on heart rate is attenuated for a prolonged period. This attenuation of cardiac vagal action is also seen after injection of NPY. Both sympathetic stimulation and exogenous NPY inhibit cardiac vagal effects by acting on postganglionic vagal nerves. Because the supply of neuropeptides to nerve terminals is by axonal transport, it might be expected that repeated stimulation of cardiac sympathetic nerves would deplete the sympathetic neural factor, proposed to be NPY. In all 11 dogs of this study, repeated episodes of stimulating the cardiac sympathetic nerve (16 Hz for 1 minute each) had a diminishing effect in attenuating cardiac vagal action. However, the episodes of sympathetic stimulation did not show diminishing effectiveness in increasing heart rate. Exogenous NPY had similar inhibitory effects on vagal action whether given at the beginning or the end of the episodes of sympathetic stimulation. Transmural stimulation of sympathetic nerves around rabbit ear arteries produced effects that are also mimicked by NPY. These are prolonged potentiation of contractions evoked by injection of norepinephrine or by brief bursts of transmural stimulation. Repeated stimulations in this case also had diminishing abilities to evoke such potentiations. Both sets of observations are consistent with repeated stimulation of sympathetic nerves causing depletion of a nonadrenergic transmitter, possibly NPY.     

Centers involved in the autonomic reflex reactions originating from stretching of the atria.

Stretching the atria in anesthetized dogs produces reflex changes in heart rate, and in cardiac and renal sympathetic nerve activity. Anemic decerebration, cord transection at C4-C5, and severance of vagal or sympathetic cardiac nerves was done to identify the pathways and centers essential for these reflexes. Stretching the right atrium produced an aceleration of the heart and a definite increase in sympathetic nerve activity. Left atrial-stretch caused biphasic responses: an initial sympathetic nerve inhibition and slower heartbeat folowed by sympathetic excitation and heart acceleration. The afferents responsible were carried mainly by the vagi; efferent neural control of the heart was mostly sympathetic. The reflex inhibition observed was integrated chiefly at the medullary level, but supramedullary structures contributed to the augmentation in sympathetic activity and heart rate. When central connections between vagal afferent and sympathetic efferent pathways were separated by cord transection, atrial stretch caused a decrease in heart rate due to reflex action through the vagal loop. After the cord was sectioned, we found that some afferent impulses from the atria traveling in sympathetic nerves produced a slight reflex augmentation of sympathetic efferent activity, though insufficient to affect the heart rate. Somatosympathetic reflexes evoked in cardiac and renal sympathetic nerves by stimulation of various somatic afferent pathways were also affected by atrial stretch indicating central nervous system interactions. Reflex responses to right atrial stretch were superimposed on accelerations of myogenic origin.     

Autonomic nervous control of heart rate: sympathetic-parasympathetic interactions and age related differences

A factorial experimental design was used to quantify the changes in heart rate produced by stimulation of the cardiac sympathetic and vagal nerves in eleven adult dogs and four puppies, and to quantify the extent of the peripheral sympathetic-vagal interactions. The chronotropic responses to autonomic stimulation were significantly less in the puppies than in the adult dogs, which suggests that autonomic regulation is functionally incomplete in the puppies. In both adult dogs and puppies, the chronotropic responses to autonomic nerve stimulation were bilaterally asymmetrical. The heart rate responses to a given level of right-sided stimulation of either the sympathetic or vagal nerves were greater than those to comparable left-sided stimulation. In both adult dogs and puppies, there were significant sympathetic-vagal interactions, such that the sympathetic enhancement of heart rate was less effective the higher the background level of vagal activity. The sympathetic-vagal interactions were prominent in the puppies as well as in the adult animals, regardless of whether the stimulated sympathetic and vagal nerves were located ipsilaterally or contralaterally to one another. Thus, the mechanisms responsible for the sympathetic-vagal interactions appear to be fully developed in puppies. Also, the cardiac sympathetic nerve endings that originate from one side of the body must lie in close apposition to the cardiac vagal nerve endings that originate from either the same side or from the opposite side of the body.     

Reflex inhibitory effects of vagal afferents in experimental myocardial infarction

In experimental myocardial infarction with hypotension, low output state and shock (produced by injection of 0.2 ml of metallic mercury into the circumflex coronary artery of closed chest anesthetized dogs) serial recordings were made of postganglionic sympathetic and aortic baroreceptor nerve activity in addition to cardiac output, mean blood pressure, electrocardiogram and heart rate. With the decrease in cardiac output and mean blood pressure after injection of mercury, aortic nerve activity decreased as expected but, contrary to expectations, postganglionic sympathetic nerve activity also decreased. It was postulated that this decrease was due to a powerful cardiac vagal afferent reflex that could override the compensatory increase of sympathetic activity usually present with systemic baroreceptor withdrawal. Cutting or blocking the vagus nerves resulted in an immediate increase in sympathetic nerve activity followed by increases in cardiac output, mean systemic blood pressure and aortic nerve activity. Atropine, although it increased heart rate, did not reproduce the effect of vagotomy on sympathetic activity and cardiac output.     

Effects of angiotensin II on the cardiac responses to sympathetic nerve stimulation in dogs

In anesthetized dogs with the left cardiac sympathetic nerves and both vagal nerves intact, angiotensin II (AII) induced a substantial, dose-dependent increase in arterial blood pressure and small increments in cardiac cycle length and ventricular contractile force. In dogs in which the cardiac sympathetic and vagal nerves had been interrupted, AII produced similar increases in blood pressure and larger increases in contractile force, but it decreased the cardiac cycle length. In both groups of dogs, AII augmented substantially the positive inotropic responses to sympathetic nerve stimulation, but it enhanced the positive chronotropic responses only slightly. However, AII did not appreciably prolong the cardiac responses to sympathetic nerve stimulation, nor did it alter significantly the cardiac responses to norepinephrine infusions. Hence, at the dosage levels used, AII probably did not inhibit the neuronal uptake of norepinephrine appreciably nor did it enhance the responsiveness of the cardiac effector sites to norepinephrine. Therefore, the potentiation of the cardiac responses to sympathetic nerve stimulation by AII in these experiments was probably achieved principally by facilitating norepinephrine release from the adrenergic nerve terminals in the heart.     

Functional significance of coactivation of vagal and sympathetic cardiac nerves.

Simultaneous recording of activity in the vagal and sympathetic supplies to the heart has revealed that in reflexly and centrally evoked activity these two "antagonists" do not necessarily change action reciprocally. Coactivation occurs in chemoreceptor reflexes and related reactions, upon stretching of the sinoatrial nodal region of the right atrium and when certain hypothalamic regions are stimulated. The objective of the present work was to assay the physiological importance of coactivation of the two potentially antagonistic cardiac nerves in anesthetized dogs. Output from the heart was monitored by recording volume flow in the thoracic aorta just below the aortic arch; cardiac contractility was measured as left ventricular dp/dt. Tape recordings of vagus and sympathetic nerve activity during chemoreceptor and baroreceptor reflexes, during reciprocal and nonreciprocal changes produced by hypothalamic stimulation, and during hypoxia and hypercapnia were used to trigger stimulators feeding a stimulus per action potential to cardiac vagus and sympathetic nerves after central connections were cut. The vagus stimulation alone produced a decrease in aortic blood flow; stimulation of the sympathetic nerve alone resulted in increased aortic blood flow. Simultaneous stimulation of vagus and sympathetic, however, produced an even greater cardiac output (measured by aortic blood flow). Intermediate degrees of heart rate and strength of myocardial contraction were maintained in coactivation. Obviously, an association of increased vagus and sympathetic actions, which can be effected reflexly or by action of higher centers, is of physiological benefit. In control reactions that relate cardiac function to body need, both reciprocal and synergistic actions (coactivation) of cardiac nerves are used.     

Influence of ANP on Sympathetic Nerve Activity and Chronotropic Regulation of the Heart

Physiological Effects of ANP. hypotension caused by atrial natriuretic peptide (ANP) is often not accompanied by the anticipated increases in beart rate or sympathetic nerve activity. the sympathetic inhibitory action of ANP occurs in cardiac and noncardiac sympathetic nerves, and has been demonstrated in conscious or anesthetized animals as well as in humans. The sympathetic inhibition by ANP occurs after atropinization but is abolisbed after va-gotomy. Thus, ANP alters sympathetic nerve activity by influencing cardiopulmonary barore-ceptors, wbich in turn is mediated by vagal afferents. In addition to the effects of ANP on cardiopulmonary baroreceptors, ANP affects arterial baroreceptors. ANP dilates the ascending aorta where some of the arterial baroreceptors are located, causing resetting of these arterial baroreceptors. When ANP is microinjected into the cerebroventricle or nucleus tractus soli-tarii, it causes inhibition of sympathetic nerve activity. It has been shown tbat ANP inhibits sympathetic ganglionic transmission and augments cardiac parasympathetic effects on heart rate. Thus., ANP may play important roles in cardiovascular regulation by influencing sympathetic nerve activity and beart rate in addition to the direct vasodilating and renal effects.     

The phase-dependency of the cardiac chronotropic responses to vagal stimulation as a factor in sympathetic-vagal interactions

We determined the effects of the timing of repetitive bursts of vagal stimulation on the positive chronotropic responses of the heart to trains of cardiac sympathetic nerve stimulation in open-chest anesthetized dogs. Trains of sympathetic stimulation alone, at frequencies of 2 and 4 Hz, decreased the cardiac cycle length by 176 +/- 19 msec (mean +/- SE) and 190 +/- 22 msec, respectively. When bursts of vagal stimuli were given once each cardiac cycle and they were placed at their least effective time in the cycle, sympathetic stimulation at frequencies of 2 and 4 Hz decreased cardiac cycle length by only 107 +/- 8 and 120 +/- 8 msec, respectively. However, when the bursts of vagal stimuli were delivered at their most effective time in each cycle, the same levels of sympathetic stimulation elicited much larger reductions in cardiac cycle length (285 +/- 32 and 330 +/- 32 msec, respectively). Therefore, the effects of sympathetic stimulation were significantly attenuated by the vagal stimuli when the vagal bursts were relatively ineffective. Conversely, the chronotropic effects of the sympathetic stimulation were exaggerated substantially when the vagal stimulus bursts were initially positioned at their most effective time in the cardiac cycle. This latter response is contrary to the characteristic "accentuated antagonism," wherein the effect of any given level of sympathetic stimulation is diminished as the level of vagal activity is increased. This vagally mediated enhancement of the positive chronotropic response to sympathetic stimulation occurs because the phase dependency of the response of the automatic cells to the bursts of vagal stimulation is altered by the increased sympathetic activity.     

Neuropeptide Y as a putative modulator of the vagal effects on heart rate

Neuropeptide Y is stored in sympathetic nerve terminals throughout the heart and has direct and indirect effects on cardiac function. Although neuropeptide Y has been shown to be released upon intense (16-30 Hz) cardiac sympathetic stimulation, we sought to determine whether effective quantities of neuropeptide Y were released from cardiac sympathetic neurons under more natural conditions. We recorded arterial pressure and cardiac cycle length in 29 anesthetized dogs. We assessed neuropeptide Y release by measuring the attenuation of vagally induced increases in cardiac cycle length (10 seconds every 2 minutes) after trains of sympathetic stimulation. We examined the effect of constant-frequency sympathetic stimulation (frequencies of 2, 5, 10, and 15 Hz, applied for train durations of 1, 3, and 5 minutes) on vagally induced chronotropic responses. We also determined the effect of varying the pattern of sympathetic stimulation. Both the magnitude and duration of the inhibition of the vagal effects on cardiac cycle length were augmented significantly by increases in the frequency or duration of sympathetic stimulation. In contrast, the inhibition of the vagally induced chronotropic responses was not significantly affected by changes in the pattern of sympathetic stimulation. We also characterized the role of adrenergic receptors. Phentolamine significantly increased the sympathetically mediated inhibition of the vagal effects on cardiac cycle length, but propranolol had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrinsic cardiac autonomic nervous system: What do clinical electrophysiologists need to know about the “heart brain”?

It is increasingly recognized that the autonomic nervous system (ANS) is a major contributor in many cardiac arrhythmias. Cardiac ANS can be divided into extrinsic and intrinsic parts according to the course of nerve fibers and localization of ganglia and neuron bodies. Although the role of the extrinsic part has historically gained more attention, the intrinsic cardiac ANS may affect cardiac function independently as well as influence the effects of the extrinsic nerves. Catheter-based modulation of the intrinsic cardiac ANS is emerging as a novel therapy for the management of patients with brady and tachyarrhythmias resulting from hyperactive vagal activation. However, the distribution of intrinsic cardiac nerve plexus in the human heart and the functional properties of intrinsic cardiac neural elements remain insufficiently understood. The present review aims to bring the clinical and anatomical elements of the immune effector cell-associated neurotoxicity together, by reviewing neuroanatomical terminologies and physiological functions, to guide the clinical electrophysiologist in the catheter lab and to serve as a reference for further research.     

Dynamic nonlinear vago-sympathetic interaction in regulating heart rate

Summary Although the characteristics of the static interactions between the sympathetic and parasympathetic nervous systems in regulating heart rate have been well established, how the dynamic interaction modulates the heart rate response remains unknown. Thus, we investigated the dynamic interaction by estimating the transfer function from nerve stimulation to heart rate, using band-limited Gaussian white noise, in anesthetized rabbits. Concomitant tonic vagal stimulation at 5 and 10Hz increased the gain of the transfer function relating dynamic sympathetic stimulation to heart rate by 55.0% ± 40.1% and 80.7% ± 50.5%, respectively (P < 0.05). Concomitant tonic sympathetic stimulation at 5 and 10Hz increased the gain of the transfer function relating dynamic vagal stimulation to heart rate by 18.2% ± 17.9% and 24.1% ± 18.0%, respectively (P < 0.05). Such bidirectional augmentation was also observed during simultaneous dynamic stimulation of the sympathetic and vagal nerves independent of their stimulation patterns. Because of these characteristics, changes in sympathetic or vagal tone alone can alter the dynamic heart rate response to stimulation of the other nerve. We explained this phenomenon by assuming a sigmoidal static relationship between autonomic nerve activity and heart rate. To confirm this assumption, we identified the static and dynamic characteristics of heart rate regulation by a neural network analysis, using large-amplitude Gaussian white noise input. To examine the mechanism involved in the bidirectional augmentation, we increased cytosolic adenosine 3,5-cyclic monophosphate (cAMP) at the postjunctional effector site by applying pharmacological interventions. The cAMP accumulation increased the gain of the transfer function relating dynamic vagal stimulation to heart rate. Thus, accumulation of cAMP contributes, at least in part, to the sympathetic augmentation of the dynamic vagal control of heart rate.     

Low-dose atropine attenuates muscle sympathetic nerve activity in healthy humans.

Central muscarinic receptors play an important role in the regulation of cardiac vagal nerve activity. We studied the inhibition of central muscarinic receptors and sympathetic nerve function in humans, since very little information is currently available on this subject. We examined the effects of graded doses of atropine (five doses, range 0.001 to 0.016 mg/kg) on heart rate, arterial pressure, heart rate variability, and muscle sympathetic nerve activity in 13 healthy young volunteers. Atropine caused biphasic effects on heart rate and the high-frequency (HF) power of R-R interval variability. At lower doses (< or =0.002 mg/kg for heart rate, 0.001 mg/kg for HF power), atropine decreased heart rate and increased HF power. In contrast, at higher doses, atropine increased heart rate and decreased HF power. Low-dose atropine significantly attenuated muscle sympathetic nerve activity, burst rate (bursts/min) by -30.5 +/- 6.0% and burst incidence (bursts/100 heart beats) by -23.8 +/- 6.9% at 0.002 mg/kg. Systolic and diastolic arterial pressure did not change with atropine infusion. Low-dose atropine (< or =0.002 mg/kg) did not significantly affect either low frequency (LF) power or LF/HF. These results suggest that central muscarinic receptors may modulate not only cardiac vagal nerve activity but also sympathetic nerve activity in the skeletal muscle vasculature.     

Vagal heart rate responses to chronic beta-blockade in human heart failure relate to cardiac norepinephrine spillover

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P<0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.     

Preserved norepinephrine reuptake but reduced sympathetic nerve endings in hypertrophic volume-overloaded rat hearts

BackgroundIn congestive heart failure (CHF), an activation of the cardiac sympathetic nervous system results in depleted cardiac norepinephrine (NE) stores. The underlying regulatory mechanisms are discussed controversially and were investigated in the present study in CHF resulting from volume overload.Methods and ResultsAorto-caval shunt (AVS) was performed in rats. Plasma NE levels were determined by radioenzymatic assay, left ventricular NE by high-performance liquid chromatography, endothelin-1 by enzyme-linked immunosorbent assay. Tyrosine-hydroxylase (TH)– and nerve growth factor (NGF)–mRNA was determined by Northern blot analysis and ribonuclease-assay. Cardiac [³H]-NE uptake was measured in isolated perfused hearts. Glyoxylic acid–induced histofluorescence was used to quantify cardiac sympathetic nerves. Compared with sham-operated animals (SH), AVS rats were characterized by depleted cardiac NE stores and enhanced NE plasma levels. Neither TH-mRNA levels in stellate ganglia, nor cardiac [³H]-NE-uptake were reduced in AVS. The left ventricular density of sympathetic nerves was markedly decreased. Gene expression of myocardial NGF (a positive regulator of NE reuptake and cardiac sympathetic nerve density) and left ventricular endothelin-1 (a negative regulator of NE reuptake and positive regulator of cardiac NGF expression) were unchanged.ConclusionIn volume-overloaded hypertrophic hearts, depletion of cardiac NE stores is caused by a reduction of the sympathetic nerve density, whereas cardiac NE reuptake is preserved.     

Endogenous angiotensin affects responses to stimulation of baroreceptor afferent nerves

OBJECTIVE: To study effects of endogenous angiotensin II on responses to standardized stimulation of afferent neural input into the central portion of the arterial and cardiac baroreflexes. DESIGN: Different dietary sodium intakes were used to physiologically alter endogenous angiotensin II activity. Candesartan, an angiotensin II type 1 receptor antagonist, was used to assess dependency of observed effects on angiotensin II stimulation of angiotensin II type 1 receptors. Electrical stimulation of arterial and cardiac baroreflex afferent nerves was used to provide a standardized input to the central portion of the arterial and cardiac baroreflexes. METHODS: In anesthetized rats in balance on low, normal and high dietary sodium intake, arterial pressure, heart rate and renal sympathetic nerve activity responses to electrical stimulation of vagus and aortic depressor nerves were determined. Compared with plasma renin activity values in normal dietary sodium intake rats, those from low dietary sodium intake rats were higher and those from high dietary sodium intake rats were lower. During vagus nerve stimulation, the heart rate, arterial pressure and renal sympathetic nerve activity responses were similar in all three dietary sodium intake groups. During aortic depressor nerve stimulation, the heart rate and arterial pressure responses were similar in all three dietary sodium intake groups. However, the renal sympathetic nerve activity response was significantly greater in the low sodium group than in the normal and high sodium group at 4, 8 and 16 Hz. Candesartan administered to low dietary sodium intake rats had no effect on the heart rate and arterial pressure responses to either vagus or aortic depressor nerve stimulation but increased the magnitude of the renal sympathoinhibitory responses. CONCLUSIONS: Increased endogenous angiotensin II in rats on a low dietary sodium intake attenuates the renal sympathoinhibitory response to activation of the cardiac and sinoaortic baroreflexes by standardized vagus and aortic depressor nerve stimulation, respectively.     

Effect of vagal stimulation on the overflow of norepinephrine into the coronary sinus during cardiac sympathetic nerve stimulation in the dog.

In anesthetized dogs with the chest open, supramaximal stimulation of the left cardiac sympathetic nerves at 2 and 4 Hz produced an increase of 40-50% in ventricular contractile force (CF) and of 40-65% in coronary sinus blood flow. At these frequencies of stimulation, norepinephrine (NE) overflow into the coronary sinus was 29.8 +/- 5.1 (SE) and 54.9 +/- 13.2 ng/min, respectively. Concurrent, supramaximal vagal stimulation, at a frequency of 15 Hz, had no significant effect on coronary sinus blood flow, but caused a 25% reduction in CF and a 30% decrease in NE overflow. The changes in CF and NE overflow evoked by vagal stimulation were prevented by atropine. These results are consistent with the hypothesis that there are muscarinic receptors on the postganglionic sympathetic terminals in the walls of the ventricles. Acetylcholine released during vagal stimulation combines with these receptors, causes a reduction in the liberation of NE, and thereby attenuates the positive inotropic response.     

Effect of ethacizin (diethylamine analog of ethmozine) on the efferent activity of the sympathetic and parasympathetic nerves of the heart

This study examined the effects of the diethylamino analogue of ethmozin (ethacizin) (1 mg/kg, i.v.) on the spontaneous and reflex elicited efferent activity in thoracic cardiac sympathetic and parasympathetic nerves. Nitroglycerin and phenylephrine (4 and 8 micrograms/kg, i.v.) were administered to 15 anesthetized mongrel dogs while monitoring blood pressure and heart rate. In each dog, two cardiac nerves were isolated and efferent neurograms were simultaneously recorded and analyzed by microprocessor. Ethacizin significantly attenuated the spontaneous sympathetic efferent activity in both left and right, preganglionic (n-8) and postganglionic (n-14) sympathetic nerves to the heart. In contrast, reflex changes in sympathetic activity elicited by baroreceptor challenges, were not affected by ethacizin. Also, ethacizin did not significantly affect either spontaneous or baroreceptor reflex-induced parasympathetic efferent activities in 8 preganglionic nerves. Thus, this new phenothiazine derivative may exert part of its antiarrhythmic action through a reduction of the spontaneous sympathetic tonic discharges to the heart. The fact that ethacizin did neither reduce the reflex-induced changes in sympathetic or parasympathetic activities nor influence the tonic vagal discharges further suggests that the compound is not likely to interfere with reflexly mediated cardiovascular adaptive changes.     

Physiological Background Underlying Short-Term Heart Rate Variability

A large number of papers has been published on heart rate variability (HRV) based on the assumption that the specific components of HRV provide specific information about cardiac parasympathetic or sympathetic efferent nerve activity. However, neural control of the cardiorespiratory system is very complex, and the physiological phenomenon underlying HRV in different conditions are far from being fully understood. This review summarizes, in the light of current literature, a series of studies focused on the mechanisms by which fluctuations in neural outflows are transferred into HRV. In the interpretation of HRV analyses, it should be taken into account that: (1) HRV seems to be strongly influenced by the parasympathetic nervous system at all the frequency components; (2) due to sympathovagal interactions, sympathetic outflow is able to reduce the variations generated by vagal modulation also in the high frequency band; and (3) the variations in heart rate reflect fluctuations in the neural activity rather than the mean level of sympathetic or parasympathetic neural activity. Thus, we should be cautious in interpreting a specific component of HRV as a specific marker of sympathetic or parasympathetic cardiac control. Furthermore, due to the complexity of the cardiorespiratory control system, the analysis of short-term HRV should be performed in well-controlled conditions, in which the behavior of the autonomic nervous system is well documented.     

严重充血性心力衰竭患者自主神经功能与心率变异的关系及地高辛的影响

对２５例重度充血性心力衰竭（ＣＨＦ）患者在地高辛治疗前后测定血浆去甲肾上腺素（ＮＥ）及心率变异（ＨＲＶ）。结果显示：ＮＥ基础值与ＨＲＶ时域指标基础水平均呈负相关（Ｐ＜０．０５或＜０．０１）。地高辛治疗前后的ＮＥ相比（２９１±８０ｐｇ／ｍｌｖｓ２１３±８２ｐｇ／ｍｌ），Ｐ＜０．００１。２４小时平均ＲＲ间期及２４小时正常ＲＲ间期标准差由治疗前的７２７±１２３ｍｓ及６７．７±２１．８ｍｓ分别增加至７７７±１２２ｍｓ及８７．２±２９．２ｍｓ（Ｐ均＜０．０５）；２４小时相邻ＲＲ间期差值的均方根（ＲＭＳＳＤ）、２４小时正常相邻ＲＲ间期之差大于５０ｍｓ的心搏数所占百分比（ＰＮＮ５０）及高频（ＨＦ）由治疗前的３６．３±３０．６ｍｓ、５．３±５．５％及３７．１±２１．２ｍｓ２分别增加至５６．１±４３．７ｍｓ、１０．８±１０．６％及７９．９±５８．２ｍｓ２（Ｐ值＜０．０５至＜０．０１）；低频（ＬＦ）由治疗前的１１８．９±１３３．２ｍｓ２增加至１７１．２±１７２．８ｍｓ２（Ｐ＜０．００５）；ＮＥ下降幅度与时域指标增加幅度均呈正相关。ＨＲＶ多数时域指标增加幅度及其绝对值与血清地高辛浓度呈正相关，以ＲＭＳＳＤ和ＰＮＮ５０尤为显著（Ｐ?     

Vagus stimulation. Mechanisms and current clinical importance in heart failure

Increased sympathetic activity and reduced vagal activity are associated with increased mortality both after myocardial infarction and in heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies indicate that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of post-infarction sudden cardiac death and of chronic heart failure. Initial clinical results demonstrate that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve quality of life, submaximal exercise capacity, and LV function. Vagus nerve stimulation derives these potential clinical benefits from multiple mechanisms of action. These include reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of pro-inflammatory cytokines, and antiarrhythmic effects.