Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation

The objective of this study was to determine how neurons within the right atrial ganglionated plexus (RAGP) and posterior atrial ganglionated plexus (PAGP) interact to modulate right atrial chronotropic, dromotropic, and inotropic function, particularly with respect to their extracardiac vagal and sympathetic efferent neuronal inputs. Surgical ablation of the PAGP (PAGPx) attenuated vagally mediated bradycardia by 26%; it reduced heart rate slowing evoked by vagal stimulation superimposed on sympathetically mediated tachycardia by 36%. RAGP ablation (RAGPx) eliminated vagally mediated bradycardia, while retaining the vagally induced suppression of sympathetic-mediated tachycardia (-83%). After combined RAGPx and PAGPx, vagal stimulation still reduced sympathetic-mediated tachycardia (-47%). After RAGPx alone and after PAGPx alone, stimulation of the vagi still produced negative dromotropic effects, although these changes were attenuated compared with the intact state. Negative dromotropic responses to vagal stimulation were further attenuated after combined ablation, but parasympathetic inhibition of atrioventricular nodal conduction was still demonstrable in most animals. Finally, neither RAGPx nor PAGPx altered autonomic regulation of right atrial inotropic function. These data indicate that multiple aggregates of neurons within the intrinsic cardiac nervous system are involved in sinoatrial nodal regulation. Whereas parasympathetic efferent neurons regulating the right atrium, including the sinoatrial node, are primarily located within the RAGP, prejunctional parasympathetic-sympathetic interactions regulating right atrial function also involve neurons within the PAGP.     

Effects of calcium channel antagonists on the vagally mediated cardiac chronotropic response in dogs

A brief electrical stimulation of the vagus nerve may elicit a triphasic response comprising (i) an initial prolongation of the same or the next cardiac cycle, (ii) a return of the subsequent cardiac cycle to about the level prior to vagal stimulation, and (iii) a secondary prolongation of cardiac cycle length that lasts several beats. We compared the effects of two calcium channel antagonists, verapamil and nifedipine, on this triphasic response to vagal stimulation in chloralose-anesthetized, open-chest dogs. In the absence of vagal stimulation, nifedipine (doses of 10, 40, and 50 micrograms/kg for a total dose of 100 micrograms/kg, i.v.) and verapamil (two doses of 100 micrograms/kg each, i.v.) increased the cardiac cycle length (A-A interval) by 16% (429 +/- 20 to 496 +/- 21 ms) and 29% (470 +/- 33 to 605 +/- 54 ms), respectively. Nifedipine (100 micrograms/kg total) attenuated the initial vagally mediated prolongation of the A-A interval, from 474 +/- 19 to 369 +/- 42 ms above the basal A-A interval. Following the initial prolongation of the vagal effect, other A-A intervals were not affected. In contrast, verapamil potentiated the vagally mediated initial prolongation in cardiac cycle length at the first dose administered (100 micrograms/kg) from 492 +/- 17 to 561 +/- 14 ms, but other increases in dosages had no further effect. Thus these two calcium channel antagonists have different effects on the sinoatrial chronotropic responses caused by brief vagal stimulation.     

猫冠状动脉缺血与再灌注对房室传导的影响

急性下壁心肌梗塞常引起房室传导功能障碍,然而这种障碍与心肌缺血的内在联系并不很清楚,本实验在去植物性神经传出纤维的猫上进行,通过模板匹配方法从Ｈｉｓ束电图检测Ａ,Ｈ,Ｖ波并测量两心房间期（ＡＡ）,心房波与Ｈｉｓ波间期（ＡＨ）,Ｈｉｓ波与心室波间期（ＨＶ）和心房波与心室波间期（ＡＶ）。结果如下：结扎右冠状动脉后,２０只动物的ＡＨ间期１４只出现增加（Ａ组）６只未出现增加（Ｂ组）对Ｂ组进行快速心房起博和     

Muscarinic type 1 receptors mediate part of nitric oxide's vagal facilitatory effect in the isolated innervated rat right atrium.

We investigated whether vagal cardiac cholinergic facilitation by nitric oxide (NO) is mediated by cardiac muscarinic receptor subtypes in the vagally innervated rat right atrium in vitro. Experiments were carried out in the presence of atenolol (4 microM). The right vagus was stimulated at 4, 8, 16, 32 Hz; pulse duration 1 ms at 20 V for 20s; vagal postganglionic activation was achieved using nicotine (0.1, 0.3, 0.5, 1mM) and the effect on cardiac interval (ms) assessed. Pirenzepine (1 microM), a M1 antagonist, attenuated vagally induced increase in cardiac interval. L-Arginine (0.34 mM) superfused with pirenzepine failed to reverse this attenuation, however, L-arginine applied alone reversed the reduction vagal cardiac slowing. Similarly, sodium nitroprusside (10 microM) applied alone, and not together with pirenzepine, was able to reverse the attenuation of vagal effects caused by pirenzepine. Synthetic MT7 (1 nM) toxin, a selective M1 antagonist confirmed these results. M3 antagonism using para-fluorohexahydrosiladifenidol (p-F-HHSiD) (300 nM) and M4 antagonism with PD 102807 (200 nM) did not affect the vagally induced increase in cardiac interval. Nicotine induced increase in cardiac interval was not altered by pirenzepine. These results show that antagonism of M1 receptors on cardiac vagal preganglionic fibres reduces vagal efficacy which can be recovered by either a nitric oxide synthase substrate or a NO donor.     

Time delay of vagally mediated cardiac baroreflex response varies with autonomic cardiovascular control.

To examine whether changes in autonomic activity have an effect on the latency of the vagally mediated cardiac baroreflex response in humans, we investigated the effects of neck suction fluctuating sinusoidally at 0.2 Hz on R-R intervals (known to be mediated mainly by vagal activity) in the supine position, during 15 degrees head-down tilt and 60 degrees head-up tilt, and during vagotonic (2 microg/kg) and vagolytic (10 microg/kg) doses of atropine while the subjects breathed at 0.25 Hz. The phase shift between fluctuations in neck chamber pressure and in R-R interval was calculated by complex transfer function analysis and was used as a measure of the time delay between carotid baroreceptor stimulation and cardiac effector response. Cardiac baroreflex responsiveness increased significantly during low-dose atropine and decreased during head-up tilt or 10 microg/kg atropine. With increasing tilt angle, the time delay between cyclic baroreceptor stimulation and oscillations in R-R interval increased from 0.32 +/- 0.27 s (head down), to 0.59 +/- 0.25 s (supine position, P < 0.05 vs. head down), and to 0.86 +/- 0.27 s (head up, P < 0.01 vs. supine). Low-dose atropine had a similar effect to head-down tilt on baroreflex latency, whereas 10 microg/kg atropine increased the time delay markedly to 1.24 +/- 0.30 s. Our results demonstrate that changes in autonomic activity, generated either by gravitational stimulus or by atropine, not only affect baroreflex responsiveness but also have a major influence on the latency of the vagally mediated carotid baroreceptor-heart rate reflex. The prolonged baroreflex latency during decreased parasympathetic function may contribute to an unstable regulation of heart rate in patients with cardiac disease.     

Dynamic sympathetic control of atrioventricular conduction time and heart period

Although power spectra of R-R and P-R intervals in response to random respiration show similar frequency distributions, the way in which dynamic sympathetic regulation contributes to such similarity remains unknown. We estimated the transfer function from sympathetic stimulation to the atrioventricular interval (AV conduction time; T(AV)) with and without constant atrial pacing in seven anesthetized cats. The transfer function from sympathetic stimulation to T(AV), except for absolute gain values, approximated a low-pass filter similar to that from sympathetic stimulation to the A-A interval (heart period; T(AA)). The 90%-rise times did not differ between the T(AA) and T(AV) step responses (32.3 +/- 1.8 vs. 29.6 +/- 3.2 s). Constant pacing augmented the T(AV) step response (-0.58 +/- 0.10 vs. -0.86 +/- 0.12 ms/Hz, P < 0.05) without affecting the 90%-rise time. These findings suggest that the dynamic characteristics of sympathetic control are similar between T(AA) and T(AV) despite the different electrophysiological mechanisms determining T(AA) and T(AV). A numerical simulation indicated that if the dynamic characteristics of the sympathetic control do not match between T(AA) and T(AV), a critical condition for initiation of reentrant tachycardia would be encountered.     

Analysis of vagally induced sinus arrhythmias.

Vagal stimulation at precise times in successive cardiac cycles can elicit sinus arrhythmias. Two mechanisms have been identified that can, but do not necessarily, cause these vagally induced sinus arrhythmias. First, changes in cycle length elicited by a given concentration of acetylcholine (ACh) depend on the phase of the pacemaker cell action potential when the ACh binds to muscarinic receptors. Second, acetylcholinesterase degrades ACh rapidly enough for the mean concentration of ACh per cardiac cycle to vary from cycle to cycle. We used a mathematical model of the underlying cellular physiology, to examine whether these mechanisms are responsible for arrhythmogenesis. Computer simulation showed that both mechanisms contribute to the vagally induced sinus arrhythmias.     

Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation

Although the beneficial effects of ventricular rate (VR) slowing during atrial fibrillation (AF) are axiomatic, the precise relationship between VR and hemodynamics has not been determined. We hypothesized that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) by varying the nerve stimulation intensity could achieve precise graded slowing and permit evaluation of an optimal VR during AF. The aims of the present study were the following: 1) to develop a method for computerized vagally controlled VR slowing during AF, 2) to determine the hemodynamic changes at each level of VR slowing, and 3) to establish the optimal anterograde VR during AF. AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 14 dogs. Four target average VR levels, corresponding to 75%, 100%, 125%, and 150% of the sinus cycle length (SCL), were achieved by computer feedback algorithm. VR slowing resulted in improved hemodynamics and polynomial fit analysis found an optimum for the cardiac output at VR slowing of 87% SCL. We conclude that this novel method can be used to maintain slow anterograde conduction with best hemodynamics during AF.     

Ventricular Pacing on the Prognosis of Patients with Pacemaker Implantation

Excessive right ventricular apex pacing has significant adverse effects on the cardiac function and hence, it is necessary to clinically optimize pacing parameters and advocate suitable physiological pacing to safeguard the cardiac function after pacemaker implant. Minimizing ventricular pacing is an atrioventricular node priority function, to encourage ventricular self conduction and to reduce unnecessary right ventricular pacing. Minimized ventricular pacing reduces ventricular pacing by encouraging self atrioventricular conduction function and extending the AV interval. This study is a prospective cohort study to evaluate the changes of cardiac function in patients and serum amino-terminal natriuretic peptide (NT-proBNP) before and after pacing, and the risk of atrial fibrillation with different CUM% VP. The study has shown that the cardiac function will deteriorate with an increase in pacing rate.     

Parasympathetic effects on cardiac electrophysiology during exercise and recovery

Depressed parasympathetic tone is associated with an increased risk of sudden cardiac death. Exercise and the postexercise recovery period, which are associated with parasympathetic withdrawal, are high risk periods for sudden death. However, parasympathetic effects on cardiac electrophysiology during exercise and recovery have not been described. Electrophysiology studies were performed using noninvasive programmed stimulation (NIPS) in nine subjects (age 59 +/- 18 yr) with implanted dual-chamber devices and normal left ventricular function during multiple bicycle exercise sessions. NIPS was performed at rest, during exercise, and in the early recovery period both before and after parasympathetic blockade with atropine. Parasympathetic effect was defined as the value of the parameter of interest in the absence of atropine minus the value of the parameter in the presence of atropine. During exercise, sinus cycle length, atrioventricular (AV) block cycle length, AV interval, and ventricular effective refractory period shortened; in recovery, the values were intermediate between the rest and exercise values (P < 0.0001 by ANOVA). Parasympathetic effects on sinus cycle length, AV block cycle length, AV interval, and ventricular effective refractory period were 247 +/- 140, 58 +/- 20, 76 +/- 20, and 8.6 +/- 7.5 ms at rest, 106 +/- 20, 37 +/- 14, 24 +/- 13, and 2.6 +/- 7.8 ms during exercise, and 209 +/- 114, 50 +/- 23, 35 +/- 21, and 9.5 +/- 11.8 ms during recovery, respectively. There was poor correlation among the parasympathetic effects noted at the sinus node, AV node, and ventricle. Further work evaluating parasympathetic effects on cardiac electrophysiology during exercise and recovery in patients with heart disease is required to elucidate its role in modulating the risk of sudden cardiac death noted at these times.     

AV blocking due to asynchronous vagal stimulation in rats

The parasympathetic nervous system innervates the heart through two cervical vagal branches. The right vagal branch mainly influences the heart rate by the modulation of the rhythmogenesis of the sinoatrial node. The left branch predominantly influences the conduction properties of the atrioventricular (AV) node. We investigated the effect of asynchronous stimulation by the vagal nerves on the occurrence of irregularities in heart rate. In rats, the vagal nerves were isolated and cut. Different vagal stimulation patterns (continuous, pulsed) were applied. The heart was beating spontaneously under continuous vagal stimulation. In case of pulsed vagal stimulation, the atria were paced at different rates. Asynchronicity was induced by delaying the right stimulus with respect to the left stimulus (early right) or the left stimulus with respect to the right stimulus (early left). The value of the fraction of deviated R-R or P-Q intervals in the distribution in the histogram was used to characterize irregularities during a stimulation protocol (duration in case of continuous stimulation: 20 s; pulsed stimulation: 120 s). Under both stimulation patterns (continuous or pulsed), we found that early left vagal stimulation introduced a much larger fraction of deviated intervals in the R-R or P-Q histogram (in R-R: 29.1 +/- 4.9%; in P-Q: 12.90 +/- 1.95%) than early right vagal stimulation (in R-R: 7.4 +/- 2.0%; in P-Q: 1. 05 +/- 0.50%) or synchronous stimulation (in R-R: 8.2 +/- 3.6%; in P-Q: 2.15 +/- 0.75%). We conclude that early stimulation by the left vagal nerve can introduce irregularities in heart rate, mainly due to different degrees of AV nodal blockade.     

Verapamil potentiates vagally mediated sinoatrial chronotropic responses in dogs

A brief burst of electrical stimuli delivered to the vagus nerve during the cardiac cycle elicits a triphasic cardiac chronotropic response. The cardiac cycle length initially increases, then briefly decreases, and subsequently increases again. We studied the effects of a calcium channel blocking agent, verapamil, on these responses to vagal stimulation during sinoatrial nodal rhythm in anesthetized, open-chest dogs. Verapamil increased the basal cardiac cycle length only slightly; however, the primary cardioinhibition was accentuated approximately 40% (from 396 to 555 ms) by verapamil. Neither the acceleratory phase of this triphasic response nor the secondary cardioinhibition was significantly affected by verapamil. These results indicate that verapamil potentiates the initial action of acetylcholine at the sinoatrial node when the vagus is activated with brief stimuli.     

Effects of auditory stimulus timing in the respiratory cycle on the evoked cardiac response in man at rest

The present experiments were carried out in 21 healthy adults to study the effects of auditory stimulus timing within the respiratory cycle on evoked cardiac response. The stimulus (80 dB white noise) was started by the first and finished by the second R-wave after change in respiratory phase, and presented in different series in either early inspiration or early expiration. The spirogram and eight sequential interbeat intervals (IBI) after respiratory phase change were recorded. The mean of IBI and standard deviation (SD) were calculated separately for each IBI of 20 trials for each subject, during both the prestimulus and poststimulus phases. The stimulus effects were expressed as changes from prestimulus conditions, in terms of delta IBI and delta SD. The mean of each of the eight IBI and its SD were found to vary consistently in the same direction, i.e., SD increased with increasing mean IBI. Stimulation during early inspiration did not produce any effect during this respiratory phase. It was not before the beginning of the following expiration that a significant deceleration was evoked, which was associated with an enhanced delta SD, whereas stimulation during early expiration promptly evoked a biphasic cardiac response of the deceleration - acceleration pattern and an increase and decrease in delta SD, respectively. While SD was found to be a function of age, no such finding was obtained for delta IBI and delta SD. These results are discussed in terms of the "vagal gating" hypothesis.     

Arrhythmia and sudden death associated with elevated cardiac chloride channel activity

The identification and analysis of several cationic ion channels and their associated genes have greatly improved our understanding of the molecular and cellular mechanisms of cardiac arrhythmia. Our objective in this study was to examine the involvement of anionic ion channels in cardiac arrhythmia. We used a transgenic mouse model to overexpress the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated chloride channel. We used RNase protection and in situ hybridization assays to determine the level of CFTR expression, and radiotelemetry and in vivo electrophysiological study in combination with pharmacological intervention to analyse the cardiac function. Cardiac CFTR overexpression leads to stress-related sudden death in this model. In vivo intracardiac electrophysiological studies performed in anaesthetized mice showed no significant differences in baseline conduction parameters including atrial-His bundle (AH) or His bundle-ventricular (HV) conduction intervals, atrioventricular (AV) Wenckebach or 2:1 AV block cycle length and AV nodal functional refractory period. However, following isoproterenol administration, there was marked slowing of conduction parameters, including high-grade AV block in transgenic mice, with non-sustained ventricular tachycardia easily inducible using programmed stimulation or burst pacing. Our sudden death mouse model can be a valuable tool for investigation of the role of chloride channels in arrhythmogenesis and, potentially, for future evaluation of novel anti-arrhythmic therapeutic strategies and pharmacological agents.     

降钙素基因相关肽在豚鼠冠脉血流量和心脏传导系统作用的比较

本文目的在于深入研究降钙素基因相关肽（ＣＧＲＰ）对豚鼠冠状血流量以及心脏传导系统各部分的作用。采用Ｌａｎｇｅｎｄｏｒｆｆ法灌流心脏,同步记录心脏表面电图和希氏束电活动。观察应用ＣＧＲＰ前后的冠脉流量、自主心率、在相同心房周期下的房室结（ＡＨ）及希浦系传导时间（ＨＶ）、心脏出现３：２文氏传导及２：１房室传导阻滞所需的最长起搏周期（ＰＣＬ３：２,ＰＣＬ２：１）。ＣＧＲＰ（３－３０ｎｍｏｌ／Ｌ）可显著增     

Time-dependency of the response to a single vagal stimulus in the rabbit heart

The time-dependency of vagal effects on P-P cycle was studied in rabbits, chosen because of high heart rate, in order to verify the occurrence of this phenomenon already described for animals with lower heart rate. In five rabbits with different resting cardiac cycles, vagal stimuli were delivered randomly. The results indicate that for heart rates higher than 120 beats/min no occurrence of Brown and Eccles' time-dependency was observed. It is evident, however, the different responsiveness of the pacemaker to vagal stimuli delivered at different times of the cardiac cycle. In particular a stimulus given beyond 40-50% of the cardiac cycle does not affect the same but the next cycle.     

Electrophysiological effects of ouabain in 6-hydroxydopamine pretreated dogs

Chemical sympathectomy and bilateral vagotomy were used to evaluate the contribution of each division of the autonomic nervous system in the electrophysiological actions of ouabain. Intact and chemically sympathectomized dogs were given successive and cumulative doses of ouabain until toxicity became manifest (ventricular extrasystoles and (or) ventricular tachycardia). An additional group of normal and sympathectomized animals was also submitted to bilateral vagotomy in the presence of a therapeutic dose of ouabain. Sinus cycle length, AH interval of the His bundle electrogram, atrioventricular junctional effective and functional refractory periods were increased by ouabain at therapeutic doses. These effects were no different in sympathectomized dogs than in intact dogs, indicating the absence of any significant contribution of efferent sympathetic neural activity. However, our results suggested that vagal enhancement was the main mechanism whereby ouabain produced sinus bradycardia and depression of atrioventricular conduction. Sympathectomy with 6-OHDA did not modify nor abolish ouabain toxicity. However, toxic doses were significantly higher in sympathectomized animals than in normal animals. Considering that increasing heart rate by cardiac pacing or vagotomy significantly lowered toxic doses of ouabain in both intact and sympathectomized dogs, it is possible that sympathectomy could influence ouabain toxicity by altering heart rate alone.     

Transposition of the pacemaker in the right atrium during stimulation of the vagus nerve in the dog

The heart rate and intraatrial latencies between epicardial electrograms from three sites of the right atrium have been studied during vagal stimulation in open-chest dogs. It has been shown that alterations of latencies started at a certain cardiac cycle length irrespective of pacing frequency. A transitional process of changes from a steady latency value in the control to another steady value during vagal stimulation has been observed. The transitional process has been simulated in experimental procedure in which two sites of the right atrium were paced at close and constant frequencies. To interpret the results obtained one-dimensional model of the sinus node has been constructed. According to the model, pacemaker shift within the sinus node results from a competition between two foci of automaticity with close intrinsic frequencies.     

D-glucose modulates synaptic transmission from the central terminals of vagal afferent fibers

Experimental evidence suggests that glucose modulates gastric functions via vagally mediated effects. It is unclear whether glucose affects only peripheral vagal nerve activity or whether glucose also modulates vagal circuitry at the level of the brain stem. This study used whole cell patch-clamp recordings from neurons of the nucleus of the tractus solitarius (NTS) to assess whether acute variations in glucose modulates vagal brain stem neurocircuitry. Increasing D-glucose concentration induced a postsynaptic response in 40% of neurons; neither the response type (inward vs. outward current) nor response magnitude was altered in the presence of tetrodotoxin suggesting direct effects on the NTS neuronal membrane. In contrast, reducing d-glucose concentration induced a postsynaptic response (inward or outward current) in 54% of NTS neurons; tetrodotoxin abolished these responses, suggesting indirect sites of action. The frequency, but not amplitude, of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was correlated with d-glucose concentration in 79% of neurons tested (n = 48). Prior surgical afferent rhizotomy abolished the ability of D-glucose to modulate spontaneous EPSC frequency, suggesting presynaptic actions at vagal afferent nerve terminals to modulate glutamatergic synaptic transmission. In experiments in which EPSCs were evoked via electrical stimulation of the tractus solitarius, EPSC amplitude correlated with D-glucose concentration. These effects were not mimicked by L-glucose, suggesting the involvement of glucose metabolism, not uptake, in the nerve terminal. These data suggest that the synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose-evoked changes in vagovagal reflexes occurs.     

Oxidative stress impairs cardiac chemoreflexes in diabetic rats

We investigated the effects of diabetes mellitus and antioxidant treatment on the sensory and reflex function of cardiac chemosensory nerves in rats. Diabetes was induced by streptozotocin (STZ; 85 mg/kg ip). Subgroups of sham- and STZ-treated rats were chronically treated with an antioxidant, vitamin E (60 mg/kg per os daily, started 2 days before STZ). Animals were studied 6-8 wk after STZ injection. We measured renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MABP), and cardiac vagal and sympathetic afferent activities in response to stimulation of chemosensitive sensory nerves in the heart by epicardial application of capsaicin (Caps) and bradykinin (BK). In cardiac sympathetic-denervated rats, Caps and BK (1-10.0 microg) evoked a vagal afferent mediated reflex depression of RSNA and MABP, which was significantly blunted in STZ-treated rats (P < 0.05). In vagal-denervated rats, Caps and BK (1-10.0 microg) evoked a sympathetic afferent-mediated reflex elevation of RSNA and MABP, which also was significantly blunted in STZ-treated rats (P < 0.05). Chronic vitamin E treatment effectively prevented these cardiac chemoreflex defects in STZ-treated rats without altering resting blood glucose or hemodynamics. STZ-treated rats with insulin replacement did not exhibit impaired cardiac chemoreflexes. In afferent studies, Caps and BK (0.1 g-10.0 microg) increased cardiac vagal and sympathetic afferent nerve activity in a dose-dependent manner in sham-treated rats. These responses were significantly blunted in STZ-treated rats. Vitamin E prevented the impairment of afferent discharge to chemical stimulation in STZ rats. The following were concluded: STZ-induced, insulin-dependent diabetes in rats extensively impairs the sensory and reflex properties of cardiac chemosensitive nerve endings, and these disturbances can be prevented by chronic treatment with vitamin E. These results suggest that oxidative stress plays an important role in the neuropathy of this autonomic reflex in diabetes.