Parasympathetic control of the heart. II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate.

Intracardiac pathways mediating the parasympathetic control of various cardiac functions are incompletely understood. Several intracardiac ganglia have been demonstrated to potently influence cardiac rate [the sinoatrial (SA) ganglion], atrioventricular (AV) conduction (the AV ganglion), or left ventricular contractility (the cranioventricular ganglion). However, there are numerous ganglia found throughout the heart whose functions are poorly characterized. One such ganglion, the posterior atrial (PA) ganglion, is found in a fat pad on the rostral dorsal surface of the right atrium. We have investigated the potential impact of this ganglion on cardiac rate and AV conduction. We report that microinjections of a ganglionic blocker into the PA ganglion significantly attenuates the negative chronotropic effects of vagal stimulation without significantly influencing negative dromotropic effects. Because prior evidence indicates that the PA ganglion does not project to the SA node, we neuroanatomically tested the hypothesis that the PA ganglion mediates its effect on cardiac rate through an interganglionic projection to the SA ganglion. Subsequent to microinjections of the retrograde tracer fast blue into the SA ganglion, >70% of the retrogradely labeled neurons found within five intracardiac ganglia throughout the heart were observed in the PA ganglion. The neuroanatomic data further indicate that intraganglionic neuronal circuits are found within the SA ganglion. The present data support the hypothesis that two interacting cardiac centers, i.e., the SA and PA ganglia, mediate the peripheral parasympathetic control of cardiac rate. These data further support the emerging concept of an intrinsic cardiac nervous system.     

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.     

Functional anatomy of canine cardiac nerves.

In 20 anesthetized dogs the thoracic autonomic nerves were carefully exposed in order to determine which produced cardiovascular responses when the afferent or efferent component of each was stimulated. Efferent parasympathetic and sympathetic fibers arise from the caudal cervical ganglion regions bilaterally as well as from the vagus caudally to that ganglion. The majority of negative chromotropic, dromotropic and inotropic fibers arise from the vagus or near the recurrent laryngeal nerves; however, some small parasympathetic fibers also arise from the vagi down to the level of the pulmonary vessels. Efferent sympathetic nerves are relatively large with the exception of the stellate cardiac nerves, and produce specific positive chronotropic or inotropic responses. Afferent fibers are numerous in the recurrent cardiac, innominate, ventromedial and dorsal nerves and not very numerous in both stellate cardiac nerves as well as in the nerves at the level of the pulmonary vessels; thus there are numerous cholinergic and adrenergic efferent fibers which exhibit specific chronotropic or inotropic responses. The correlation between neural anatomy and specific physiological cardiodynamics illustrates beautifully the interrelationship of structure and function which exists within the autonomic nervous system.     

迷走神经对心室功能的调控机制研究进展

自主神经系统由交感神经系统和副交感神经系统（迷走神经）组成,二者相互拮抗,对哺乳动物心脏的功能调控具有重要的作用。副交感（迷走）神经对心房可产生变时、变传导和变力作用,但是对心室的支配及对心室的调控作用还不清楚。一直以来都存在一个误解,认为交感神经支配心脏的各个部位而副交感神经仅支配心脏的室上性组织,对心室没有支配。近年来的研究显示在一些哺乳动物的心脏上,胆碱能神经在心室也有分布,且对左心室的功能有重要的调控作用。本文从解剖及组织化学、分子生物学和功能学三个方面阐述迷走神经对心室的支配及调控证据,并对心章收缩功能的迷走神经（毒蕈碱）调控及其信号转导途径进行综述。     

Fade of the responses of the isolated, blood-perfused dog atrium to cholinergic interventions

In the isolated, blood-perfused, canine right atrium, intramural parasympathetic nerve stimulation and intra-arterial infusions of acetylcholine induced substantial negative chronotropic and inotropic responses. The responses to parasympathetic stimulation reached their maximum values quickly, and then usually faded back toward control levels over the next 1 or 2 min of stimulation. The fade of the responses at high stimulation frequencies (greater than or equal to 30 Hz) was significantly greater than that at lower frequencies. The inotropic responses to acetylcholine infusion (1 microgram/min) faded slightly but significantly, whereas the chronotropic responses did not fade at all. These results suggest that the fade of the cardiac responses to parasympathetic stimulation is mainly ascribable to a progressive reduction in the rate of acetylcholine release from the nerve endings, especially at higher stimulation frequencies. The fade of the inotropic responses was more pronounced and had a longer time course than that of the chronotropic responses. Furthermore, the fade of the inotropic responses diminished significantly as the response magnitude was augmented by an increase in stimulation voltage. Conversely, the fade of chronotropic responses was not significantly affected by this intervention. These differences in the inotropic and chronotropic responses to neural stimulation, and the occurrence of a slight fade of the inotropic response to acetylcholine infusion, suggest that in addition to the predominant prejunctional mechanism, a postjunctional phenomenon may also be partly responsible for the fade of the inotropic response to cholinergic interventions.     

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na(+) channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or beta-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not beta-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.     

The inotropic and chronotropic responses of the guinea pig and dog myocardium to isoprenaline and salbutamol.

The relative effects of isoprenaline and salbutamol on the inotropic and chronotropic responses of the denervated myocardium of the chloralose anesthetized dog and of the isolated guinea pig atrium, and the inotropic response of the isolated dog papillary muscle were studied. Both the in vivo dog heart and the in vitro guinea pig atrium displayed a similar relative response pattern to isoprenaline and salbutamol with regard to their inotropic and chronotropic responses. However, a comparison of the relative inotropic responses of the dog heart in vivo and in vitro showed that in vitro, salbutamol has a much lower affinity and efficacy for the adrenergic receptors than isoprenaline.     

Autonomic regulation of subsidiary atrial pacemakers during exercise

Cardiac responses to graded treadmill exercise were compared in conscious dogs before and after excision of the sinoatrial node (SAN) and adjacent tissue along the sulcus terminalis. The chronotropic and dromotropic responses to dynamic exercise were compared with and without selective muscarinic (atropine) and/or beta-adrenergic (timolol) blockade. With the SAN intact, cardiac acceleration was prompt during onset of exercise and in proportion to work intensity. Immediately after SAN excision (1-7 days), pacemaker activity exhibited marked instability in rate and pacemaker location, with rapid shifts between atrial and junctional foci. Soon thereafter (1-2 wk), subsidiary atrial pacemakers (SAPs) assumed the primary pacemaker function. Although the SAP foci demonstrated stable heart rates and atrioventricular (AV) intervals at rest and during exercise, heart rates at rest and during steady-state exercise were reduced 34% from corresponding levels in the SAN-intact state, both with and without selective autonomic blockade. For control of dromotropic function, animals with SAP foci showed pronounced shortening in AV interval in conjunction with exercise that was further exacerbated by pretreatment with atropine. Eight weeks after excision of the primary SAN pacemakers, direct electrophysiological mapping localized the SAP foci to either the inferior right atrium along the sulcus terminalis or the dorsal cranial right atrium (in or near Bachmann's bundle). Animals with SAPs localized to the inferior right atrium had a more marked suppression in heart rate with a corresponding greater decrease in AV interval during exercise than dogs with SAP foci identified within the dorsal cranial right atrium.     

Role of the endothelial glycocalyx in dromotropic, inotropic, and arrythmogenic effects of coronary flow

Coronary flow regulates cardiac functions, and it has been suggested that endothelial membrane glycosylated proteins are the primary shear stress mechanosensors. Our hypothesis was that if these proteins are the sensors for flow, then intracoronary perfusion of lectins or specific antibodies should differentially depress coronary flow-enhanced responses of different parenchymal cell types such as auricular-ventricular (A-V) nodal cells (dromotropic effect), contractile myocytes (inotropic effect), and junctional Purkinje-muscle cells (spontaneous ventricular rhythm). The coronary flow stimulatory effects on A-V delay and spontaneous ventricular rhythm were selectively depressed by six of eight lectins. None of the lectins depressed the coronary flow inotropic effect. Antibodies against endothelial surface proteins, alpha(v)beta(5)-integrin and sialyl-Lewis(b) glycan, depressed the dromotropic but not the inotropic effects of coronary flow, whereas the vascular cell adhesion molecule 1 antibody had no effect on the dromotropic, but enhanced the inotropic, effect. The fact that lectins and antibodies differentially depressed regional coronary flow effects suggests that there is a chemical distinctiveness in their intravascular endothelial cell surfaces. However, nonselective cross-linking of endothelial glycocalyx proteins with 2,000-kDa dextran-aldehyde or vitronectin indistinctively depressed the dromotropic and inotropic effects of coronary flow. These results indicate that coronary flow-induced stress acts on specific structures located in the capillary intravascular membrane glycocalyx.     

Chronotropic and inotropic effects of PGE2 on isolated rat atria from normal and spontaneously hypertensive rats (SHR)

Prostaglandin E₂ (PGE₂) was tested for its ability to produce a positive chronotropic and inotropic response on isolated atria obtained from normal (NWR) and spontaneously hypertensive rats (SHR). There was no significant difference in the basal in vitro heart rate of atria from NWR and SHR. There was no significant difference in the increase in heart rate or contractile force produced by PGE₂ (0.568 μM and 5.68 μM) on atria obtained from NWR compared to SHR. It appears there is no difference in the in vitro cardiac reactivity to PGE₂ of atrial tissue from SHR compared to normotensive controls under the conditions of these experiments. This is in contrast to the previously reported decrease in contractile responses of atrial tissue of SHR to certain cardiac stimulants, and the diminished contractile response produced by PGE₂ on arterial tissue from SHR compared to NWR.     

Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.     

Cardiac activity of some peptide hormones in the frog,Rana tigrina

1. The cardiac responses of isolated frog (Rana tigrina) atria to peptide hormones were studied.2. Calcitonin gene-related peptide (CGRP), arginine vasotocin (AVT), bovine parathyroid hormone fragment (bPTH-(1–34)) and oxytocin (OXY) produced dose-related positive chronotropic and inotropic responses; atrial natriuretic peptide (ANP) was negative chronotropic and inotropic; cholecystokinin (CCK), vasoactive intestinal peptide (VIP) were without effects.3. The dose-related responses under bPTH-(1–34) stimulation but not CGRP or AVT were attenuated in the presence of ANP (300 ng/ml, ≈0.98 × 10⁻⁷ M). As expected ANP decreased the basal AR and AT responses of the isolated atria and the inhibitory effects were dose-dependent.4. As shown previously, propranolol blocked the atrial tension stimulated by bPTH (1–34) but did not alter the cardiac responses to CGRP and AVT.5. In the presence of β-adrenergic blocker (propranolol 10⁻⁷M) or ANP (10⁻⁷M), the AR and AT changes under ISO stimulation in the frog were also decreased.6. These cardiac changes suggest the cardiac inhibitory effects of ANP are related to β-adrenoceptor activity and ANP might be a β antagonist.     

Cardiac histamine receptors.

Current evidence pertinent to the identification of cardiac histamine receptors in the guinea pig is reviewed. Pharmacological characterization has been aided by the use of selective agonists and antagonists for both types of histamine receptors. It appears that both H1 and H2 receptors mediate the cardiac effects of histamine. Histamine H2 receptors mediate the positive chronotropic and ventricular inotropic effects. H1 receptors mediate the negative dromotropic effect of histamine and possibly the atrial inotropic effect. Histamine-induced arrhythmias involve H1 receptors (arrhythmias of conduction) or H2 receptors (arrhythmias of automaticity), or both. The receptors mediating the histamine-induced increase in coronary flow are not as clearly defined: both H1 and H2 receptors might be implicated.     

Pharmacological evidence for cardiac muscarinic receptor subtypes

The chronotropic and inotropic effects of muscarinic receptor agonists (Acetylcholine, Arecoline, Carbachol, Furtrethonium) and antagonists (Atropine, N-methyl and N-butyl scopolammonium, pirenzepine) on isolated guinea-pig atria were studied. All had a greater affinity constants for muscarinic receptors as assessed in terms of inotropic effects than in terms of chronotropic effects. This difference, well correlated with the pharmacological effect, suggests the occurrence of cardiac muscarinic receptor subtypes, one mediating heart rate and the other contractile force. The ratio of chronotropic to inotropic potencies for each agent shows that the physiological mediator. Acetylcholine, differentiates best between the two subtypes, while atropine is the least discriminatory.     

Direct actions of prostaglandins E1, A1, and F2α on myocardial contraction

The inotropic and chronotropic actions of prostaglandin (PG) types PGE₁, PGA₁, and PGF_2α were studied in isolated guinea pig right and left atria, and papillary muscles; rabbit atria; and toad ventricular strips in order to more completely define the cardiac contractile properties of PG. All three prostaglandins, in muscle bath concentrations of 10μg/ml, exerted positive inotropic and chronotropic actions on guinea pig atrium. These contractile effects were persistent after removal of PG from the muscle bath and appeared to limit the relative response to a subsequent dose of PG. The inotropic action of PGE₁ was present over a wide range of bath calcium concentrations (1.1 to 4.4 mM/L). Beta adrenergic receptor blockade, histamine blockade, and pretreatment with reserpine failed to significantly affect the inotropic actions of PG. Norepinephrine and histamine produced more potent inotropic and chronotropic effects on guinea pig atria than did PG and these contractile effects did not exhibit persistence or tachyphylaxis. The prostaglandins did not significantly affect dose response curves for norepinephrine inotropic and chronotropic actions. The prostaglandins had no effect on the force or frequency of contraction in rabbit atria. PGE₁ exerted a positive inotropic effect on toad ventricular myocardium whereas PGA₁ had no effect and PGF_2α had a negative inotropic action.     

Actions of Ya-hom, a herbal drug combination, on isolated rat aortic ring and atrial contractions

The effect of the Thai popular medicine Ya-hom on cardiovascular function was studied in isolated rat aortic ring and atrium by comparison with norepinephrine (NE). Water extraction of Ya-hom at concentrations of 0.83, 1.67, 8.33 and 16.67 mg/ml stimulated aortic ring contraction dose-dependently. The maximum contraction, at 16.67 mg/ml, was about 14% that of NE. This stimulatory effect of Ya-hom was inhibited partially by phentolamine, which indicated that the effect of Ya-hom was partially dependent on the alpha receptor, similar to NE. Administration of Ya-hom with NR decreased the force of aortic ring contraction as compared to the effect of NE alone, indicating that Ya-hom may have a partial alpha-agonist activity. Ya-hom at concentrations of 1.67, 8.33 and 16.67 mg/ml showed a dose-dependent, positive inotropic and negative chronotropic effects. Ya-hom increased the force of isolated atrial contraction with a slow onset and prolonged action. In contrast to norephinephrine, which acted on beta1 receptor, causing positive inotropic and chronotropic effects, propranolol did not alter the effect of Ya-hom on the atrial contraction. This shows that the action of Ya-hom on atrial contraction does not involve beta receptor.     

The effect of adrenomedullin,amylin fragment 8-37 and calcitonin gene-related peptide on contractile force,heart rate and coronary perfusion pressure in isolated rat hearts

The effect of human adrenomedullin, human amylin fragment 8-37 (amylin 8-37) and rat calcitonin gene-related peptide (CGRP) on contractile force, heart rate and coronary perfusion pressure has been investigated in the isolated perfused rat hearts. Adrenomedullin (2x10(-10), 2x10(-9) and 2x10(-8) M) produced a significant decrease in contractile force and perfusion pressure, but only the peptide caused a decline in heart rate at the highest dose. Amylin (10(-9), 10(-8) and 10(-7) M) significantly increased and then decreased contractile force. Two doses of amylin (10(-8) and 10(-7) M) induced a significant increase in heart rate, however amylin did not change perfusion pressure in all the doses used. Rat alpha CGRP (10(-8), 10(-7) and 10(-6) M) evoked a slight decline in contractile force following a significant increase in contractile force induced by the peptide. CGRP in all the doses raised heart rate and lowered perfusion pressure. Our results suggest that adrenomedullin has negative inotropic, negative chronotropic and coronary vasodilator actions. Amylin produces a biphasic inotropic effect and evokes a positive chronotropy. CGRP causes positive inotropic, positive chronotropic and vasodilatory effects in isolated rat hearts.     

Compensatory possibilities of the crayfish cardiovascular system under conditions of progressing hypoxia

Under laboratory conditions, the rate of oxygen consumption and changes of inotropic and chronotropic parameters of work of the crayfish heart were studied under conditions of hypoxia and anoxia. In all studied crayfishes regardless of species and sex there exists regulation of the rate of oxygen consumption until its concentration in water about 1 mg/l at room temperature, the rate of standard metabolism being independent of oxygen concentration above 24% from saturation; below this level the rate of oxygen consumption amounts to 54% of its standard consumption. The ability to regulate metabolism in hypoxia is also presents in small crayfishes; however, their respiration rate is several times higher than in adult animals. Under conditions of severe hypoxia the cardiovascular system (CVS) of crayfish functions in economic regime with use of dependent regimes of initiation of inotropic and chronotropic heart parameters; with increase of severity of the hypoxic factor, a tendency is observed for a decrease of the heart rate (HR) and for an increase of amplitude parameters. Under anoxic conditions the crayfish demonstrated the heart contractile activity for almost 10 h; analysis of the HR by the method of variation pulsometry has shown deterioration of the crayfish functional state, which was due to desynchronization of regulatory processes in the central and peripheral chains of control of CVS.     

Enhancement of Gustatory Neural Responses by Parasympathetic Nerve in the Frog

The autonomic nervous system affects the gustatory responses in animals. Frog glossopharyngeal nerve (GPN) contains the parasympathetic nerve. We checked the effects of electrical stimulation (ES) of the parasympathetic nerves on the gustatory neural responses. The gustatory neural impulses of the GPNs were recorded using bipolar AgCl wires under normal blood circulation and integrated with a time constant of 1 s. Electrical stimuli were applied to the proximal side of the GPN with a pair of AgCl wires. The parasympathetic nerves of the GPN were strongly stimulated for 10 s with 6 V at 30 Hz before taste stimulation. The integrated neural responses to 0.5 M NaCl, 2.5 mM CaCl₂, water, and 1 M sucrose were enhanced to 130–140% of the controls. On the other hand, the responses for 1 mM Q-HCl and 0.3 mM acetic acid were not changed by the preceding applied ES. After hexamethonium (a blocker of nicotinic ACh receptor) was intravenously injected, ES of the parasympathetic nerve did not modulate the responses for all six taste stimuli. The mechanism for enhancement of the gustatory neural responses is discussed.     

Roles of the AV junction in determining the ventricular response to atrial fibrillation.

The statistical properties of RR interval sequences during cholinergic atrial fibrillation were studied in anesthetized dogs both in control conditions and after the selective injection of dromotropic agents into the atrioventricular (AV) node artery. It was observed that RR interval histogram configurations depended mainly on the mean heart rate, regardless of whether it was a control or a post-injection sequence. The sequences were found to vary from almost regular at fast rates to highly irregular at slow rates, covering all intermediate possibilities. Since the injections of dromotropic agents into the AV node artery were carried out during sinus rhythm between the episodes of fibrillation, their influences on the AV junction, as reflected both on the length of the PR interval during sinus rhythm and on the RR interval dispersion during fibrillation, could be compared. The dispersion of RR intervals was found to increase as the PR interval duration became longer. In addition, it was observed that the generally random character of the RR interval sequences during fibrillation was not affected by the injection of dromotropic agents into the AV node artery. These results were interpreted as an indication that, for a well-established atrial fibrillation, the degree of ventricular irregularity (dispersion of RR intervals) is related to the conductivity within the AV junction and that the random character of RR interval sequences is related to the atrial fibrillatory activity itself.