Intrinsic cardiac nervous system in tachycardia induced heart failure

The purpose of this study was to test the hypothesis that early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiac function. After 2 wk of rapid ventricular pacing in nine anesthetized canines, cardiac and right atrial neuronal function were evaluated in situ in response to enhanced cardiac sensory inputs, stimulation of extracardiac autonomic efferent neuronal inputs, and close coronary arterial administration of neurochemicals that included nicotine. Right atrial neuronal intracellular electrophysiological properties were then evaluated in vitro in response to synaptic activation and nicotine. Intrinsic cardiac nicotine-sensitive, neuronally induced cardiac responses were also evaluated in eight sham-operated, unpaced animals. Two weeks of rapid ventricular pacing reduced the cardiac index by 54%. Intrinsic cardiac neurons of paced hearts maintained their cardiac mechano- and chemosensory transduction properties in vivo. They also responded normally to sympathetic and parasympathetic preganglionic efferent neuronal inputs, as well as to locally administered alpha-or beta-adrenergic agonists or angiotensin II. The dose of nicotine needed to modify intrinsic cardiac neurons was 50 times greater in failure compared with normal preparations. That dose failed to alter monitored cardiovascular indexes in failing preparations. Phasic and accommodating neurons identified in vitro displayed altered intracellular membrane properties compared with control, including decreased membrane resistance, indicative of reduced excitability. Early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiodynamics. While maintaining its capacity to transduce cardiac mechano- and chemosensory inputs, as well as inputs from extracardiac autonomic efferent neurons, intrinsic cardiac nicotine-sensitive, local-circuit neurons differentially remodel such that their capacity to influence cardiodynamics becomes obtunded.     

Function of human intrinsic cardiac neurons in situ

We sought to determine the behavior of intrinsic cardiac neurons in human subjects undergoing cardiac surgery and to correlate their activity with hemodynamics status. A lead II electrocardiogram, pulmonary artery pressure, and systemic arterial pressure were recorded along with extracellular activity generated by right atrial neurons in 10 patients undergoing coronary artery bypass surgery. Identified neurons generated spontaneously activity that was, for the most part, unrelated to the cardiac cycle. Most neurons were activated by gentle mechanical distortion of ventricular epicardial loci. The activity generated by neurons in each patient increased when arterial pressure increased and decreased when arterial pressure fell. Intrinsic cardiac neurons continued to generate activity during cardioplegia and cardiopulmonary bypass, but at reduced levels. Normal neuronal activity was restored postbypass. It is concluded that human intrinsic cardiac neurons generate spontaneous activity and that many receive inputs from ventricular mechanosensory neurites. The latter may account for the fact that their behavior depends, in part, on cardiac dynamics. They are also sensitive to intravenously administered pharmacological agents. These data also indicate that cardiopulmonary bypass and cardioplegia do not induce residual depression of their function.     

Effects of chronic cardiac decentralization on functional properties of canine intracardiac neurons in vitro

Although intrinsic cardiac neurons display ongoing activity after chronic interruption of extrinsic autonomic inputs to the heart, the effects of decentralization on individual neurons remain unknown. The objective of this study was to determine the effects of chronic (3-4 wk) surgical decentralization on intracellular properties of, and neurotransmission among, neurons contained within the canine intrinsic right atrial ganglionated plexus in vitro. Properties of neurons from decentralized hearts were compared with those of neurons from sham-operated hearts (controls). Two populations of neurons were identified by their firing behavior in response to intracellular current injection. Fifty-nine percent of control neurons and 72% of decentralized neurons were phasic (discharged one action potential on excitation). Forty-one percent of control neurons and 27% of decentralized neurons were accommodating (multiple discharge with decrementing frequency). After chronic decentralization, input resistance of phasic neurons increased, whereas the duration of afterhyperpolarization of accommodating neurons decreased. Postsynaptic responses to interganglionic nerve stimulation were evoked in 89% of control neurons and 83% of decentralized neurons; the majority of these responses involved nicotinic receptors. These results show that, after chronic decentralization, intrinsic cardiac neurons 1) undergo changes in membrane properties that may lead to increased excitability while 2) maintaining synaptic neurotransmission within the intrinsic cardiac ganglionated plexus.     

Cardiac neuronal hierarchy in health and disease

The cardiac neuronal hierarchy can be represented as a redundant control system made up of spatially distributed cell stations comprising afferent, efferent, and interconnecting neurons. Its peripheral and central neurons are in constant communication with one another such that, for the most part, it behaves as a stochastic control system. Neurons distributed throughout this hierarchy interconnect via specific linkages such that each neuronal cell station is involved in temporally dependent cardio-cardiac reflexes that control overlapping, spatially organized cardiac regions. Its function depends primarily, but not exclusively, on inputs arising from afferent neurons transducing the cardiovascular milieu to directly or indirectly (via interconnecting neurons) modify cardiac motor neurons coordinating regional cardiac behavior. As the function of the whole is greater than that of its individual parts, stable cardiac control occurs most of the time in the absence of direct cause and effect. During altered cardiac status, its redundancy normally represents a stabilizing feature. However, in the presence of regional myocardial ischemia, components within the intrinsic cardiac nervous system undergo pathological change. That, along with any consequent remodeling of the cardiac neuronal hierarchy, alters its spatially and temporally organized reflexes such that populations of neurons, acting in isolation, may destabilize efferent neuronal control of regional cardiac electrical and/or mechanical events.     

Chronic decentralization of the heart differentially remodels canine intrinsic cardiac neuron muscarinic receptors

The objective of the study was to determine if chronic interruption of all extrinsic nerve inputs to the heart alters cholinergic-mediated responses within the intrinsic cardiac nervous system (ICN). Extracardiac nerve inputs to the ICN were surgically interrupted (ICN decentralized). Three weeks later, the intrinsic cardiac right atrial ganglionated plexus (RAGP) was removed and intrinsic cardiac neuronal responses were evaluated electrophysiologically. Cholinergic receptor abundance was evaluated using autoradiography. In sham controls and chronic decentralized ICN ganglia, neuronal postsynaptic responses were mediated by acetylcholine, acting at nicotinic and muscarinic receptors. Muscarine- but not nicotine-mediated synaptic responses that were enhanced after chronic ICN decentralization. After chronic decentralization, muscarine facilitation of orthodromic neuronal activation increased. Receptor autoradiography demonstrated that nicotinic and muscarinic receptor density associated with the RAGP was unaffected by decentralization and that muscarinic receptors were tenfold more abundant than nicotinic receptors in the right atrial ganglia in each group. After chronic decentralization of the ICN, intrinsic cardiac neurons remain viable and responsive to cholinergic synaptic inputs. Enhanced muscarinic responsiveness of intrinsic cardiac neurons occurs without changes in receptor abundance.     

Adenosine A1 receptor activation reduces myocardial reperfusion effects on intrinsic cardiac nervous system

The intrinsic cardiac nervous system is the final common integrator of regional cardiac function. The ischemic myocardium modifies this nervous system. We sought to determine the role that intrinsic cardiac neuronal P(1) purinergic receptors play in transducing myocardial ischemia and the subsequent reperfusion. The activity generated by ventricular neurons was recorded concomitant with cardiac hemodynamic variables in 44 anesthetized pigs. Regional ventricular ischemia was induced by briefly occluding (30 s) the ventral interventricular coronary artery distal to the arterial blood supply of identified ventricular neurons. Adenosine (100 microM) was administered to these neurons via their local arterial blood supply during or immediately after transient coronary artery occlusion. Occlusion was also performed following local administration of adenosine A(1) [8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] or A(2) [3,7-dimethyl-1-propargylxanthine (DMPX)] receptor blocking agents. The activity generated by ventricular neurons was modified by transient coronary artery occlusion and the subsequent reperfusion (||Delta|| 112 +/- 14 and 168 +/- 34 impulses/min, respectively; P < 0.01 vs. preischemic states). Locally administered adenosine attenuated neuronal responses to reperfusion (-75%; P < 0.01 compared with normal reperfusion) but not ischemia. The neuronal stabilizing effects that adenosine elicited during reperfusion persisted in the presence of DMPX but not DPCPX. It is concluded that activation of neuronal adenosine A(1) receptors stabilizes the intrinsic cardiac nervous system during reperfusion.     

Cardiac responses elicited by peptides administered to canine intrinsic cardiac neurons.

In order to study the effects of peptides on intrinsic cardiac neurons, substance P, bradykinin, oxytocin, calcitonin gene related peptide, atrial natriuretic peptide and vasoactive intestinal peptide were administered into canine atrial or ventricular ganglionated plexi. When substance P was injected into right atrial or cranial medial ventricular ganglionated plexi heart rate, atrial force and ventricular intramyocardial pressures were augmented. No cardiac changes occurred when similar volumes of saline (i.e., peptide vehicle) were injected into these ganglionated plexi. When bradykinin was injected into atrial or ventricular ganglionated plexi heart rate, atrial force and ventricular force were augmented in approximately 50% and depressor responses were elicited in approximately 50% of these animals. When oxytocin was injected into right atrial ventral ganglionated plexi heart rate and atrial forces were reduced in five of ten dogs studied. No cardiac changes occurred when oxytocin was injected into left atrial or ventricular ganglionated plexi. No responses were elicited when calcitonin gene related peptide, atrial natriuretic peptide or vasoactive intestinal peptide was administered into atrial or ventricular ganglionated plexi. Following acute decentralization of the heart, no significant responses were elicited by repeat administrations of substance P, bradykinin or oxytocin, implying that connectivity with central nervous system neurons was necessary for consistent responses to be elicited. It is concluded that substance P, bradykinin and oxytocin can affect neurons on the heart such that cardiodynamics are modified, these different peptides eliciting different cardiac responses.     

Distribution of intrinsic cardiac neurons in whole-mount guinea pig atria identified by multiple neurochemical coding

Functional data indicate that neurons in distinct regions of the heart exert preferential regional cardiac control. To date the regional distribution of specific types of neurons within the intrinsic cardiac nervous system remains unknown, as does their associations with distinct neurotransmitter and/or neuromodulatory profiles. This study was designed to ascertain: (1) the distribution of different classes of neurons within the intrinsic cardiac nervous system as determined by microscopic analysis; (2) the neurochemical profiles of neurons in differing atrial loci; (3) which neurochemicals are co-localized within specific populations of intrinsic cardiac neurons; and (4) the distribution of specific sub-populations of neurons expressing specific immunoreactivities. Taking advantage of confocal laser scanning microscopy and distinct immunoreactive fluorescent markers in various double-label combinations, several sub-populations of intrinsic cardiac neurons were identified. Of all identified neurons, 85-90% were located in ganglia (ganglionic neurons), the rest being isolated (individual neurons). The two general neuronal markers protein gene product 9.5 (PGP 9.5) and microtubule-associated protein (MAP-2) were associated with neurons clustered primarily in the interatrial septum and around the origins of the two vena cavae. Ganglia (group 1) contained three sub-populations of neurons: approx. 80% of ganglionic neurons were large (15-40 microm diameters; group 1a) and approx. 20% had smaller diameters (less than 15 microm; group 1b). All of these neurons were PGP-immunoreactive, exhibiting choline acetyltransferase (ChAT) immunoreactivity (IR), tyrosine hydroxylase (TH) IR, neuropeptide Y (NPY) IR, vasoactive peptide (VIP) IR and substance P (SP) IR. The remaining 5% of ganglionic neurons were small (group 1c; less than 20 microm). These displayed TH immunoreactivity but not MAP, PGP, CHAT, NPY or SP immunoreactivity. Ten to fifteen percent of all neurons loosely distributed outside of ganglia were small (10-25 microm) and located primarily around the origin of the superior vena cava. They displayed immunoreactivity to TH, ChAT, VIP, NPY and SP, but not to MAP-2 or PGP 9.5. These data provide anatomical and immunohistochemical evidence for specific localization of differing populations of intrinsic cardiac neurons with respect to their size, ganglionic distributions and capacity to express multiple neurotransmitters. Although the functional importance of such a regional distribution of differing populations of intrinsic cardiac neurons remains unknown, these anatomical data support the thesis that unique clustering of specific populations of neurons within this nervous system represents the anatomical substrate for complex local cardiac regulatory phenomena occurring at the level of the target organ.     

Chronic myocardial infarction induces phenotypic and functional remodeling in the guinea pig cardiac plexus

Chronic myocardial infarction (CMI) is associated with remodeling of the ventricle and evokes adaption in the cardiac neurohumoral control systems. To evaluate the remodeling of the intrinsic cardiac nervous system following myocardial infarction, the dorsal descending coronary artery was ligated in the guinea pig heart and the animals were allowed to recover for 7-9 wk. Thereafter, atrial neurons of the intrinsic cardiac plexus were isolated for electrophysiological and immunohistochemical analyses. Intracellular voltage recordings from intrinsic cardiac neurons demonstrated no significant changes in passive membrane properties or action potential configuration compared with age-matched controls and sham-operated animals. The intrinsic cardiac neurons from chronic infarcted hearts did demonstrate an increase in evoked action potential (AP) frequency (as determined by the number of APs produced with depolarizing stimuli) and an increase in responses to exogenously applied histamine compared with sham and age-matched controls. Conversely, pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increases in intrinsic cardiac neuron-evoked AP frequency were similar between control and CMI animals. Immunohistochemical analysis demonstrated a threefold increase in percentage of neurons immunoreactive for neuronal nitric oxide synthase (NOS) in CMI animals compared with control and the additional expression of inducible NOS by some neurons, which was not evident in control animals. Finally, the density of mast cells within the intrinsic cardiac plexus was increased threefold in preparations from CMI animals. These results indicate that CMI induces a differential remodeling of intrinsic cardiac neurons and functional upregulation of neuronal responsiveness to specific neuromodulators.     

Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ～4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.     

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.     

A mathematical model of human atrioventricular nodal function incorporating concealed conduction

This work develops a mathematical model for the atrioventricular (AV) node in the human heart, based on recordings of electrical activity in the atria (the upper chambers of the heart) and the ventricles (the lower chambers of the heart). Intracardiac recordings of the atrial and ventricular activities were recorded from one patient with atrial flutter and one with atrial fibrillation. During these arrhythmias, not all beats in the atria are conducted to the ventricles. Some are blocked (concealed). However, the blocked beats can affect the properties of the AV node. The activation times of the atrial events were regarded as inputs to a mathematical model of conduction in the AV node, including a representation of AV nodal concealment. The model output was compared to the recorded ventricular response to search for and identify the best possible parameter combinations of the model. Good agreement between the distribution of interbeat intervals in the model and data for durations of 5 min was achieved. A model of AV nodal behavior during atrial flutter and atrial fibrillation could potentially help to understand the relative roles of atrial input activity and intrinsic AV nodal properties in determining the ventricular response.     

Presence and co-localization of vasoactive intestinal polypeptide with neuronal nitric oxide synthase in cells and nerve fibers within guinea pig intrinsic cardiac ganglia and cardiac tissue

The presence of vasoactive intestinal polypeptide (VIP) has been analyzed in fibers and neurons within the guinea pig intrinsic cardiac ganglia and in fibers innervating cardiac tissues. In whole-mount preparations, VIP-immunoreactive (IR) fibers were present in about 70% of the cardiac ganglia. VIP was co-localized with neuronal nitric oxide synthase (nNOS) in fibers innervating the intrinsic ganglia but was not present in fibers immunoreactive for pituitary adenylate cyclase-activating polypeptide, choline acetyltransferase (ChAT), tyrosine hydroxylase, or substance P. A small number of the intrinsic ChAT-IR cardiac ganglia neurons (approximately 3%) exhibited VIP immunoreactivity. These few VIP-IR cardiac neurons also exhibited nNOS immunoreactivity. After explant culture for 72 h, the intraganglionic VIP-IR fibers degenerated, indicating that they were axons of neurons located outside the heart. In cardiac tissue sections, VIP-IR fibers were present primarily in the atria and in perivascular connective tissue, with the overall abundance being low. VIP-IR fibers were notably sparse in the sinus node and conducting system and generally absent in the ventricular myocardium. Virtually all VIP-IR fibers in tissue sections exhibited immunoreactivity to nNOS. A few VIP-IR fibers, primarily those located within the atrial myocardium, were immunoreactive for both nNOS and ChAT indicating they were derived from intrinsic cardiac neurons. We suggest that, in the guinea pig, the majority of intraganglionic and cardiac tissue VIP-IR fibers originate outside of the heart. These extrinsic VIP-IR fibers are also immunoreactive for nNOS and therefore most likely are a component of the afferent fibers derived from the vagal sensory ganglia. This work was supported by NIH grant HL65481 (R.L.P.) and HL54633 (D.B.H.). Use of the DeltaVision Restoration microscope was provided through the Imaging/Physiology Core supported by NIH Grant P20 RR16435 from the COBRE program of the National Center for Research Resources     

Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat

Deficient bioenergetic signaling contributes to myocardial dysfunction and electrical instability in both atrial and ventricular cardiac chambers. Yet, approaches capable to prevent metabolic distress are only partially established. Here, in a canine model of tachycardia-induced congestive heart failure, we compared atrial and ventricular bioenergetics and tested the efficacy of metabolic rescue with the vasopeptidase inhibitor omapatrilat. Despite intrinsic differences in energy metabolism, failing atria and ventricles demonstrated profound bioenergetic deficiency with reduced ATP and creatine phosphate levels and compromised adenylate kinase and creatine kinase catalysis. Depressed phosphotransfer enzyme activities correlated with reduced tissue ATP levels, whereas creatine phosphate inversely related with atrial and ventricular load. Chronic treatment with omapatrilat maintained myocardial ATP, the high-energy currency, and protected adenylate and creatine kinase phosphotransfer capacity. Omapatrilat-induced bioenergetic protection was associated with maintained atrial and ventricular structural integrity, albeit without full recovery of the creatine phosphate pool. Thus therapy with omapatrilat demonstrates the benefit in protecting phosphotransfer enzyme activities and in preventing impairment of atrial and ventricular bioenergetics in heart failure.     

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.     

Localization and mobility of the delayed-rectifer K+ channel Kv2.1 in adult cardiomyocytes

The delayed-rectifier voltage-gated K(+) channel (Kv) 2.1 underlies the cardiac slow K(+) current in the rodent heart and is particularly interesting in that both its function and localization are regulated by many stimuli in neuronal systems. However, standard immunolocalization approaches do not detect cardiac Kv2.1; therefore, little is known regarding its localization in the heart. In the present study, we used recombinant adenovirus to determine the subcellular localization and lateral mobility of green fluorescent protein (GFP)-Kv2.1 and yellow fluorescent protein-Kv1.4 in atrial and ventricular myocytes. In atrial myocytes, Kv2.1 formed large clusters on the cell surface similar to those observed in hippocampal neurons, whereas Kv1.4 was evenly distributed over both the peripheral sarcolemma and the transverse tubules. However, fluorescence recovery after photobleach (FRAP) experiments indicate that atrial Kv2.1 was immobile, whereas Kv1.4 was mobile (tau = 252 +/- 42 s). In ventricular myocytes, Kv2.1 did not form clusters and was localized primarily in the transverse-axial tubules and sarcolemma. In contrast, Kv1.4 was found only in transverse tubules and sarcolemma. FRAP studies revealed that Kv2.1 has a higher mobility in ventricular myocytes (tau = 479 +/- 178 s), although its mobility is slower than Kv1.4 (tau(1) = 18.9 +/- 2.3 s; tau(2) = 305 +/- 55 s). We also observed the movement of small, intracellular transport vesicles containing GFP-Kv2.1 within ventricular myocytes. These data are the first evidence of Kv2.1 localization in living myocytes and indicate that Kv2.1 may have distinct physiological roles in atrial and ventricular myocytes.     

Coupled pacing improves cardiac efficiency during acute atrial fibrillation with or without cardiac dysfunction

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction (CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.     

Muscarinic Receptor Modulation of the Cerebellar Interpositus Nucleus In Vitro

How the cerebellum carries out its functions is not clear, even for its established roles in motor control. In particular, little is known about how the cerebellar nuclei (CN) integrate their synaptic and neuromodulatory inputs to generate cerebellar output. CN neurons receive inhibitory inputs from Purkinje cells, excitatory inputs from mossy fibre and climbing fibre collaterals, as well as a variety of neuromodulatory inputs, including cholinergic inputs. In this study we tested how activation of acetylcholine receptors modulated firing rate, intrinsic properties and synaptic transmission in the CN. Using in vitro whole-cell patch clamp recordings from neurons in the interpositus nucleus, the acetylcholine receptor agonist carbachol was shown to induce a short-term increase in firing rate, increase holding current and decrease input resistance of interpositus CN neurons. Carbachol also induced long-term depression of evoked inhibitory postsynaptic currents and a short-term depression of evoked excitatory postsynaptic currents. All effects were shown to be dependent upon muscarinic acetylcholine receptor activation. Overall, the present study has identified muscarinic receptor activation as a modulator of CN activity.

     

The anatomy and physiology of the stomatogastric nervous system ofSquilla

Summary The stomatogastric nervous system of a mantis shrimp,Squilla oratoria, is described. The motor nerves of the stomatogastric ganglion (STG) and their innervation of muscles of the posterior cardiac plate (pcp) and pyloric systems are detailed.The STG contains more than 25 neurons. It sends out one pair of major output nerves. The pcp-pyloric cycle recorded from the motor axons in this nerve consists of rhythmic bursts of several units which fire with a characteristic phase relationship to each other. The rhythm is intrinsic to the STG itself, but it is modifiable.Recordings from the peripheral nerves reveal that identifiable cardiac plate, pyloric dilator and pyloric neurons control sequential contractions of the pcp and pyloric muscles to constrict or dilate a number of their attached ossicles.Several modulatory input fibres in the stomatogastric nerve, activated via stimulation of the superior or inferior oesophageal nerve (son, ion), prime or trigger the cyclic motor outputs. The son inputs induce distinct effects on the cardiac and pcp-pyloric pattern generators, while the ion inputs, via the oesophageal ganglion, excite only the pcp-pyloric generator.On the basis of anatomical and physiological observations, the possible functions of motor neurons involved in the pcp-pyloric cycle are described with reference to opening of the pcp and pyloric channels.This stomatogastric nervous system inSquilla is compared to that in decapods which has been well analyzed.Abbreviations CG commissural ganglion - ion inferior oesophageal nerve - lvn lateral ventricular nerve - OG oesophageal ganglion - pep posterior cardiac plate - son superior oesophageal nerve - STG stomatogastric ganglion - stn stomatogastric nerve - ivn inferior ventricular nerve     

Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs

Spinal cord stimulation (SCS) applied to the dorsal aspect of the cranial thoracic cord imparts cardioprotection under conditions of neuronally dependent cardiac stress. This study investigated whether neuronally induced atrial arrhythmias can be modulated by SCS. In 16 anesthetized dogs with intact stellate ganglia and in five with bilateral stellectomy, trains of five electrical stimuli were delivered during the atrial refractory period to right- or left-sided mediastinal nerves for up to 20 s before and after SCS (20 min). Recordings were obtained from 191 biatrial epicardial sites. Before SCS (11 animals), mediastinal nerve stimulation initiated bradycardia alone (12 nerve sites), bradycardia followed by tachyarrhythmia/fibrillation (50 sites), as well as tachyarrhythmia/fibrillation without a preceding bradycardia (21 sites). After SCS, the number of responsive sites inducing bradycardia was reduced by 25% (62 to 47 sites), and the cycle length prolongation in residual bradycardias was reduced. The number of responsive sites inducing tachyarrhythmia was reduced by 60% (71 to 29 sites). Once elicited, residual tachyarrhythmias arose from similar epicardial foci, displaying similar dynamics (cycle length) as in control states. In the absence of SCS, bradycardias and tachyarrhythmias induced by repeat nerve stimulation were reproducible (five additional animals). After bilateral stellectomy, SCS no longer influenced neuronal induction of bradycardia and atrial tachyarrhythmias. These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protective effects depend on the integrity of nerves coursing via the subclavian ansae and stellate ganglia.