Cardiopulmonary Nerves Research Articles

Cardiopulmonary nerve stimulation as a novel therapy for cardiac autonomic nervous system modulation.

Cardiopulmonary nerve stimulation as a novel therapy for cardiac autonomic nervous system modulation.

Abstract 15569: The Effect of Cardiac Pulmonary Nerve Stimulation on Cardiac Inotropy and Quality of Life in Patients With Acute Decompensated Heart Failure

Background: Acute decompensated heart failure (ADHF) results in over 1 million hospitalizations annually and involves neurohormonal disruption as well as autonomic dysfunction. Neuromodulation of the cardiac plexus using cardiopulmonary nerve stimulation (CPNS), currently being evaluated in clinical trials, is a novel strategy to treat ADHF. Methods: An interim analysis of 12 patients from ongoing trials was conducted. Patients were admitted with a principal diagnosis of ADHF (elevated NT-proBNP and LVEF≤50%) and underwent implant of a 16-electrode catheter (Figure 1A) in the right pulmonary artery, allowing cardiac plexus stimulation for 48 hrs. Stimulation was performed at 20 Hz frequency, 2.0 ms pulse width, and stimulation amplitude/vector (2.5-10 mA) to optimize cardiac function. LV pressure, arterial pressure, and ECG were concurrently recorded. An additional 12 patients not implanted were followed as a parallel standard of care (SOC) cohort. Results: There were no device-related serious adverse events (SAEs) during the index hospitalization or at 30 days post-discharge. Two SAEs unrelated to device occurred in 2 patients (clonic seizure and post-discharge pneumonia resulting in death). In response to stimulation, there was a statistical increase in maximum LV dP/dt (from 799 to 824 mmHg/sec, p<0.01) and a statistical decrease in pressure time index (from 27.9 to 27.5 mmHg*sec, p<0.05). Patients that received CPNS reported a significantly greater improvement in symptoms, function, and quality of life at 30 days (KCCQ-12; from 14.1 to 74.7, p<0.0001) compared to patients in the SOC cohort (Figure 1B; 60.6 vs. 8.4, p<0.05). Conclusion: In-hospital CPNS therapy is feasible and well-tolerated in ADHF patients. Stimulation increased cardiac inotropy, decreased energy consumption, and improved symptoms, function, and quality of life. Further investigation is required to determine if CPNS therapy leads to sustained improvement in clinical outcomes.

Novel Therapeutic Devices in Heart Failure.

Heart failure (HF) constitutes a significant clinical problem and is associated with a sizeable burden for the healthcare system. Numerous novel techniques, including device interventions, are investigated to improve clinical outcome. A review of the most notable currently studied devices targeting pathophysiological processes in HF was performed. Interventions regarding autonomic nervous system imbalance, i.e., baroreflex activation therapy; vagus, splanchnic and cardiopulmonary nerves modulation; respiratory disturbances, i.e., phrenic nerve stimulation and synchronized diaphragmatic therapy; decongestion management, i.e., the Reprieve system, transcatheter renal venous decongestion system, Doraya, preCardia, WhiteSwell and Aquapass, are presented. Each segment is divided into subsections: potential pathophysiological target, existing evidence and weaknesses or unexplained issues. Novel therapeutic devices represent great potential in HF therapy management; however, further evidence is necessary to fully evaluate their utility.

Catheter-Based Cardiopulmonary Nerve Stimulation Impacts Left Ventricular Contractility And Relaxation: First In Human Experience

Introduction There are limited strategies addressing the reversible hypoperfusion and fluid retention observed in acute decompensated heart failure (ADHF). Aberrant autonomic reflex physiology is believed to contribute to clinical decompensation. Our previous work demonstrated catheter-based cardiopulmonary nerve stimulation (CPNS) can increase cardiac contractility. Objective The study objective was to evaluate short-term safety and feasibility of a novel CPNS System. Methods Subjects (n=18) undergoing a catheterization procedure or ICD/CRT implant were studied. After the index procedure, the investigational CPNS neuromodulation catheter was delivered to the right PA. Stimulus sequences were used to evoke cardiac responses. Changes in LV contractility (LV dP/dt max), LV relaxation (LV dP/dt min), arterial blood pressure, and heart rate were measured with and without stimulation over a period of 1-3 hours. Results No adverse events occurred over the course of the study. Fifteen (15) of the eighteen (18) subjects (83%) exhibited increased contractility with CPNS (stimulation time between 60 -120 seconds). The increase in LV contractility was substantial 60% [6, 173%]. LV relaxation 18% [-11, 70%], mean arterial pressure 13% [-1, 60%], arterial pulse pressure 26% [-3, 80%], and estimated stroke volume calculated from pulse pressure +13% [-12,70] also increased while HR was relatively unchanged 1% [-20, +13%]. Conclusions CPNS to increase cardiac contractility is feasible and likely safe. Heart rate neutral changes in LV contractility, relaxation, and arterial blood pressure were reproducible over the short period of testing. Additional and longer-term studies are required to assess the impacts on clinical heart failure endpoints. There are limited strategies addressing the reversible hypoperfusion and fluid retention observed in acute decompensated heart failure (ADHF). Aberrant autonomic reflex physiology is believed to contribute to clinical decompensation. Our previous work demonstrated catheter-based cardiopulmonary nerve stimulation (CPNS) can increase cardiac contractility. The study objective was to evaluate short-term safety and feasibility of a novel CPNS System. Subjects (n=18) undergoing a catheterization procedure or ICD/CRT implant were studied. After the index procedure, the investigational CPNS neuromodulation catheter was delivered to the right PA. Stimulus sequences were used to evoke cardiac responses. Changes in LV contractility (LV dP/dt max), LV relaxation (LV dP/dt min), arterial blood pressure, and heart rate were measured with and without stimulation over a period of 1-3 hours. No adverse events occurred over the course of the study. Fifteen (15) of the eighteen (18) subjects (83%) exhibited increased contractility with CPNS (stimulation time between 60 -120 seconds). The increase in LV contractility was substantial 60% [6, 173%]. LV relaxation 18% [-11, 70%], mean arterial pressure 13% [-1, 60%], arterial pulse pressure 26% [-3, 80%], and estimated stroke volume calculated from pulse pressure +13% [-12,70] also increased while HR was relatively unchanged 1% [-20, +13%]. CPNS to increase cardiac contractility is feasible and likely safe. Heart rate neutral changes in LV contractility, relaxation, and arterial blood pressure were reproducible over the short period of testing. Additional and longer-term studies are required to assess the impacts on clinical heart failure endpoints.

B-PO04-184 CATHETER-BASED CARDIOPULMONARY NERVE STIMULATION IMPACTS LEFT VENTRICULAR CONTRACTILITY AND RELAXATION: FIRST IN HUMAN EXPERIENCE

There are limited strategies addressing the reversible hypoperfusion and fluid retention observed in acute decompensated heart failure (ADHF). Aberrant autonomic reflex physiology is believed to contribute to clinical decompensation. Our previous work demonstrated catheter-based cardiopulmonary nerve stimulation (CPNS) can increase cardiac contractility.

Partial Body Weight Support Benefits the Function of Cardiopulmonary and Cardiac Autonomic Nerve in the Early Stage of Heart Failure Rehabilitation

Goal: To investigate the clinical benefits of partial body weight support for the function of Cardiopulmonary and Cardiac autonomic nerve in the early stage of Heart failure rehabilitation. Materials and Methods: We selected 90 patients with heart failure, divided into observation group (n = 45) and control group (n = 45). Both patients had the conventional drug therapy, while the observation group had the partial body weight support additionally within the 3 months treatment period. Serological examination includes brain natriuretic peptide (BNP) and aldosterone. Echocardiography detects left ventricular morphology, cardiac ejection function (EF) and cardiac autonomic nerve function. Minnesota quality of life scale (MHL) evaluates the life quality of the patients. Results: Before any treatment, there is no significant difference of serum brain natriuretic peptide (BNP), aldosterone, cardiac autonomic nerve function and the Minnesota quality of life scale (MHL) (P > 0.05). After treatment, outcome measures declined, including serum brain natriuretic peptide (BNP) and aldosterone (P < 0.01), LVESD and ESV (P < 0.01), LVEDD and EDV (P > 0.05). Outcome measures raised, including SV, CI, EF%, ΔD%. Among them, EF% had significant difference with P value < 0.05, and ΔD% with P value < 0.01. Both LF and HF raised, but LF/HF declined. The Minnesota quality of life scale (MHL) is significantly lower than before. Conclusion: Partial body weight support obviously reduces serum brain natriuretic peptide (BNP) and aldosterone, as well as improves the function of cardiopulmonary and cardiac autonomic nerve of the patients with heart failure, which at last improves the life quality.

Regulation of arterial blood pressure

In each cardiac cycle arterial blood pressure fluctuates between diastolic and systolic pressure. However, the body behaves from day to day as if it regulated the mean arterial blood pressure, which is the average between diastolic and systolic pressures. Such regulation is achieved by interdependent adjustments of only 3 parameters: Heart rate (HR), ventricular stroke volume (SV) and total peripheral vascular resistance (TPVR). These are related as follows: HR - SV = Cardiac Output (CO); CO - TPVR = Mean Arterial Blood Pressure. The regulatory system includes stretch-sensitive sensors, central nervous integrators/evaluators and neuro-humoral effector mechanisms. Central nervous integration and evaluation of incoming signals occurs mostly in the pons/medulla regions of the midbrain. The most important effector mechanisms are the parasympathetic and sympathetic divisions of the autonomic nervous system, the renin-angiotensin system and vasopressin. Short-term regulation of arterial blood pressure is dominated by the baroreceptor mechanism, whereby pressure is sensed by both cardio-pulmonary nerve endings and stretch-sensitive cells in renal afferent arterioles. Long-term regulation involves mainly the regulation of extracellular fluid volume by pressure natriuresis mechanisms residing in the kidney and by widespread actions of angiotensin 2. Studies in hypertensives have suggested that the long-term-controlled variable is not arterial blood pressure, but the balance between intake and output of fluid and electrolytes. If the kidney requires a higher perfusion pressure to achieve that balance then daily blood pressure regulation occurs around an appropriately higher setpoint.

Sympathetic denervation and reinnervation after arterial switch operation for complete transposition.

Sympathetic cardiopulmonary nerves arise from the cervical sympathetic trunks and the stellate ganglia and subsequently course along the origin of the great arteries and the coronary arteries to innervate the ventricles. Therefore, the sympathetic nerves may be obligatorily interrupted by the arterial switch operation (ASO) for complete transposition of the great arteries. To demonstrate and characterize the possible sympathetic denervation, 51 patients after ASO, 4.8 years old (range, 1 month to 10.1 years), underwent [123I]metaiodobenzylguanidine (MIBG) imaging of the sympathetic nerve terminal. MIBG uptake to the heart was graded by quantitative analysis using the heart-to-mediastinum (H/M) ratio of MIBG uptake. A quantitative criterion for absent uptake of MIBG was set to 1.48 in the H/M ratio. Four patients < 1 month after ASO showed complete absence of MIBG uptake, which had been observed preoperatively. In contrast, 47 patients late after ASO (range, 15 months to 10.1 years) showed various degrees of uptake of MIBG. Patients operated on at < or =55 days of age showed positive MIBG uptake much more frequently than those operated on at later ages. Heart rate and rate-pressure product at peak exercise on a treadmill exercise test were significantly greater in patients with positive uptake than in those with absent uptake of MIBG. Cardiac sympathetic nerves were denervated early after and reinnervated late after ASO. Neonatal ASO may be favorable to facilitate sympathetic reinnervation, which may affect exercise tolerance late after surgery.

Brainstem cells of origin of physiologically identified cardiopulmonary nerves in the rhesus monkey ( Macaca mulatta)

The distributions of brainstem cells of origin of the cervical vagus nerve, its cervical and thoracic branches, and of neurons projecting to the cricothyroid muscle and the stomach wall were identified and compared following injections of horseradish peroxidase (HRP) in 18 Rhesus monkeys. Physiologically and/or anatomically identified cardiopulmonary nerves were injected with 3–20 μl of HRP to identify the locations of vagal preganglionic cardioinhibitory neurons in 10 of these monkeys. After injections into cardiopulmonary nerves, retrogradely labelled cells were concentrated ipsilaterally in the most lateral parts of the dorsal motor nucleus of the vagus nerve (DMV) and in the ventrolateral nucleus ambiguus (NA). Fewer labelled neurons were identified close to or in the principal (dorsal) division of the NA and in the intermediate zone between the DMV and NA. The results indicate that monkey cardiopulmonary nerves have multiple origins; their somata are located primarily in the ventrolateral NA and to a lesser extent in the lateral DMV. In monkeys, there is a stronger representation in the lateral DMV than in cat, dog and pig. The viscerotopic organization of the cells of origin of primate vagal nerves is similar to that in other species. The cells of origin of vagal projections to the superior laryngeal nerve and cricothyroid muscle were located in the NA rostrally to those of the inferior laryngeal nerve. Injections into the superior laryngeal nerve also resulted in significant labelling in the DMV and intermediate zone (IZ). The cells of origin of projections to the anterior stomach wall were restricted to the DMV with a bilateral distribution of labelled cells, concentrated medially in the nucleus.

Anatomy of medullary and peripheral autonomic neurons innervating the neonatal porcine heart

Gross and microscopic anatomical investigations were carried out in 14 piglets aged from 4 to 66 days. True Blue (7–50 μl) and Diamidino Yellow (7–50 μl) were injected individually into 2 different cardiac sites (the right atrial ganglionated plexus, the inferior vena cava, inferior atrial ganglionated plexus, the right atrium or the right ventricle). Gross anatomy: Globular superior cervical and nodose ganglia, elongated stellate ganglia, multiple small middle cervical ganglia and multiple small mediastinal ganglia along the course of cardiopulmonary nerves were identified. Microscopic anatomy: Neurons innervating specific cardiac regions or intrinsic cardiac ganglionated plexuses were distributed relatively evenly among stellate (primarily in their cranial poles) and middle cervical ganglia bilaterally, fewer labeled neurons being located in the superior cervical and mediastinal ganglia bilaterally. Parasympathetic efferent preganglionic neurons associated with either intrinsic cardiac ganglionated plexus studied were identified primarily throughout the ventrolateral region (the external formation) of the nucleus ambiguus bilaterally. Labeled neurons were also identified throughout the right and left nodose ganglia. Individual neurons did not project axons to different cardiac regions, as no double-labeled neurons were identified. No correlation between age and the numbers and locations of labeled neurons was apparent. Thus, porcine sympathetic efferent neurons which innervate individual cardiac regions, including intrinsic cardiac ganglionated plexuses, lie scattered primarily throughout the right and left mediastinal and middle cervical ganglia as well as the cranial poles of stellate ganglia at birth, apparently changing little during the first 2 months of age. Porcine cardiac parasympathetic efferent preganglionic neurons are located primarily in the external formation of the nucleus ambiguus bilaterally at birth. The numbers of afferent cardiac neurons distributed throughout the nodose ganglia bilaterally also change little during that time. It is concluded that most of the autonomic neurons which innervate the heart are in place at birth.

Shortening of the QT interval of the EKG is associated primarily with increased ventricular contractility rather than heart rate.

The objective of this study was to gather direct evidence on whether the duration of the QT interval relates primarily to heart rate or to ventricular contractility. The electrocardiographic and cardiodynamic consequences of electrical stimulation (15 V, 5 ms, 10Hz) of various intrathoracic sympathetic efferent neuronal structures were studied in 10 anesthetized mongrel dogs. Stimulation of efferent sympathetic axons in the right intraganglionic nerve, which innervates the sinoatrial node, induced tachycardia (110 +/- 5 - 133 +/- 6 bpm; p < 0.01) without significantly altering right or left ventricular intramyocardial ventricular chamber pressures. The QT interval, as determined by leads I, II and III of the EKG and a transthoracic lead, was not affected by this intervention 310 +/- 8 - 302 +/- ms). Increasing heart rate to a similar degree (111 +/- 3 - 131 +/- 3 bpm) by right atrial pacing did not induce changes in the QT interval. When right (23 +/- 3 - 49 +/- 8 mm Hg; p < 0.01) and left (81 +/- 10 - 127 +/- 19 mm Hg; p < 0.01) ventricular forces were augmented without concomitant increases in heart rate by stimulating efferent sympathetic axons in the left caudal pole cardiopulmonary nerve the QT interval shortened (322 +/- 11 - 290 +/- 12 ms; p < 0.01). Only when an efferent sympathetic nerve, that contains fibers destined for both the sinoatrial node and the ventricles was stimulated did both heart rate and ventricular contractility augment and QT shorten (318 +/- 10 - 290 +/- 11 ms; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Vagal innervation influences the whole body oxygen consumption-delivery relationship in the dog.

Vagotomy alters regional blood flow distribution by interrupting the tonic central inhibitory effect of cardiopulmonary vagal afferent nerves on sympathetic outflow predominantly to the renal, splanchnic, and cutaneous circulations. We hypothesized that the alteration of blood flow distribution by vagotomy would lead to disruption of the oxygen consumption-oxygen delivery relationship (VO2/DO2), increase critical DO2 (DO2Crit), and decrease whole-body oxygen extraction ratio (O2ER). Nineteen chloralose-anesthetized, paralyzed, splenectomized dogs were submitted to either bilateral vagosympathectomy (n = 7), bilateral vagotomy (n = 6), or sham denervation (n = 6) following baseline cardiorespiratory parameter measurement. VO2 was measured by indirect calorimetry and carotid blood flow by ultrasonic flow probe. Incremental hemorrhages (1-5 mL/kg) were performed to determine the VO2/DO2 relationship. Cardiorespiratory parameters were measured after each hemorrhage at steady-state VO2. DO2Crit was derived from the VO2/DO2 relationship using a best-fit regression analysis technique. The average DO2Crit values of the vagotomy (9.1 +/- .54) and vagosympathectomy (11.5 +/- 1.2 mL/min/kg) groups were significantly greater than the control group (7.72 +/- .43). After hemorrhage had been performed to a point that decreased mean arterial pressure to approximately 70 mmHg from baseline values, carotid blood flow in the vagosympathectomy group was significantly greater than the control group. We conclude that vagotomy disrupts the VO2/DO2 relationship. Vagosympathectomy causes a severe disruption of the VO2/DO2 relationship, probably by the combined effect of vagotomy and interruption of sympathetic nervous system control of blood flow to the head and neck.

Segmental organization of visceral and somatic input onto C3-T6 spinothalamic tract cells of the monkey.

1. Referred pain of visceral origin has three major characteristics: visceral pain is referred to somatic areas that are innervated from the same spinal segments as the diseased organ; visceral pain is referred to proximal body regions and not to distal body areas; and visceral pain is felt as deep pain and not as cutaneous pain. The neurophysiological basis for these phenomena is poorly understood. The purpose of this study was to examine the organization of viscerosomatic response characteristics of spinothalamic tract (STT) neurons in the rostral spinal cord. Interactions were determined among the following: 1) segmental location, 2) effects of input by cardiopulmonary sympathetic, greater splanchnic, lumbar sympathetic, and urinary bladder afferent fibers, 3) location of excitatory somatic field, e.g., hand, forearm, proximal arm, or chest, 4) magnitude of response to hair, skin, and deep mechanoreceptor afferent input, and 5) regional specificity of thalamic projection sites. 2. A total of 89 STT neurons in segments C3-T6 were characterized for responses to visceral and somatic stimuli. Neurons were activated antidromically from the contralateral ventroposterolateral oralis or caudalis nuclei of the thalamus. Cell responses to visceral and somatic stimuli were not different on the basis of the thalamic site of antidromic activation. Recording sites for 61 neurons were located histologically; 87% of lesion sites were located in laminae IV-VII or X. There was no relationship between response properties of the neurons and spinal laminar location. 3. Different responses to visceral stimuli were observed in three zones of the rostral spinal cord: C3-C6, C7-C8, and T1-T6. In C3-C6, urinary bladder distension (UBD) and electrical stimulation of greater splanchnic and lumbar sympathetic afferent fibers inhibited STT cells. Electrical stimulation of cardiopulmonary sympathetic afferents increased cell activity in C5 and C6 and either excited or inhibited STT cells in C3 and C4. In the cervical enlargement (C7-C8), STT cells generally were either inhibited or showed little response to stimulation of visceral afferent fibers. In T1-T6, input from greater splanchnic and cardiopulmonary sympathetic afferent nerves increased activity of STT cells. Lumbar sympathetic afferent input inhibited cells in T1-T2 and had little effect on cells in T3-T6, whereas UBD decreased cell activity in all segments studied. 4. In general, stimulation of somatic structures increased activity of STT neurons in segments that received primary afferent innervation from the excitatory somatic receptive field or in the segments immediately adjacent to these segments. Only input from the forelimb, especially the hand, markedly excited cells in C7 and C8.+

Human cardiac nerve stimulation

Cardiovascular responses were elicited in 12 patients undergoing cardiac operations when cardiopulmonary neural elements between the aortic root and pulmonary artery or in the right atrial ganglionated plexus were stimulated. Heart rate and left ventricular intramyocardial systolic pressure were augmented when cardiopulmonary nerves between the aorta and pulmonary artery were stimulated in 11 of the 12 patients. Right ventricular intramyocardial systolic pressure was augmented in 7 of these 11 patients. Cardiodepressor responses were elicited when the right atrial ganglionated plexus (9 patients) or a cardiopulmonary nerve (2 patients) was stimulated. These results demonstrate that electrical stimulation of the human extrinsic and intrinsic cardiac nervous systems can alter cardiodynamics, different responses being elicited when different neural structures are stimulated. These data are in accord with those obtained from canine experiments and suggest that the human extrinsic and intrinsic cardiac nervous system contains functionally similar neural elements to those found in other mammals.

Influence of selective autonomic decentralization on myocardial deoxyglucose uptake initiated by cardio-cardiac reflexes

The aim of this study was to evaluate the effect of autonomic reflexes as initiated by stimulation of the right recurrent cardiopulmonary nerve afferent axons on myocardial deoxyglucose uptake and to determine how such uptake can be modified by selective neural ablation. The afferent axon in the right recurrent cardiopulmonary nerve was stimulated 30 s/min for 1 h in five anesthetized open-chest dogs in which 14-C labeled deoxyglucose was i.v. injected at the beginning of the stimulation period. Three additional sham-operated dogs served as neurally intact controls. Concentrations of label and glucose were measured in plasma. Regional myocardial deoxyglucose concentration was measured by quantitative autoradiography, following the calibration of plasma samples autoradiographic density by beta counting. Stimulation of right recurrent cardiopulmonary nerve afferent axons in the intact nervous system preparation did not significantly enhance deoxyglucose uptake as compared to neurally intact controls. When the right cervical vagosympathetic complex was cut a similar uptake was observed. Following decentralization of the right stellate ganglion, uptake was markedly reduced, as well as when the right cervical vagosympathetic was cut and the right stellate ganglion decentralized. Activation of afferent axons from cardiopulmonary receptors does not alter myocardial deoxyglucose uptake. Reduction in uptake occurs following unilateral stellate ganglion decentralization.

Epicardial distribution of ST segment and T wave changes produced by stimulation of intrathoracic ganglia or cardiopulmonary nerves in dogs

Sixty-three ventricular epicardial electrograms were recorded simultaneously in 8 atropinized dogs during stimulation of acutely decentralized intrathoracic autonomic ganglia or cardiopulmonary nerves. Three variables were measured: (1) isochronal maps representing the epicardial activation sequence, (2) maps depicting changes in areas under the QRS complex and T wave (regional inhomogeneity of repolarization), and (3) local and total QT intervals. Neural stimulations did not alter the activation sequence but induced changes in the magnitude and polarity of the ST segments and T waves as well as in QRST areas. Stimulation of the same neural structure in different dogs induced electrical changes with different amplitudes and in different regions of the ventricles, except for the ventral lateral cardiopulmonary nerve which usually affected the dorsal wall of the left ventricle. Greatest changes occurred when the right recurrent, left intermediate medial, left caudal pole, left ventral lateral cardiopulmonary nerves and stellate ganglia were stimulated. Local QT durations either decreased or did not change, whereas total QT duration as measured using a root-mean-square signal did not change, indicating the regional nature of repolarization changes. Taken together, these data indicate that intrathoracic efferent sympathetic neurons can induce regional inhomogeneity of repolarization without prolonging the total QT interval.

Activity of canine in situ left atrial ganglion neurons

The responses of 135 spontaneously active neurons were recorded from ganglionated plexi located in the three epicardial fat pads on the ventral surface of the left atrium of ten dogs. Ganglia, some of which were adjacent to the recording sites, containing varying numbers of neurons were identified throughout these fat pads. Spontaneous activity in 50% of the identified neurons was correlated with specific phases of the cardiac cycle when arterial systolic pressure was between approximately 70 and 180 mmHg and in 28% it was correlated with the respiratory cycle. More neurons displaying cardiovascular-related activity were recorded when systolic pressure was increased after administration of positive inotropic agents or aortic occlusion. However, when systolic pressure increased above approximately 150 mmHg the number of active neurons decreased, and when pressure reached approximately 180 mmHg no activity was recorded. The activity of 36% of identified neurons was altered when discrete regions of the heart, great thoracic vessels, lungs, neck, upper limb, chest wall, or abdominal wall were mechanically distorted by gentle touch. After acute decentralization of the intrathoracic nervous system some neurons still displayed spontaneous cardiovascular- or respiratory-related activity. Single stimuli or trains of stimuli delivered to the vagosympathetic complexes, stellate ganglia, or cardiopulmonary nerves activated neurons in intact or acutely decentralized preparations. It is concluded that ventral left atrial ganglionated plexi neurons display activity related to cardiovascular or respiratory dynamics, and that these neurons are influenced by sympathetic and parasympathetic efferent axons, as well as by cardiac and other mechanoreceptors.

Activity of in vivo canine ventricular neurons

The spontaneous activity of 113 neurons located in the ganglionated plexus in the epicardial fat overlying the cranial portion of the ventral intraventricular groove and the origin of the circumflex coronary artery was recorded in ten anesthetized dogs. Ganglia that contained varying numbers of neurons, some with two or more nucleoli, were subsequently identified anatomically in the vicinity of the recording sites. Spontaneous activity was correlated with the cardiac cycle in 81% and with the respiratory cycle in 17% of the identified neurons. The spontaneous cardiovascular-related activity occurred in relation to specific phases of the cardiac cycle when arterial pressure was between approximately 80 and 175 mmHg. When systolic pressures fell below approximately 80 mmHg or increased above approximately 175 mmHg, neurons displaying cardiovascular-related activity were inactive. The activity of 62% of all identified neurons was altered when discrete regions of the heart or pulmonary tissue were mechanically distorted by gentle touch. In many instances mechanical distortions of tissues were still able to alter neuronal activity following acute decentralization. Single stimuli or trains of stimuli delivered to the vagosympathetic complexes, stellate ganglia, or cardiopulmonary nerves generated bursts of activity in ganglionic neurons. Spontaneous activity occurred whether the ganglia were connected to the central nervous system or acutely decentralized. It is concluded that some neurons located on the canine ventricle display spontaneous activity that is related to cardiovascular or respiratory dynamics. The results also demonstrate that ventricular neurons can be influenced by sympathetic or parasympathetic efferent axons as well as cardiac mechanoreceptors.

α-Adrenergic receptor modulation of the intrathoracic efferent sympathetic nervous system regulating the canine heart

The augmentation of ventricular inotropism induced by electrical stimulation of acutely decentralized efferent sympathetic preganglionic axons was reduced, but still present, following administration of hexamethonium (10 mg/kg i.v.). While hexamethonium continued to be administered, the cardiac augmentations so induced were enhanced significantly following administration of the alpha-adrenergic receptor blocking agent, phentolamine myselate (1 mg/kg i.v.). Stimulation of the sympathetic efferent postganglionic axons in cardiopulmonary nerves induced cardiac augmentations that were unchanged following administration of these agents singly or together. The cardiac augmentations induced by stimulation of efferent preganglionic sympathetic axons were unchanged when phentolamine was administered alone. The augmentations of cardiac inotropism induced by efferent postganglionic sympathetic axonal stimulation were decreased following local administration of the beta-adrenergic antagonist timolol into the ipsilateral stellate and middle cervical ganglia. Thereafter, these augmentations were unchanged following the subsequent intravenous administration of phentolamine. It is concluded that the activation of cardiac neurons in the stellate and middle cervical ganglia by stimulation of efferent preganglionic sympathetic axons can be modified by alpha-adrenergic receptors and that these effects are dependent upon beta-adrenergic receptors, not nicotinic ones, in intrathoracic ganglia.

Ganglionic distribution of afferent neurons innervating the canine heart and cardiopulmonary nerves

The ganglionic distribution of the perikarya of afferent axons in cardiopulmonary nerves or the heart was studied in 64 dogs by injecting horseradish peroxidase into physiologically identified cardiopulmonary nerves or different regions of the heart. In 6 additional dogs, horseradish peroxidase was injected into the aortic arch, pericardial sac, left ventricular cavity or the skin. After injections into cardiopulmonary nerves, retrogradely labeled perikarya were found in the ipsilateral nodose ganglion and the ipsilateral C 7-T 7 dorsal root ganglia. After injections into different regions of the heart, retrogradely labeled neurons were found in the nodose ganglia bilaterally and in the C 6-T 6 dorsal root ganglia bilaterally. Many more retrogradely labeled neurons were found in the nodose ganglia in comparison to the dorsal root ganglia. The largest numbers of retrogradely labeled perikarya in the dorsal root ganglia occurred in the T 2- 4 ganglia following nerve or heart injections. Following injections into specific regions of the heart or individual physiologically identified cardiopulmonary nerves, regional distributions of labeled neurons could not be identified within or among ganglia with respect to the structures injected. Perikarya in dorsal root ganglia which were labeled after heart injections ranged in area from 436–3280 μm 2 ( X = 1279 ± 51 S.E.M.) while after skin injections labeled perikarya ranged in area from 224–5701 μm 2 ( X = 1631 ± 104 S.E.M.). The results show that the afferent innervation of the canine heart is provided by neurons located throughout the nodose ganglia and to a lesser degree in the C 6-T 6 dorsal root ganglia bilaterally. The bilateral distribution of cardiac afferent neurons raises questions regarding mechanisms underlying unilateral symptoms frequently associated with heart disease.