Effect of central CO(2) drive on lung inflation responses of expiratory bulbospinal neurons in dogs.

The purpose of these studies is to better understand the nature of the reflex interactions that control the discharge patterns of caudal medullary, expiratory (E) bulbospinal neurons. We examined the effect of central chemodrive inputs measured as arterial CO(2) tension (Pa(CO(2))) during hyperoxia on the excitatory and inhibitory components of the lung inflation responses of these neurons in thiopental sodium-anesthetized, paralyzed dogs. Data from slow ramp inflation and deflation test patterns, which were separated by several control inflation cycles, were used to produce plots of neuronal discharge frequency (F(n)) versus transpulmonary pressure (P(t)). P(t) was used as an index of the activity arising from the slowly adapting pulmonary stretch receptors (PSRs). Changes in inspired CO(2) concentrations were used to produce Pa(CO(2)) levels that ranged from 20 to 80 mmHg. The data obtained from 41 E neurons were used to derive an empirical model that quantifies the average relationship for F(n) versus both P(t) and Pa(CO(2)). This model can be used to predict the time course and magnitude of E neuronal responses to these inputs. These data suggest that the interaction between Pa(CO(2)) and PSR-mediated excitation and inhibition of F(n) is mainly additive, but synergism between Pa(CO(2)) and excitatory inputs is also present. The implications of these findings are discussed.

The effects of the new antiarrhythmic E 047/1 on postoperative ischemia-induced arrhythmias in dogs.

UNLABELLED: Perioperative malignant ventricular tachyarrhythmias pose an imminent clinical danger by potentially precipitating myocardial ischemia and severely compromising hemodynamics. Thus, immediate and effective therapy is required, which is not always provided by currently recommended IV drug regimens, indicating a need for more effective drugs. We examined antiarrhythmic effects of the new benzofurane compound E 047/1 on spontaneous ventricular tachyarrhythmia in a conscious dog model. One day after experimental myocardial infarction, 40 dogs exhibiting tachyarrhythmia randomly received (bolus plus 1-h infusion) E 047/1 6 mg/kg plus 6 mg x kg(-1) x h(-1), lidocaine 1 mg/kg plus 4.8 mg x kg(-1) x h(-1), flecainide 1 mg/kg plus 0.05 mg x kg(-1) x h(-1), amiodarone 10 mg/kg plus 1.8 mg x kg(-1) x h(-1), or bretylium 10 mg/kg plus 20 mg x kg(-1) x h(-1). Electrocardiogram was evaluated for number of premature ventricular contractions (PVC), normally conducted beats originating from the sinoatrial node, and episodes of ventricular tachycardia. Immediately after the bolus, E 047/1 reduced PVCs by 46% and increased sinoatrial beats from 4 to 61 bpm. The ratio of PVCs to total beats decreased from 98% to 58%. Amiodarone and flecainide exhibited antiarrhythmic effects with delayed onset. Lidocaine did not suppress PVCs significantly, and bretylium was proarrhythmic. The antiarrhythmic E 047/1 has desirable features, suppressing ischemia-induced ventricular tachyarrhythmia quickly and efficiently, and may be a useful addition to current therapeutic regimens. IMPLICATIONS: Life-threatening arrhythmias of the heart after myocardial infarction or ischemia may be treated quickly and efficiently by the new drug E 047/1.

Anesthetics and automaticity of dominant and latent pacemakers in chronically instrumented dogs. IV. Dysrhythmias after sinoatrial node excision.

BACKGROUND: Subsidiary atrial pacemakers assume control after sinoatrial (SA) node excision, and anesthetic-catecholamine interactions can produce severe bradycardia during isoflurane anesthesia. We hypothesized that epinephrine enhances atrial, atrioventricular junctional, and ventricular dysrhythmias after SA node excisions in dogs and that inhalation anesthetics would facilitate such dysrhythmias. METHODS: In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, at the His bundle, and along the sulcus terminalis. Site of the earliest atrial activation and incidences of nonatrial beats were determined in the conscious state, with methylatropine, with epinephrine, and during halothane, isoflurane, or enflurane anesthesia. RESULTS: After SA node excision, a stable, regular subsidiary atrial pacemaker rhythm resulted. Epinephrine and halothane shifted the site of earliest activation to more remote atrial sites. Epinephrine-induced ventricular escape was increased by all anesthetics tested, but atropine prevented ventricular escape. Epinephrine-induced His bundle (atrioventricular junctional) and premature ventricular beats were increased by halothane and enflurane. After SA node excision, ventricular escape occurred as a result of epinephrine-anesthetic interactions, especially during anesthesia with isoflurane. CONCLUSIONS: In dogs with excised SA nodes, anesthetic-catecholamine interaction facilitates ventricular escape, His bundle dysrhythmias, and premature ventricular beats. In addition, halothane and enflurane, more than isoflurane, facilitate ectopic ventricular tachydysrhythmias with epinephrine. Compared to intact dogs, dogs with excised SA nodes may be more susceptible to epinephrine anesthetic dysrhythmias. If findings can be extrapolated to humans, intrinsic SA node dysfunction may facilitate severe cardiac dysrhythmias with inhalation anesthetics and catecholamines.

Anesthetics and automaticity of dominant and latent atrial pacemakers in chronically instrumented dogs. III. Automaticity after sinoatrial node excision.

BACKGROUND: Management of patients with sinus node dysfunction must consider the stability of subsidiary pacemakers during anesthesia and treatment with antimuscarinic or sympathomimetic drugs. Baroreflex regulation of atrial pacemaker function is known to contribute to the interactions between inhalation anesthetics and catecholamines. Sinoatrial (SA) node excision can be a model for intrinsic SA node dysfunction. Subsidiary atrial pacemakers are expected to emerge after SA node excision, but they may respond differently to humoral and neural modulation. Isolated and combined effects of epinephrine and methylatropine should help characterize subsidiary pacemaker function during anesthesia with halothane, isoflurane, and enflurane. METHODS: In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, the His bundle, and along the sulcus terminalis. Spontaneous pacemaker automaticity and subsidiary atrial pacemaker recovery time were measured in the conscious state, in the presence of methylatropine, with 1 and 2 micrograms.kg-1.min-1 epinephrine and during 1.25 and 2 MAC halothane, isoflurane, and enflurane. RESULTS: After SA node excision, a stable and regular subsidiary atrial pacemaker rhythm emerged. Each anesthetic prolonged subsidiary atrial pacemaker recovery times. This prolongation was greater in the presence of methylatropine. Without methylatropine, isoflurane and enflurane, but not halothane, further enhanced the baroreflex-mediated negative chronotropic effects of epinephrine, whereas with methylatropine, each anesthetic reduced the direct positive chronotropic effects of epinephrine. CONCLUSIONS: Halothane, isoflurane, and enflurane have significant depressant effects on the spontaneous and epinephrine-altered automaticity of subsidiary atrial pacemakers. Depression of subsidiary atrial pacemaker automaticity was most apparent in dogs with muscarinic blockade.

Dose-dependent effects of halothane on the carbon dioxide responses of expiratory and inspiratory bulbospinal neurons and the phrenic nerve activities in dogs.

BACKGROUND: Expiratory bulbospinal and inspiratory bulbospinal neurons in the ventral respiratory group provide drive for thoracoabdominal expiratory and phrenic and thoracic inspiratory motor neurons. Potent inhalational agents such as halothane may have differential effects on inspiratory and expiratory neurons, but detailed studies comparing neurons at a homologous level are lacking. METHODS: The dose-dependent effects of anesthesia with 1.0-2.5 minimum alveolar concentration halothane on the CO2 responses of single expiratory and inspiratory bulbospinal neurons of the ventral respiratory group and on phrenic neural activities were studied in nonpremedicated, anesthetized, paralyzed, vagotomized dogs. Hyperventilation with O2 and the addition of CO2-O2 mixtures were used to produce low, medium, and high steady-state levels of central CO2 drive. RESULTS: Peak neuron discharge frequency decreased progressively with increasing halothane dose at all levels of CO2 drive for both types of neurons. The sensitivities of inspiratory and expiratory bulbospinal neuronal activities to halothane were not significantly different from one another, whereas the sensitivity to halothane of the peak phrenic activity was markedly greater than those of the neurons. Increasing halothane dose caused a downward, predominantly parallel shift of the CO2 response curves. Phrenic nerve activity also showed a decrease in slope of the CO2 response. CONCLUSIONS: The activities of respiratory premotor neurons are less depressed by increasing doses of halothane than is phrenic nerve activity. The greater depression of phrenic activity may result from additional anesthetic actions on the efferent motor pathways, resulting in decreased descending synaptic inputs to phrenic motor neurons.

Interaction between chemoreceptor and stretch receptor inputs at medullary respiratory neurons.

The interaction between afferent inputs from carotid body chemoreceptors (CCRs) and from slowly adapting pulmonary stretch receptors (PSRs) on the discharge patterns of medullary inspiratory (I) and expiratory (E) neurons was characterized in thiopental sodium-anesthetized, paralyzed, ventilated dogs. A cycle-triggered ventilator was used to produce control and test pulmonary afferent input patterns. The CCRs were stimulated by phase-synchronized bolus injections of CO2-saturated saline into the common carotid arteries. Only those neurons whose discharge time course was altered by both inflation and CCR activation were studied. The dorsal respiratory group (DRG) I inflation-insensitive neurons were also included. Cycle-triggered histograms of unit activity were obtained for the neuronal responses to inflation, CO2 bolus, and their combination, as well as for the spontaneous control condition. Linearity of the interaction was tested by comparing the sum of the net individual responses to the net response of the combined afferent inputs. The results suggest that a linear (additive) interaction between CCR and PSR inputs exists for the DRG I inflation-sensitive neurons, the ventral respiratory group (VRG) I decrementing, and caudal VRG E augmenting neurons, while a nonadditive interaction exists for caudal VRG E decrementing bulbospinal neurons. The implications of these findings are discussed.

Expiratory bulbospinal neurons of dogs. I. Control of discharge patterns by pulmonary stretch receptors.

To better understand expiratory bulbospinal (EBS) neuronal processing of afferent patterns from slowly adapting pulmonary stretch receptors (PSRs), the responses of these caudal medullary neurons to various inflation patterns were analyzed in thiopental sodium-anesthetized paralyzed dogs. Normocapnic ventilation was obtained from lung inflations delivered during the neural inspiratory phase of control respiratory cycles by a solenoid ventilator triggered by the onset of phrenic nerve activity. Test inflation patterns, delivered during the neural expiratory (E) phase of specific cycles, were separated by 6-10 control cycles and consisted of slow augmenting and decrementing ramps and steps. Transpulmonary pressure (Pt) was used as an index of PSR activity, and the discharge patterns of single EBS neurons were quantified using cycle-triggered histograms. Based on the time course of the discharge pattern during no-inflation cycles, two types of neurons were identified. Type D, the most common, exhibited a decrementing-like pattern, while type A exhibited an augmenting-plateau pattern. Plots of discharge frequency vs. Pt for type D neurons consisted of a linear excitatory phase (1 less than Pt less than 4.6 mmHg) and a linear inhibitory phase (4.6 less than Pt less than 12 mmHg). Type A neurons exhibited only a linear inhibitory phase for 3.3 less than Pt less than 12 mmHg. Because the responses to step inflations (4 s duration) exhibited only a small amount of time dependency, and the activation Pt of PSRs, but not of the other pulmonary receptors with vagal fibers, is in the proper range, it appears that PSRs may mediate both excitatory and inhibitory components of the neuronal response. These data suggest that discharge patterns of the caudal EBS neurons in dogs are highly dependent on the time course of Pt in a predictable manner, and implicate the importance of instantaneous lung volume in the control of the E musculature and the optimization of the breathing pattern.

Expiratory bulbospinal neurons of dogs. II. Laterality of responses to spatial and temporal pulmonary vagal inputs.

Pulmonary mechanoreceptors with vagal fibers produce a combination of excitation and inhibition in the majority of the expiratory bulbospinal (EBS) neurons of dogs. Both aspects of this transpulmonary pressure-dependent neuronal response appear to be slowly adapting and activated at low pressure levels, suggesting the involvement of the slowly adapting pulmonary stretch receptors (PSRs). The purpose of the present study was to determine the contribution of different afferent pathways to each of the response components and to characterize the spatial and temporal processing of ipsi-, contra-, and bilateral vagal afferent inputs by two types of EBS neurons. For this purpose low-intensity electrical stimulation of the intact, desheathed, vagus nerves was used in thiopental sodium-anesthetized paralyzed dogs. The phrenic neurogram was used to synchronize both ventilation and stimulation. During test respiratory cycles, pulse trains (4-5 s duration) were applied during the neural expiratory phase to each and both vagus nerves. The mean discharge frequency (Fn) during the stimulus period was obtained from cycle-triggered histogram data. Plots of Fn vs. stimulus strength and Fn vs. stimulus frequency suggest that inhibition of both type D and type A EBS neurons is mediated mainly by the ipsilateral vagus nerve, and that the excitation of type D neurons is mediated bilaterally. These conclusions are also supported by inflation responses obtained before and after unilateral vagotomies. Differences in latencies and spatial and temporal summation characteristics suggest the possible involvement of different 1) types of PSRs, 2) central pathways, and/or 3) synaptic mechanisms in the biphasic response of the caudal ventral EBS neurons to lung inflation.

Respiratory responses to aortic and carotid chemoreceptor activation in the dog.

Respiratory responses arising from both chemical stimulation of vascularly isolated aortic body (AB) and carotid body (CB) chemoreceptors and electrical stimulation of aortic nerve (AN) and carotid sinus nerve (CSN) afferents were compared in the anesthetized dog. Respiratory reflexes were measured as changes in inspiratory duration (TI), expiratory duration (TE), and peak averaged phrenic nerve activity (PPNG). Tonic AN and AB stimulations shortened TI and TE with no change in PPNG, while tonic CSN and CB stimulations shortened TE, increased PPNG, and transiently lengthened TI. Phasic AB and AN stimulations throughout inspiration shortened TI with no changes in PPNG or the following TE; however, similar phasic stimulations of the CB and CSN increased both TI and PPNG and decreased the following TE. Phasic AN stimulation during expiration decreased TE and the following TI with no change in PPNG. Similar stimulations of the CB and CSN decreased TE; however, the following TI and PPNG were increased. These findings differ from those found in the cat and suggest that aortic chemoreceptors affect mainly phase timing, while carotid chemoreceptors affect both timing and respiratory drive.

Processing of pulmonary afferent input patterns by respiratory I-beta neurons.

To characterize the dynamics of the control of respiratory I-beta neurons by slowly adapting pulmonary stretch receptors, the neuronal discharge responses to lung inflation and electrically induced vagal input patterns were analyzed. Unitary recordings from single medullary I-beta neurons and whole phrenic nerve activity were recorded in chloralose-urethan-anesthetized paralyzed cats. Neuronal discharge patterns were quantified in terms of cycle-triggered histograms. The net response to a test afferent input pattern generated during neural inspiration was expressed as the difference between the central component of I-beta activity and the total response. The central component was obtained during control respiratory cycles in which lung inflation occurred during neural expiration and no vagal feedback occurred during neural inspiration. For a set of test inflations with different ramp rates, the net responses, measured at fixed times with respect to the onset of neural inspiration, were linearly related to transpulmonary pressure. However, the slopes of these relationships increased as a function of time during neural inspiration. Neuronal responses to electrically induced ramp vagal input patterns were similar to those produced by ramp inflation. The net response due to electrically induced ipsilateral step patterns consisted of a rapid excitatory and a slow inhibitory component, whereas only the slow inhibitory component was observed for contralateral patterns. The implications of these findings with respect to the modes of neural processing and effects on phrenic output patterns are discussed.