Quantitative description of the adaptation of vagal effects by means of an electromechanical coupling model]

A four compartments model describes the electrotropic and the inotropic vagal effect time courses during long time stimulation. The model realises electro-mechanical coupling. A differential equation for the coupling model is developed, solutions are given and a numerical treatment is described. The model shows the essential properties of effect adaptation: time delay and smaller extent of electrotropic effect adaptation.     

Modification of efferent vagal effects on the isolated atrium by increased extracellular K+ concentrations

Isolated vagal-innervated rabbit atria are electrically driven. Alterations of action potential, contraction, and electrotropic and inotropic vagal effects are investigated during variations of the external potassium concentration. Action potential area and contraction amplitude decrease by increasing external potassium concentration. If the potassium concentration is higher than 11 mM, the action potential disappears. At 24 mM potassium concentration the contraction amplitude of the driven atrium is reduced to 2%. Adrenaline (2.10(-5) g/ml) causes a restitution of the action potential and the contraction. With increasing potassium concentration the inotropic and the electrotropic vagal effectivity increases also. The vagal effects at the adrenaline restituted action potentials and contractions (15 mM potassium, 2.10(-5) g/ml adrenaline) are also higher than in normal solutions. The relations of electromechanical coupling are altered by potassium variation at the same coupling curve. With increasing potassium concentration the reproducibility of the vagal effects decreases.     

Effect of the vagus nerve on isolated rabbit atria in ganglionic blockade due to hexamethonium]

By quantitative stimulation of the vagus nerves of isolated rabbit atria frequency-response relations were obtained for both the electrotropic effect (reduction of the area of the monophasic action potential) and the inotropic response. An addition of hexamethonium in a final concentration of 10(-5) g/ml resulted in a diminution of vagal effectivity in the range of lower and medium frequencies of stimulation, and was connected with a shift of the frequency-response characteristic to the right. At higher frequencies vagal effectivity was increased. In contrast to the inhibitory effect of hexamethonium the facilitating action is irreversible. By raising the concentration up to 4-10(-5) g/ml the vagal effects were reduced to a large extent, and the frequency dependence of the response was abolished at medium frequencies. In the range of 20 sec(-1) to 100 sec(-1) this dependence was re-established and may be considered as a part of a normal frequency-response relation extremely shifted to the right. The time courses of both types of effect are characterized by a steep rise and a decay of the response during the stimulation period. A mathematical handling of the frequency-response characteristics provides quantitative evidence for the extent of the hexamethonium blockade of vagal ganglion cells in the atria; furthermore it leads to the conception of these cells to act as a distributing system for a homogeneous innervation by a widespread divergency of postganglionic fibres.     

Biocybernetic studies on reflectory heart modification in the rabbit]

In rabbits the depressor nerves and cardiac vagal branches were stimulated. Their actions on heart rate, atrio-ventricular conduction time, myocardial action potential and mean central blood pressure were recorded. The frequency-effect characteristics of the chronotropic, dromotropic and electrotropic actions on the heart, resulting from afferent and efferent nerve stimulation, are compared. The participation of each of the depressor nerves in their total effects on heart rate and blood pressure is studied. Time courses of heart rate and blood pressure decrease by afferent and efferent nerve stimulation with sinusoidally modulated pulse rates are presented. The results are discussed with respect to the different dynamics of blood pressure and heart rate control. It is concluded that at least two mechanisms are involved in blood pressure control by the depressor nerves: 1. Decrease of vascular resistance by lowering the sympathetic tone. 2. Decrease of heart rate by enhancing the cardiac vagal activity. It is suggested that the parasympathetic control unit compensates rapid disturbances, whereas the slow-acting sympathetic vascular mechanism exerts a long-time pressure control of high efficiency.     

Effect of cesium ions on the electrotropic actions of acetylcholine in the rabbit atrium

Cs+ (15-20 mM) decreases the electrotropic vagal effects on an isolated vagal innervated rabbit atrium. By means of investigating the action potentials and the phase plane trajectories of trabeculae from the rabbit atrium using a modified single sucrose gap technique the anomalous rectification disappears and also the effect of acetylcholine (ACh) on action potential duration. We presume that the anomalous rectification should be a necessary condition of electrotropic vagal (ACh) action on the rabbit atrium.     

The influence of prostaglandins E2 and F2 alpha on electrotropic and inotropic vagal effects on the isolated rabbit atrium

1. PG E2 (2.10(-8) g/ml) produces a positive inotropic effect and lengthens the duration of the action potential at the level of 50% and 90% of repolarization. 2. PG F2 alpha acts negatively inotropic and shortens the action potential at the level of 75% and 90% of repolarization. 3. PG F2 alpha (2.10(-8) g/ml) increases both the electrotropic and inotropic vagal effects, PG E2 (2.10(-8) g/ml) decreases them. 4. PG E2 improves the electromechanical coupling, PG F2 alpha reduces it.     

Vagus effect on action potentials of rest-potentiated contractions in the isolated left atrium of the rabbit

After a period of rest action potentials in constantly driven preparations of left rabbit atria show a marked change in configuration. After the upstroke an early repolarization takes place which is followed by a prolonged phase of secondary depolarization. This depolarization is strongly suppressed by vagal stimulation. Frequency-response characteristics of this electrotropic effect were obtained by stimulating the vagal supply of the preparation with frequencies in the range from 1.0 to 40.0 s-1 and compared with those of the constantly driven preparation. In most cases studied the frequency-response curves for the post rest action potential are steeper in rise and shifted to the left. By placing a series of vagal stimulations at different moments into the resting interval vagal effects could be composed to reflect the time course of transmitter action in a non beating preparation. It was shown that such time course is not essentially altered compared with that of a driven preparation. From a mathematical treatment of the frequency-response relations it is concluded that post rest action potentials show a higher sensitivity towards the transmitter action and that the amount of transmitter liberated after a period of rest may be increased. Possible explanations for this behaviour are proposed.     

Action of acetylcholine on the mammalian auricle influenced by verapamil

The action of acetylcholine (ACh) and verapamil (VePa) on the action potential (V(t)), phase plane trajectories of V(t) (dV/dt--V(t) -- plot) and isotonic contractions were investigated using an isolated vegal innervated preparation from rabbit atrium (method I) and investigating action potentials from atrial trabeculae by means a modified sucrose gap technique (method II). If the VePa-concentration increases to 4 mg/1 the duration of the action potential decreases at 20 and 90% repolarization (driving frequencies 2 s-1). In the VePa-solutions phase plane trajectories of the action potential did not change significantly. ACh application favours the disappearance of a region in the repolarization phase plane plot showing anomalous rectification (d(--dV/dt)/dV less than 0) both by control conditions and verapamil. The electrotropic ACh-and vagal effects will be unchanged by verapamil. The inotropic ACh-and vegal action (method I) increases by VePa (2 mg/1). The action of ACh and verapamil will be analysed using a mathematical model for reconstructing the repolarization phase of mammalian atrial myocardium action potentials.     

Interaction of the inotropic effect of norepinephrine and acetylcholine on the guinea pig's myocardium]

The experiments on guinea pig myocardium slices have been carried out to study the interaction of inotropic effects of different doses of norepinephrine (NE, from 10(-7) to 10(-5) mol/l) and acetylcholine (AC, from 10(-8) to 10(-6) mol/l). With an increase of NE concentration the negative influence of AC on the inotropic action is replaced by positive one. It is shown that there are optimal concentrations of NE and AC to exert a negative influence of AC on adrenergic inotropic effect (in these experiments--3 x 10(-7) mol/l for both influences). A decrease in frequency of contractions of AC on NE effect and positive influence of adrenergic myocardium stimulation on inotropic effect of AC, respectively. Such a type of relation of cardial effects of choline- and adrenergic influences is suggested to be designated by term "negatively accentuative antagonism" unlike the opposite type of choline-adrenergic interaction--"positive accentuative antagonism", under which AC increases inotropic effect of adrenergic myocardium stimulation, while adrenergic positive inotropic influences decrease AC effect.     

电刺激家兔迷走神经中枢端诱导的黑-伯反射中的非联合型学习现象

本文旨在研究电刺激家兔迷走神经诱导的黑-伯（Hering-Breuer,HB）反射中的学习和记忆现象。选择性电刺激家兔迷走神经中枢端（频率10～100Hz,强度20～60μA,波宽0．3ms,持续60s）,观察对膈神经放电的影响。以不同频率电刺激家兔迷走神经可模拟HB反射的两种成分,即类似肺容积增大所致抑制吸气的肺扩张反射和类似肺容积缩小所致加强吸气的肺萎陷反射。（1）长时高频（≥40Hz,60s）电刺激迷走神经可模拟呼吸频率减慢,呼气时程延长的肺扩张反射。随着刺激时间的延长,膈神经放电抑制的程度逐渐衰减,表现为呼吸频率的减慢（主要由呼气时程延长所致）在刺激过程中逐渐减弱或消失,显示为适应性或“习惯化”的现象;刺激结束时呼吸运动呈现反跳性增强,表现为一过性的呼气时程缩短,呼吸频率加快,然后才逐渐恢复正常。长时低频（〈40Hz,60s）电刺激迷走神经可模拟呼吸频率加快、呼气时程缩短的肺萎陷反射。随着刺激时间的延长,膈神经放电增强的程度逐渐衰减,同样表现出“习惯化”现象;刺激结束后,膈神经放电不是突然降低,而是继续衰减,表现为呼气时程逐渐延长,呼吸频率逐渐减慢,直至恢复到前对照水平,表现了刺激后的短时增强效应。（2）HB反射的适应性或“习惯化”程度反向依赖于刺激强度和刺激频率,表现为随着刺激强度和频率的增加,膈神经放电越远离正常基线水平,即爿惯化程度减弱。结果表明,家兔HB反射具有“习惯化”这一非联合型学习现象,反映与其有关的呼吸神经元网络具有突触功能的可翅性,呼吸的中枢调控反射具有一定的适应性。     

Temporal changes in effectiveness of an inspiratory inhibitory electrical pontine stimulus

We determined the temporal changes in effectiveness of inspiratory-shortening expiratory-prolonging stimulus trains delivered in the region of the nucleus parabrachialis medialis and compared the responses to those observed during trains delivered to the vagus in the same animals (pentobarbital, sodium-anesthetized paralyzed cats). The inspiratory inhibitory effect of the pontine stimulus was assessed from the effect the stimulus has on threshold for terminating inspiration. Stimulus effect increased gradually, reached a peak at 0.2-0.4 s, and declined thereafter. The time of occurrence of peak effect was different from that observed in the course of vagal stimulus trains. With long stimulus trains (19-40 s), the initial effect on inspiratory duration (TI) (i.e., shortening) rapidly subsided and, in six of eight animals, was replaced by TI prolongation. The initial effect on expiratory duration (TE) (i.e., prolongation) also gradually declined with time but TE remained above control throughout. The time constant of adaptation was very similar with vagal and pontine stimulus trains (12.2 and 11.0 s, respectively), but the gain of the adapting response was much more pronounced with pontine stimuli, resulting in a paradoxical effect while stimulation continued. We conclude that the response to pontine stimuli, as with vagal stimuli, displays both integrative and adaptive characteristics. The similarity of the time constants for vagal and pontine adaptation responses suggests that these two inputs share common processing pathways.     

Cholinergic reactivity of tracheal smooth muscle after infection with feline herpesvirus I

Airway responsiveness was studied in cats 3 or 6 days after exposure to feline herpesvirus I. Control cats were sham inoculated with tissue culture media. Intrathoracic airway caliber was evaluated by pulmonary resistance (RL) and dynamic compliance (Cdyn). Trachealis shortening was quantitated with microfoil strain gauges, which measured the external diameter of tracheal ring 4. Airway smooth muscle contraction was produced using vagal stimulation and local infusion of acetylcholine. The diameter of tracheal ring 4 decreased with increasing frequency of vagal stimulation, and there was more constriction at 3 (PID3) than at 6 days postinfection (PID6) or in control cats. RL increased and Cdyn tended to decrease with increasing frequency of stimulation, but there was no difference between control and infected cats. Infected and control cats did not differ in their response to locally infused acetylcholine. Virus was consistently cultured from conjunctival, nasal, and oral mucous membranes, trachea, and main stem bronchi at PID3 but not from the trachea and main stem bronchi at PID6. Virus was never isolated distal to the main stem bronchi. Tracheal hyperresponsiveness to vagal stimulation correlates with the presence of virus at PID3 and is apparently presynaptic in origin.     

CO2 elimination by high-frequency oscillation: effects of vagosympathetic stimulation

The effects of electrical stimulation of the vagi on gas transport mediated by high-frequency, low tidal volume ventilation (HFV) was examined in 10 anesthetized, paralyzed, propranolol-treated dogs. Gas transport efficiency was estimated by measuring the rate of CO2 removed from the lungs (Vco2) achieved during 45-s bursts of HFV applied before (control 1), during, and after (control 2) electrical stimulation of the transected vagi. During vagal stimulation the heart rate was maintained by electrical pacing. During the 15-s phase of vagal stimulation pulmonary impedance increased from 3.6 +/- 0.7 to 6.2 +/- 2.2 cmH2O X l-1 X s, and Vco2 increased. When the electrical stimulation of the vagi was stopped, impedance and Vco2 returned to prestimulation values. Vco2 was always higher during electrical stimulation of the vagi when HFV of a fixed volume was applied over a range of frequencies or when a fixed oscillation frequency was used over a range of tidal volumes. The effects of vagal stimulation on HFV-mediated gas transport were quite similar to the effects of moving the locations of the bias flow inlet and outlet into the lung such that tracheal volume was decreased by 20 ml, an amount equivalent to estimated change in control airway volume thought to occur during vagal stimulation. We simulated the effects of vagal stimulation and decreased tracheal volume on Vco2 by using a previously described model of HFV-mediated gas transport.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vagal effects on sinoatrial and atrial conduction studied with epicardial mapping in dogs: the influence of pacemaker shifts on the measurement of sinoatrial conduction time

The influence of pacemaker shifts on sinoatrial conduction time (SACT) was studied by investigating the effects of vagal stimulation on SACT and atrial conduction in anesthetized open-chest dogs. Isochronal maps were drawn from unipolar electrograms simultaneously recorded at 60 epicardial sites on the right atrial free wall and the inferior and superior vena cava. Vagal stimulation caused atrial conduction velocity to increase from 0.99 +/- 0.10 m/s (mean +/- SD) to 1.23 +/- 0.23 m/s (p less than 0.01), and the pacemaker to shift to lower positions along the superior vena cava - right atrial junction. As a result of the changes, the distances and the atrial conduction times from the stimulating and recording electrodes to the pacemaker site varied, and hence, the SACT values obtained indirectly by premature atrial stimulation varied. The isochronal maps were used to measure the atrial conduction times from stimulating to recording electrodes (a), from stimulating electrode to pacemaker site (b), and from pacemaker site to recording electrode (c). Indirect SACT was lengthened by vagal stimulation from 43 +/- 16 to 64 +/- 22 ms (p less than 0.02). After correcting by subtracting the atrial conduction time (b + c - a), these values became 26 +/- 6 ms (control) and 40 +/- 11 ms (vagal stimulation) (p less than 0.01). SACT values measured directly from the electrograms were 27 +/- 7 ms (control) and 42 +/- 10 ms (vagal stimulation) (p less than 0.01). Corrected indirect SACTs were closer to direct SACTs than were the uncorrected indirect SACTs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscarinic potassium channels augment dynamic and static heart rate responses to vagal stimulation

Vagal control of heart rate (HR) is mediated by direct and indirect actions of ACh. Direct action of ACh activates the muscarinic K(+) (K(ACh)) channels, whereas indirect action inhibits adenylyl cyclase. The role of the K(ACh) channels in the overall picture of vagal HR control remains to be elucidated. We examined the role of the K(ACh) channels in the transfer characteristics of the HR response to vagal stimulation. In nine anesthetized sinoaortic-denerved and vagotomized rabbits, the vagal nerve was stimulated with a binary white-noise signal (0-10 Hz) for examination of the dynamic characteristic and in a step-wise manner (5, 10, 15, and 20 Hz/min) for examination of the static characteristic. The dynamic transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with a lag time. Tertiapin, a selective K(ACh) channel blocker (30 nmol/kg iv), significantly decreased the dynamic gain from 5.0 +/- 1.2 to 2.0 +/- 0.6 (mean +/- SD) beats.min(-1).Hz(-1) (P < 0.01) and the corner frequency from 0.25 +/- 0.03 to 0.06 +/- 0.01 Hz (P < 0.01) without changing the lag time (0.37 +/- 0.04 vs. 0.39 +/- 0.05 s). Moreover, tertiapin significantly attenuated the vagal stimulation-induced HR decrease by 46 +/- 21, 58 +/- 18, 65 +/- 15, and 68 +/- 11% at stimulus frequencies of 5, 10, 15, and 20 Hz, respectively. We conclude that K(ACh) channels contribute to a rapid HR change and to a larger decrease in the steady-state HR in response to more potent tonic vagal stimulation.     

Scattered light intensity fluctuation in the canine ventricular myocardium: correlation with inotropic drug effect

Scattered light intensity fluctuation (SLIF) of coherent light by a strip of ventricular muscle during diastole is believed to be due to asynchronous cellular motion within the myocyte as a result of spontaneous release of Ca from the sacoplamic reticulum. Previous studies have shown a correlation between inotropic agents, such as ouabain and elevated extracellular Ca or decreased extracellular Na, and SLIF. The purpose of this study was to see if this correlation could be extended to other inotropic agents. The digitalis genin, ouabagenin, produces inotropy by increasing intracellular free Ca. In toxic concentrations the drug produces abnormal aftercontractions by spontaneous Ca release from the sarcoplasmic reticulum. On the other hand, the Ca channel agonist BAY k 8644 is also positively inotropic, but its effect is associated with a decrease in Ca release from the sarcoplasmic reticulum, manifested by conversion of "rest potentiation" to "rest depression." The effects of these inotropic agents on the power spectra of SLIF were dissimilar. Both frequency and amplitude of SLIF were increased after ouabagenin (1 microM), but these changes were most marked after the onset of toxicity, at which time contractility was decreased, rather than during the positive inotropic response. In contrast, BAY k 8644 (1 microM) decreased SLIF at all levels of inotropic response. The beta-adrenoceptor stimulant drug, dobutamine, and the adenylate cyclase activator, forskolin, produced minimal increase in SLIF at inotropic concentrations but caused a large increase in SLIF only after the onset of toxicity. These results suggest that SLIF is a better indicator of intracellular Ca overload and toxic oscillatory contractions in the presence of an inotrope and not of increased inotropy, per se.     

Low frequency-dependent mechanism of the M2 receptor function on vagally mediated bronchoconstriction in rabbits in vivo.

The present study was carried out to investigate whether there is the difference between low and high frequencies of vagal stimulation on the functional appearance of M2 receptors in the rabbit. The animals were anesthetized, artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose-dependent. Although administration of methoctramine (50 and 300 microg/kg), a selective M2 receptor antagonist, had no significant effect on ACh-induced bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn responses to vagal stimulation at 5-15 Hz but did not potentiate bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D-Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5-15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz. Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results suggest that M2 receptors function as the inhibitory receptors in the bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15 Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at a higher frequency (30 Hz) results in the release of SP from the lungs.     

Motor reactivity of isolated heart of the grass-snake (Natrix natrix L.)

Stimulation of the vagus nerve with a volley of electric impulses changed the action of grass-snake heart producing a negative chronotropic and inotropic effect. The effect of vagal stimulation was not different from the effect of acetylcholine administration and it was absent in the presence of atropine and hexamethonium. It was not possible to demonstrate sympathetic nervous fibres in the stimulated segment of the vagus nerve and trials of finding a separate nerve increasing the heart rate were unsuccessful. Parasympathicotonic agents caused bradycardia and a fall in the amplitude of cardiac contractions, and in sufficiently high doses they arrested the heart in diastole. The action of muscarine-like agents was stronger than that of nicotine, and the anticholinergic action of tubocurarine was weaker than that of atropine. Catecholamines exerted a positive inotropic and chronotropic effect which was completely blocked by propranolol in some tests only.     

Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.