The efferent sympathetic activity of the rabbit renal nerve during local application of adrenaline to the carotid sinus]

Adrenalin solution (1:1000) administered at the carotid sinus, through excitation of the depressoric C-fibre system of the carotid nerve, induces a strong, lasting reflectoric decrease of arterial pressure with slowing heart rate, associated with an almost complete inhibition of the efferent sympathetic activity of the renal nerve. The efferent sympathetic activity, arterial blood pressure and heart rate, both at the onset and at the height of adrenalin action, show corresponding activity changes: the relative inhibition of the sympathetic nerve is strongest correlated with the depressoric blood-pressure effect, while the decrease of heart rate, related to the initial activity, is least pronounced.     

Cardiac, respiratory, and renal responses to stimulation of the external cuneate nucleus

The cardiac, respiratory, and renal responses of electrical stimulation and microinjection of excitatory amino acids into the external cuneate nucleus were investigated in 57 cats anesthetized with pentobarbital sodium, paralyzed, and artificially ventilated. Trains of rectangular cathodal pulses of 40-100 microA at 50 Hz and 0.1 ms duration were delivered through monopolar glass microelectrodes with a tip diameter of 10-20 micron, filled with indium-Woods metal alloy. Electrical stimulation at 232 histologically identified sites within the external cuneate nucleus could evoke changes in arterial blood pressure, heart rate, and efferent renal sympathetic nerve activity. In a further set of experiments, a change in respiration was observed at 74 identified sites. An increase or decrease in all parameters measured could be elicited at different stimulus sites within the external cuneate nucleus. Repositioning of the electrode (0.2-0.4 mm) in depth or laterally could result in a different response with stimulation. Microinjections of D,L-homocysteic acid or glutamate could mimic the evoked changes in blood pressure, heart rate, efferent renal sympathetic nerve activity, and respiration. This suggests that the external cuneate nucleus contains cell bodies that may modulate components of various cardiac, respiratory and renal reflexes. It is proposed that the external cuneate nucleus may be involved in the integration of somato-autonomic reflex responses.     

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.     

Corticotropin-releasing factor (CRF): mechanism to elevate mean arterial pressure and heart rate

The efferent mechanisms by which central administration of corticotropin-releasing factor (CRF) elevates mean arterial pressure and heart rate were assessed in unanesthetized, unrestrained rats. CRF increased blood pressure and heart rate by stimulating noradrenergic sympathetic nervous outflow. CRF-induced cardiovascular changes were not dependent on anterior pituitary hormone release, adrenomedullary epinephrine secretion, the renin-angiotensin system or circulating vasopressin.     

Respiratory modulation of the autonomic nervous system during Cheyne-Stokes respiration

Cheyne-Stokes respiration (CSR) is associated with increased mortality among patients with heart failure. However, the specific link between CSR and mortality remains unclear. One possibility is that CSR results in excitation of the sympathetic nervous system. This review relates evidence that CSR exerts acute effects on the autonomic nervous system during sleep, and thereby influences a number of cardiovascular phenomena, including heart rate, blood pressure, atrioventricular conduction, and ventricular ectopy. In patients in sinus rhythm, heart rate and blood pressure oscillate during CSR in association with respiratory oscillations, such that both peak heart rate and blood pressure occur during the hyperpneic phase. Inhalation of CO2 abolishes both CSR and the associated oscillations in heart rate and blood pressure. In contrast, O2 inhalation sufficient to eliminate hypoxic dips has no significant effect on CSR, heart rate, or blood pressure. In patients with atrial fibrillation, ventricular rate oscillates in association with CSR despite the absence of within-breath respiratory arrhythmia. The comparison of RR intervals between the apneic and hyperpneic phases of CSR indicates that this breathing disorder exerts its effect on ventricular rate by inducing cyclical changes in atrioventricular node conduction properties. In patients with frequent ventricular premature beats (VPBs), VPBs occur more frequently during the hyperpneic phase than the apneic phase of CSR. VPB frequency is also higher during periods of CSR than during periods of regular breathing, with or without correction of hypoxia. In summary, CSR exerts multiple effects on the cardiovascular system that are likely manifestations of respiratory modulation of autonomic activity. It is speculated that the rhythmic oscillations in autonomic tone brought about by CSR may ultimately contribute to the sympatho-excitation and increased mortality long observed in patients with heart failure and CSR.     

Cardiovascular effects produced by injections of thyrotropin-releasing hormone in specific preoptic and hypothalamic nuclei in the rat

Microinjection of 1.4 pmol TRH (0.5 ng; 50–150 nl) into both the preoptic suprachiasmatic nucleus (pos) and the A6800–7000 region of the medial preoptic nucleus (pom) produced increases in blood pressure and heart rate of 7% and 19%, respectively; heart rate responses in these two areas were higher than those occurring in other areas tested. TRH induced a significant increase in blood pressure and heart rate in the posterior hypothalamic nucleus (nhp) and increased heart rate only in the anterior (nha) and dorsomedial (ndm) hypothalamic nuclei. A small decrease in both blood pressure and heart rate resulted with TRH injections in the A7050–7400 region of the pom. No changes in respiratory rate or rectal temperature were observed at any site with this dose of TRH. Preliminary studies into the mechanism of the cardiovascular actions of TRH suggested that inhibition of the parasympathetic nerves to the heart make a partial contribution to the TRH-induced heart rate increase in the pos and that adrenal catecholamine release mediates the TRH response in the nhp. Neither methylatropine pretreatment nor adrenalectomy prevented the response to TRH injected into the nha, suggesting that activation of the cardiac sympathetic nerves may mediate TRH actions in this region. In the ndm, neither methylatropine nor adrenalectomy prevented the response to TRH; however, there was a tendency for the response to be less after methylatropine. Therefore, both inhibition of the parasympathetic and activation of the sympathetic nervous systems may contribute to the response observed, but no adrenal involvement could be demonstrated. Discrete injections of 0.8 nmol TRH produced increases in heart rate and blood pressure in all preoptic and hypothalamic nuclei tested with accompanying changes in respiratory rate and rectal temperature in some areas. Lateral cerebral ventricle injections of as little as 2.8 pmol TRH produced increases in blood pressure and heart rate; cardiovascular responses to higher doses (0.8–22 nmol) in the ventricle were often accompanied by arousal, piloerection, “wet dog” shakes and changes in respiratory rate and rectal temperature. Previous immunohistochemical demonstration of nerve cells and fibers in the preoptic-hypothalamic area and the present finding of specific sites responsive to low dose TRH injections (1.4 pmol) both support a physiological role for this peptide in central control of the cardiovascular system.     

Neural mechanisms in body fluid homeostasis

Under steady-state conditions, urinary sodium excretion matches dietary sodium intake. Because extracellular fluid osmolality is tightly regulated, the quantity of sodium in the extracellular fluid determines the volume of this compartment. The left atrial volume receptor mechanism is an example of a neural mechanism of volume regulation. The left atrial mechanoreceptor, which functions as a sensor in the low-pressure vascular system, is located in the left atrial wall, which has a well-defined compliance relating intravascular volume to filling pressure. The left atrial mechanoreceptor responds to changes in wall left atrial tension by discharging into afferent vagal fibers. These fibers have suitable central nervous system representation whose related efferent neurohumoral mechanisms regulate thirst, renal excretion of water and sodium, and redistribution of the extracellular fluid volume. Efferent renal sympathetic nerve activity undergoes appropriate changes to facilitate renal sodium excretion during sodium surfeit and to facilitate renal sodium conservation during sodium deficit. By interacting with other important determinants of renal sodium excretion (e.g., renal arterial pressure), changes in efferent renal sympathetic nerve activity can significantly modulate the final renal sodium excretion response with important consequences in pathophysiological states (e.g., hypertension, edema-forming states).     

Baroreflex dysfunction in rats submitted to protein restriction

Earlier studies from the authors' laboratory showed that malnourishment induces alterations in the cardiovascular homeostasis increasing the basal mean arterial pressure and heart rate. In this study, the authors evaluated whether the sympathetic and parasympathetic efferent activities contribute to changes in the cardiovascular homeostasis through altered modulation of the arterial baroreflex of malnourished rats. After weaning, male Fischer rats were given 15% (Normal Protein--NP) or 6% (Low Protein--LP) protein diet for 35 d. The baroreflex gain and latency were evaluated before and after selective autonomic blockades in control and malnourished rats. It was observed that malnourishment affected the baroreflex gain in response to activation and deactivation of the arterial baroreflex. Moreover, malnourished rats showed increased baroreflex latency as compared to that of control rats. Regarding the autonomic efferent activity directed to the heart, the data showed increased sympathetic and decreased parasympathetic efferent activities in malnourished rats, and such alterations could be related to the observed changes in the arterial baroreflex gain as well as in the basal mean arterial pressure and heart rate.     

Organization of Efferent Sympathetic Influences Related to Cardiogenic Depressor Reflexes

In acute experiments on anesthetized dogs under open chest conditions, we studied characteristics of the efferent sympathetic influences on the heart and vessels related to realization of cardiogenic depressor vagus-mediated reflexes. Catheterization of the heart cavities and parallel recording of the mass efferent spike activities in the cardiac and vertebral sympathetic nerves and of the pressure in the aortic ventricle of the heart were used. We found that reflex shifts in the spike activity in the cardiac and vertebral nerves elicited by pharmacological stimulation of the left heart (intracoronary injections of veratrine or adrenaline) and by its nidal immune impairment resulting from injection of a cytotoxic serum demonstrate similar direction (a drop in the frequency of the efferent sympathetic activity). Yet, the dynamics of such inhibitory responses to the influence of the same stimulus and their intensity in one nerve or another and those in one and the same nerve under the influence of different stimuli are considerably dissimilar. Thus, realization of vagus-mediated cardiogenic reflexes is characterized by clear heterogeneity of the efferent sympathetic control of different regions of the cardiovascular system. Such a specificity can provide differential regulation of the heart function and functions of the vascular bed related to different cardiogenic influences (both in the norm and under conditions of formation of an injury nidus in the heart).     

Circadian and short-term regulation of blood pressure and heart rate in transgenic mice with cardiac overexpression of the beta1-adrenoceptor

Congestive heart failure is associated with a loss of circadian and short-term variability in blood pressure and heart rate. In order to assess the contribution of elevated cardiac sympathetic activity to the disturbed cardiovascular regulation, we monitored blood pressure and heart rate in mice with cardiac overexpression of the β₁-adrenoceptor prior to the development of overt heart failure. Telemetry transmitters for continuous monitoring of blood pressure and heart rate were implanted in 8 to 9-week-old wildtype and transgenic mice, derived from crosses of heterozygous transgenic (line β₁TG4) and wildtype mice. Cardiovascular circadian patterns were analyzed under baseline conditions and during treatment with propranolol (500 mg/L in drinking water). Short-term variability was assessed by spectral analysis of beat-to-beat data sampled for 30 min at four circadian times. Transgenic β₁TG4 mice showed an increase in 24 h heart rate, while blood pressure was not different from wildtype controls. Circadian patterns in blood pressure and heart were preserved in β₁TG4 mice. Addition of propranolol to the animals' drinking water led to a reduction in heart rate and its 24 h variation in both strains of mice. Short-term variability in blood pressure was not different between wildtype and β₁TG4 mice, but heart rate variability in the transgenic animals showed a rightward shift of the high-frequency component in the nocturnal activity period, suggesting an increase in respiratory frequency. In conclusion, the present study shows that both the circadian and the short-term regulation of blood pressure and heart rate are largely preserved in young, nonfailing β₁-transgenic mice. This finding suggests that the loss of blood pressure and heart rate variability observed in human congestive heart failure cannot be attributed solely to sympathetic overactivity but reflects the loss of adrenergic responsiveness to changes in the activity of the autonomic nervous system.     

Spectral analysis of muscle sympathetic nerve activity in heat-stressed humans

Whole body heating increases muscle sympathetic nerve activity (MSNA); however, the effect of heat stress on spectral characteristics of MSNA is unknown. Such information may provide insight into mechanisms of heat stress-induced MSNA activation. The purpose of the present study was to test the hypothesis that heat stress-induced changes in systolic blood pressure variability parallel changes in MSNA variability. In 13 healthy subjects, MSNA, electrocardiogram, arterial blood pressure (via Finapres), and respiratory activity were recorded under both normothermic and heat stress conditions. Spectral characteristics of integrated MSNA, R-R interval, systolic blood pressure, and respiratory excursions were assessed in the low (LF; 0.03-0.15 Hz) and high (HF; 0.15-0.45 Hz) frequency components. Whole body heating significantly increased skin and core body temperature, MSNA burst rate, and heart rate, but not mean arterial blood pressure. Systolic blood pressure and R-R interval variability were significantly reduced in both the LF and HF ranges. Compared with normothermic conditions, heat stress significantly increased the HF component of MSNA, while the LF component of MSNA was not altered. Thus the LF-to-HF ratio of MSNA oscillatory components was significantly reduced. These data indicate that the spectral characteristics of MSNA are altered by whole body heating; however, heat stress-induced changes in MSNA do not parallel changes in systolic blood pressure variability. Moreover, the reduction in LF component of systolic blood pressure during heat stress is unlikely related to spectral changes in MSNA.     

The development of sympathetic innervation and the functional state of the cardiovascular system in newborn dogs.

The present study in dogs indicates that the peripheral sympathetic fibers develop mostly after birth and reach a full maturity at about 2 months of life. The norepinephrine content of the heart, spleen, intestine, salivary glands, and adrenal glands increased from birth to 56 days of age. In contrast, the content of the stellate ganglia decreased during this period. In most of the organs studied, the uptake of [3H] norepinephrine developed in parallel with the norepinephrine content, except in the right atrium and salivary glands where it was fully developed soon after birth. During development, the systemic blood pressure increased from 40 to 100 mm Hg. Bilateral adrenal vessel clamping failed to induce a fall in blood pressure in growing dogs which indicates that the adrenal medulla or the baroreceptors did not fully compensate for the lack of peripheral sympathetic fibers and for the lower blood pressure in newborn animals. Although cardiac norepinephrine content was still very low in 10-day-old animals, cardiovascular responses to direct and reflex sympathetic stimulation were similar to those observed in 56-day-old animals. These results indicate that the sympathetic nervous system becomes functional before the fibers reach their full maturity.     

Amplitude and frequency characteristics of sympathetic nerve discharge in normotensive rats

Electrical discharges in the cervical sympathetic trunk and arterial blood pressure were recorded in chloralose-anaesthetized Wistar rats. Some experiments were performed in rats with impaired baroreceptor reflex. The efferent electrical activity was analysed in amplitude and frequency domain. It has been shown that arterial and cardio-pulmonary mechanoreceptors do not affect magnitude of the electrical activity. However, arterial and cardio-pulmonary baroreceptor reflex arc seems to be involved in frequency modulation of the efferent sympathetic activity.     

Circadian and Short-Term Regulation of Blood Pressure and Heart Rate in Transgenic Mice with Cardiac Overexpression of The β1-Adrenoceptor

Congestive heart failure is associated with a loss of circadian and short-term variability in blood pressure and heart rate. In order to assess the contribution of elevated cardiac sympathetic activity to the disturbed cardiovascular regulation, we monitored blood pressure and heart rate in mice with cardiac overexpression of the β₁-adrenoceptor prior to the development of overt heart failure. Telemetry transmitters for continuous monitoring of blood pressure and heart rate were implanted in 8 to 9-week-old wildtype and transgenic mice, derived from crosses of heterozygous transgenic (line β₁TG4) and wildtype mice. Cardiovascular circadian patterns were analyzed under baseline conditions and during treatment with propranolol (500 mg/L in drinking water). Short-term variability was assessed by spectral analysis of beat-to-beat data sampled for 30 min at four circadian times. Transgenic β₁TG4 mice showed an increase in 24 h heart rate, while blood pressure was not different from wildtype controls. Circadian patterns in blood pressure and heart were preserved in β₁TG4 mice. Addition of propranolol to the animals’ drinking water led to a reduction in heart rate and its 24 h variation in both strains of mice. Short-term variability in blood pressure was not different between wildtype and β₁TG4 mice, but heart rate variability in the transgenic animals showed a rightward shift of the high-frequency component in the nocturnal activity period, suggesting an increase in respiratory frequency. In conclusion, the present study shows that both the circadian and the short-term regulation of blood pressure and heart rate are largely preserved in young, nonfailing β₁-transgenic mice. This finding suggests that the loss of blood pressure and heart rate variability observed in human congestive heart failure cannot be attributed solely to sympathetic overactivity but reflects the loss of adrenergic responsiveness to changes in the activity of the autonomic nervous system.     

Heart Rate Variability and Blood Pressure during Dynamic and Static Exercise at Similar Heart Rate Levels

Aim was to elucidate autonomic responses to dynamic and static (isometric) exercise of the lower limbs eliciting the same moderate heart rate (HR) response. Method: 23 males performed two kinds of voluntary exercise in a supine position at similar heart rates: static exercise (SE) of the lower limbs (static leg press) and dynamic exercise (DE) of the lower limbs (cycling). Subjective effort, systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), rate pressure product (RPP) and the time between consecutive heart beats (RR-intervals) were measured. Time-domain (SDNN, RMSSD), frequency-domain (power in the low and high frequency band (LFP, HFP)) and geometric measures (SD1, SD2) as well as non-linear measures of regularity (approximate entropy (ApEn), sample entropy (SampEn) and correlation dimension D2) were calculated. Results: Although HR was similar during both exercise conditions (88±10 bpm), subjective effort, SBP, DBP, MAP and RPP were significantly enhanced during SE. HRV indicators representing overall variability (SDNN, SD 2) and vagal modulated variability (RMSSD, HFP, SD 1) were increased. LFP, thought to be modulated by both autonomic branches, tended to be higher during SE. ApEn and SampEn were decreased whereas D₂ was enhanced during SE. It can be concluded that autonomic control processes during SE and DE were qualitatively different despite similar heart rate levels. The differences were reflected by blood pressure and HRV indices. HRV-measures indicated a stronger vagal cardiac activity during SE, while blood pressure response indicated a stronger sympathetic efferent activity to the vessels. The elevated vagal cardiac activity during SE might be a response mechanism, compensating a possible co-activation of sympathetic cardiac efferents, as HR and LF/HF was similar and LFP tended to be higher. However, this conclusion must be drawn cautiously as there is no HRV-marker reflecting “pure” sympathetic cardiac activity.     

Baroreflex control of muscle sympathetic nerve activity during skin surface cooling.

Skin surface cooling improves orthostatic tolerance through a yet to be identified mechanism. One possibility is that skin surface cooling increases the gain of baroreflex control of efferent responses contributing to the maintenance of blood pressure. To test this hypothesis, muscle sympathetic nerve activity (MSNA), arterial blood pressure, and heart rate were recorded in nine healthy subjects during both normothermic and skin surface cooling conditions, while baroreflex control of MSNA and heart rate were assessed during rapid pharmacologically induced changes in arterial blood pressure. Skin surface cooling decreased mean skin temperature (34.9 +/- 0.2 to 29.8 +/- 0.6 degrees C; P < 0.001) and increased mean arterial blood pressure (85 +/- 2 to 93 +/- 3 mmHg; P < 0.001) without changing MSNA (P = 0.47) or heart rate (P = 0.21). The slope of the relationship between MSNA and diastolic blood pressure during skin surface cooling (-3.54 +/- 0.29 units.beat(-1).mmHg(-1)) was not significantly different from normothermic conditions (-2.94 +/- 0.21 units.beat(-1).mmHg(-1); P = 0.19). The slope depicting baroreflex control of heart rate was also not altered by skin surface cooling. However, skin surface cooling shifted the "operating point" of both baroreflex curves to high arterial blood pressures (i.e., rightward shift). Resetting baroreflex curves to higher pressure might contribute to the elevations in orthostatic tolerance associated with skin surface cooling.     

Ergoreflex: The essence and mechanisms

Physical load increases sympathetic nervous activity, which results in an increased cardiac output, constriction of peripheral vessels, and elevated systemic blood pressure. These changes are outcomes of two mechanisms: the central command from cerebral structures that trigger voluntary movements to activate the vasomotor center and the reflexes initiated by mechanical and metabolic changes in a working muscle. The latter mechanism of the sympathetic system activation is termed ergoreflex. The main effects of ergoreflex on the indices of systemic hemodynamics are the following: activation of mechanosensitive afferents mainly leads to inhibition of the tonic vagal effects on the heart, which explains the rapid increase in heartbeats upon loading; activation of chemosensitive afferents comes with some delay in pace with metabolite accumulation in muscles and leads to an increase in efferent sympathetic activity and a rise in blood pressure. The metabolic reflex effect is particularly high in the case of muscle fatigue. This review deals with the mechanisms underlying the ergoreflex and their adaptation to hypodynamia, physical training, and some pathologies.     

Dynamic baroreflex control of blood pressure: influence of the heart vs. peripheral resistance

The aim in the present experiments was to assess the dynamic baroreflex control of blood pressure, to develop an accurate mathematical model that represented this relationship, and to assess the role of dynamic changes in heart rate and stroke volume in giving rise to components of this response. Patterned electrical stimulation [pseudo-random binary sequence (PRBS)] was applied to the aortic depressor nerve (ADN) to produce changes in blood pressure under open-loop conditions in anesthetized rabbits. The stimulus provided constant power over the frequency range 0-0.5 Hz and revealed that the composite systems represented by the central nervous system, sympathetic activity, and vascular resistance responded as a second-order low-pass filter (corner frequency approximately 0.047 Hz) with a time delay (1.01 s). The gain between ADN and mean arterial pressure was reasonably constant before the corner frequency and then decreased with increasing frequency of stimulus. Although the heart rate was altered in response to the PRBS stimuli, we found that removal of the heart's ability to contribute to blood pressure variability by vagotomy and beta(1)-receptor blockade did not significantly alter the frequency response. We conclude that the contribution of the heart to the dynamic regulation of blood pressure is negligible in the rabbit. The consequences of this finding are examined with respect to low-frequency oscillations in blood pressure.     

Mechanisms of the inhibitory effect of the stellate ganglion on cardiac activity

The mechanisms of cardiac activity inhibition caused by stimulation of the stellate ganglion were studied in acute experiments on 28 dogs and 37 cats and chronic experiments on 12 cats. It was shown that inhibition of cardiac activity is caused by stimulation of the parasympathetic fibers of the vagus, anastomozing with stellate ganglion branches and ingoing as part of these fibers to the heart. The hypothesis of change over of the sympathetic nerve fibers to the intracardial cholinergic neurons and the hypothesis of the cholinergic component in the mechanism of catecholamine release by the sympathetic nerve terminals was not confirmed. Therefore, the known Dale's principle as to that one neuron exerts its efferent effect with the aid of one transmitter is quite just. alpha-Adrenoreceptors does not produce any noticeable effect on cardiac activity.     

Tonic sympathetic activity in the rabbit sciatic nerve

Tonic activity of sympathetic nerve fibers of the tibial and peroneal nerves was investigated in rabbits anesthetized with urethane by the multichannel coherent recording technique. Activity of stochastic character was shown to predominate in the tonic activity of these fibers. A component of activity with the frequency of the heart beat also is frequently observed, but the power of this component is never more than half the total power of activity. Activity with a frequency of 10 Hz, observed by other workers, and also modulation of tonic activity in the rhythm of respiration were not recorded in these experiments. Slow changes in the power of activity from zero to a level several times above average were observed when the blood pressure was stable.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 3, pp. 351–358, May–June, 1985.