Pontomedullary transection attenuates central respiratory modulation of sympathetic discharge, heart rate and the baroreceptor reflex in the in situ rat preparation

Previous studies have indicated a major role for the pons in the genesis of the respiratory pattern. The respiratory rhythm is coupled to the cardiovascular system to ensure optimal matching of minute ventilation and cardiac output. Since much of this coupling results from cross-talk between brainstem circuits, we have assessed the role of the pons in both the co-ordination of respiratory and cardiovascular efferent activities and the baroreceptor reflex efficacy. Using the arterially perfused in situ rat preparation, we recorded neural activities from the left phrenic nerve, central end of the vagus nerve, thoracic sympathetic chain (T8-T10) and heart rate. Respiratory sinus arrhythmia, respiratory modulation of sympathetic nerve activity (and Traube-Hering waves in arterial pressure) and postinspiratory discharges recorded from vagal efferents were eliminated after pontine transection. We also found that although the sympathetic arterial baroreflex remained intact, respiratory gating of the baroreceptor reflex (i.e. both bradycardia and sympathoinhibition) was abolished after pontine removal. We propose that neural activity of the pons is essential for physiological coupling of centrally generated respiratory and cardiovascular efferent activities.     

Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin

Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure(CHF) induced by coronary artery ligation and contributes to the over-excitation of sympathetic activity.We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were enhanced in adriamycin-induced CHF and whether angiotensin II(Ang II) in the paraventricular nucleus(PVN) was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex.Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks(15 mg/kg).Six weeks after the first injection,the rats underwent anesthesia with urethane and α-chloralose.After vagotomy and baroreceptor denervation,cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure(MAP) response to epicardial application of capsaicin(1.0 nmol).The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity.The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depressor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats.Bilateral PVN microinjection of angiotensin II(Ang II) caused larger responses of the cardiac sympathetic afferent reflex,baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats.These results indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure.     

Baroreflex control of renal sympathetic nerve activity and heart rate in near-term fetal sheep

Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 ± 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 ± 14 to 58 ± 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension; this finding has implications for the ability of the late preterm fetus to adapt to low BP.     

Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats

Aims: G protein‐coupled receptors such as the AT_1aR are frequently subject to desensitization, extensively studied in cell culture but to small extent in hypertensive models. Recently, angiotensin II (ANG II)‐induced desensitization was shown to last 10 min in isolated afferent arterioles (AAs), suggesting impact on ANG II vasoactivity. In the present study, we explored ANG II desensitization and effects of adenosine (Ado) in AAs from two‐kidney, one‐clip (2K1C) hypertensive rats. Our main hypothesis was that Ado affects ANG II contractility differently in 2K1C, because of persistently elevated levels of ANG II. Methods: Afferent arterioles were isolated with the agarose‐infusion/enzyme‐treatment technique from normotensive and 2K1C hypertensive rats, and stimulated with ANG II (10^?7 m ) at baseline and re‐stimulated after 20 or 40 min, with or without Ado (2.5 × 10^?5 m ) in the vessel bath. Results: Afferent arterioles from normotensive rats re‐stimulated with ANG II after 20 min displayed a blunted contraction (Δ12.8 ± 4.3%, P < 0.05), which disappeared when AAs were stimulated after 40 min (Δ2.7 ± 2.3%, NS), indicating that desensitization lasted for 30 ± 10 min. Ado augmented ANG II contractions after 20 min, but not after 40 min, suggesting that only de‐sensitized vessels were affected. Similar experiments in AAs from the clipped and non‐clipped kidneys revealed no desensitization when re‐stimulated with ANG II after 20 and 40 min, and contractions were unaffected by Ado. Conclusions: Reduced duration of desensitization in AAs from 2K1C may cause vessels to be sensitized longer and increase vasoconstriction. The present study demonstrates that Ado does not augment ANG II‐induced contractions in AAs from 2K1C as in normotensive rats, possibly because of a reduced period of desensitization.     

Cardiac sympathetic afferent reflex and its implications for sympathetic activation in chronic heart failure and hypertension

Persistent excessive sympathetic activation greatly contributes to the pathogenesis of chronic heart failure (CHF) and hypertension. Cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex with positive feedback characteristics. Humoral factors such as bradykinin, adenosine and reactive oxygen species produced in myocardium due to myocardial ischaemia stimulate cardiac sympathetic afferents and thereby reflexly increase sympathetic activity and blood pressure. The CSAR is enhanced in myocardial ischaemia, CHF and hypertension. The enhanced CSAR at least partially contributes to the sympathetic activation and pathogenesis of these diseases. Nucleus of the solitary tract (NTS), hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla are the most important central sites involved in the modulation and integration of the CSAR. Angiotensin II, AT₁ receptors and NAD(P)H oxidase‐derived superoxide anions pathway in the PVN are mainly responsible for the enhanced CSAR in CHF and hypertension. Central angiotensin‐(1‐7), nitric oxide, endothelin, intermedin, hydrogen peroxide and several other signal molecules are involved in regulating CSAR. Blockade of the CSAR shows beneficial effects in CHF and hypertension. This review focuses on the anatomical and physiological basis of the CSAR, the interaction of CSAR with baroreflex and chemoreflex, and the role of enhanced CSAR in the pathogenesis of CHF and hypertension.     

Angiotensin AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats

Sympathetic activity is enhanced in hypertension, which contributes to the pathogenesis of hypertension and progression of organ damage. The cardiac sympathetic afferent reflex (CSAR) is enhanced in renovascular hypertension and involved in the sympathetic activation. The present study was designed to investigate whether angiotensin II (Ang II) and Ang II type 1 (AT(1)) receptors in paraventricular nucleus (PVN) contribute to the enhanced CSAR and sympathetic outflow in experimental renovascular hypertensive rats. Hypertension was induced by the two-kidney one-clip (2K1C) method. The normotensive rats underwent sham operation (Sham). Acute experimentation was carried out at the end of the 4th week. Under urethane and α-chloralose anaesthesia, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in rats with sino-aortic denervation and cervical vagotomy. The AT(1) receptor expression was determined with Western blot. The CSAR was evaluated by the response of RSNA and MAP to epicardial application of 1.0 nmol of capsaicin. The AT(1) receptor expression in the PVN was increased, and Ang II in the PVN augmented the enhanced CSAR and RSNA in 2K1C rats. The effects of Ang II were abolished by pretreatment with the AT(1) receptor antagonist, losartan, in 2K1C rats. Losartan in the PVN normalized the enhanced CSAR and decreased the RSNA and MAP in 2K1C rats. These results indicate that the increased activity of AT(1) receptors in the PVN contributes to the enhanced CSAR and excessive sympathetic activation in renovascular hypertensive rats.     

Endogenous hydrogen peroxide in paraventricular nucleus mediating cardiac sympathetic afferent reflex and regulating sympathetic activity

We previously reported that reactive oxygen species (ROS) in paraventricular nucleus (PVN) mediated cardiac sympathetic afferent reflex (CSAR). The present study investigated the role of endogenous hydrogen peroxide (H₂O₂), a ROS, in the PVN in mediating the CSAR and regulating sympathetic activity. The CSAR was evaluated by the response of renal sympathetic nerve activity (RSNA) to epicardial application of bradykinin (BK) in rats. Bilateral microinjection of polyethylene glycol-catalase (PEG-CAT, an analogue of endogenous catalase) or polyethylene glycol-superoxide dismutase (PEG-SOD, an analogue of endogenous superoxide dismutase) into the PVN abolished the CSAR, decreased baseline RSNA and mean arterial pressure (MAP). Moreover, pretreatment with PEG-CAT or PEG-SOD blocked the enhanced CSAR and RSNA responses induced by exogenous angiotensin II (Ang II) in the PVN. Aminotriazole (ATZ, a catalase inhibitor) alone potentiated the CSAR, increased RSNA and MAP, but failed to augment the Ang II-induced CSAR enhancement responses. Pretreated with PEG-SOD, ATZ still increased baseline RSNA and MAP but inhibited the CSAR and Ang II-induced CSAR and RSNA enhancement responses. These results suggested that endogenous H₂O₂ in the PVN mediated both the CSAR and Ang II-induced CSAR enhancement responses. H₂O₂ in the PVN were involved in regulating sympathetic activity and arterial pressure.     

c-Src in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats

Enhanced cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation in renovascular hypertension. The study was to determine whether c-Src in paraventricular nucleus (PVN) is involved in the enhanced CSAR and sympathetic activation in hypertensive rats induced by two-kidney one-clip (2K1C). At the end of the fourth week after 2K1C surgery, renal sympathetic nerve activity (RSNA) was recorded in anesthetized rats with baroreceptor denervation and vagotomy. The CSAR was evaluated by the RSNA response to epicardial application of capsaicin. In the PVN, c-Src activity was higher in 2K1C rats than sham-operated (Sham) rats while c-Src expression was not. Epicardial application of capsaicin or PVN microinjection of angiotensin II (Ang II) increased c-Src activity more in 2K1C than Sham rats. PVN microinjection of selective Src family kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazol [3,4-D] pyrimidine (PP2) or 2,3-Dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1?H-indol-2-yl)methylene]-1?H-indole-5-sulfonamide (SU6656) abolished the CSAR and decreased RSNA more in 2K1C than Sham rats. The Ang II-induced RSNA and CSAR enhancement was abolished by PP2 or SU6656 pretreatment in 2K1C and Sham rats. NAD(P)H oxidase activity and superoxide anion level in PVN were higher in 2K1C rats, which was attenuated by PP2 but increased by epicardial application of capsaicin or PVN microinjection of Ang II. The effects of capsaicin or Ang II were abolished by PP2. These results indicate that c-Src in the PVN is involved in the enhanced CSAR and sympathetic activation in renovascular hypertension, and mediates the excitatory effects of Ang II in the PVN on the CSAR and sympathetic activity via NAD(P)H oxidase-derived generation of superoxide anions.     

Sleep apnea in heart failure increases heart rate variability and sympathetic dominance

AIMS: Sleep disordered breathing (SDB) is common in heart failure and ventilation is known to influence heart rate. Our aims were to assess the influence of SDB on heart rate variability (HRV) and to determine whether central sleep apnea (CSA) and obstructive sleep apnea (OSA) produced different patterns of HRV. METHODS AND RESULTS: Overnight polysomnography was performed in 21 patients with heart failure and SDB. Two 10-minute segments each of SDB and stable breathing from each patient were visually identified and ECG signal exported for HRV analysis. SDB increased total power (TP) with very low frequency (VLF) power accounting for the greatest increase (1.89+/-0.54 vs 2.96+/-0.46 ms2, P <0.001); LF/HF ratio increased during SDB (1.2+/-1.0 vs 2.7+/-2.1, P <0.001). Compared to OSA, CSA was associated with lower absolute LF (2.10+/-0.47 vs 2.52+/-0.55 ms2, P = 0.049) and HF power (1.69+/-0.41 vs 2.34+/-0.58 ms2, P = 0.004), increased VLF% (78.9%+/-13.4% vs 60.9%+/-19.2%, P = 0.008), decreased HF% (6.9%+/-7.8% vs 16.0%+/-11.7%, P = 0.046) with a trend to higher LF/HF ratio. CONCLUSIONS: SDB increases HRV in the setting of increased sympathetic dominance. HRV in CSA and OSA have unique HRV patterns which are likely to reflect the different pathophysiological mechanisms involved.     

Postural effects on muscle nerve sympathetic activity in man

1. Pulse-synchronous bursts of multi-unit sympathetic activity (MSA) were recorded in peroneal muscle nerve fascicles in eight healthy subjects when lying, sitting and standing. The sympathetic activity was quantitated by counting the number of bursts in the mean voltage neurogram/min. Postural changes were analysed by considering the total activity to be a product of the number of bursts in relation to the number of heart beats (burst incidence) and the heart rate.2. In lying there were large interindividual differences in total activity, but for all subjects the activity increased when going from lying to sitting and from sitting to standing. With a few exceptions the increase between the lying and sitting postures was associated with an increase in both burst incidence and heart rate whereas between the sitting and standing postures there was an increase in heart rate but on the average no change in burst incidence.3. When going from lying to sitting or from sitting to standing the magnitude of the change in burst incidence was inversely related to the initial burst incidence so that subjects with low initial values usually showed greater increases in burst incidence than subjects with high initial values. Some subjects with high initial values decreased their burst incidence.4. With changes in postures there was an inverse linear relationship between the fraction of the change in MSA associated with a change in burst incidence and the fraction associated with a change in heart rate. An increase in total activity could be obtained by changing only burst incidence, by increasing heart rate without changing burst incidence, or by appropriate changes in both parameters. The slope of the regression line was -0.53 indicating that for adequate postural compensation fewer additional bursts were required when the compensatory response involved an increase in heart rate rather than an increase in only burst incidence.5. It is suggested that an impairment of the ability to regulate heart rate will make subjects with high burst incidence in the lying position orthostatically more vulnerable than those with low burst incidence.6. Shortly after standing up one subject developed bradycardia and subsequently fainted. The nerve recording was maintained until the subject collapsed. During the initial bradycardia no sympathetic bursts occurred suggesting that the syncope was associated with an interruption of normal baroreflex feedback between blood pressure and sympathetic outflow.     

Muscle sympathetic activity and plasma noradrenaline in normotensive and hypertensive man

Micro-electrode recordings of muscle sympathetic activity were made in the peroneal nerve of 20 normotensive subjects and 18 patients with essential hypertension resting in the recumbent posture. The level of sympathetic activity was quantitated as bursts/100 heart beats or bursts/min. On another occasion blood was sampled from an antecubital vein and analyzed for plasma noradrenaline using radioenzymatic technique. In both groups the level of sympathetic activity increased with age and taking age into account there was no significant difference in sympathetic activity between normotensive and hypertensive subjects. There was no significant difference in plasma levels of noradrenaline between the groups. Both for normotensive and for hypertensive subjects there was a positive correlation between a subject's level of sympathetic activity and his plasma concentration of noradrenaline, and the regression lines did not differ significantly between the groups. It is suggested (a) that outflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma concentrations of noradrenaline at rest both in normotensive and hypertensive subjects; (b) that neither for muscle sympathetic activcity nor for plasma noradrenaline do the resting levels differ between normotensive and hypertensive subjects     

Fluctuations in heart rate caused by prolonged sympathetic stimulation

Summary Experiments on isolatedRana temporaria hearts were carried out in order to determine the effect of prolonged sympathetic nerve stimulation on cardiac action, and to study the neurohumoral shifts in cardiac muscle produced. The sympathetic chain was stimulated for 30 minutes at the second and third ganglia. In several experiments, it was found that periodic changes in cardiac muscle activity occurred, as shown by periods of increased and decreased cardiac action. The intensified phase was associated with the appearance of adrenalinlike substances in the heart, while the depressed phase was connected first, with the appearance of acetylcholine, and secondly, with that of adrenalin oxidation products. Thus, the phasic changes induced by prolonged sympathetic nerve stimulation are evidently due to periodic biochemical changes caused by the prolonged action of adrenalinlike substances and their oxidation products.(Presented by Active Member AMN SSSR S. E. Severin) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 50, No. 8, pp. 3–8, August, 1960     

Effect of hypothermia on baroreflex control of heart rate and renal sympathetic nerve activity in anaesthetized rats

The present study investigated the effect of acute hypothermia on baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) by generating baroreflex logistic function curves, using bolus doses of phenylephrine and sodium nitroprusside, in anaesthetized male Wistar rats at a core temperature ( T _b) of 37°C, during acute severe hypothermia at T _b= 25°C and on rewarming to 37°C. Comparisons were made between rats without (euthermic, n = 6) and with (acclimated, n = 7) prior exposure to lower ambient temperatures and shorter photoperiod, simulating adaptation to winter conditions. In both groups of rats, acute hypothermia to T _b= 25°C shifted the baroreflex-RSNA curve slightly leftwards and downwards with decreases in the setpoint pressure and maximal gain, whereas it markedly impaired the baroreflex-HR curve characterized by decreases in response range by ∼90% ( P < 0.001), minimum response by ∼10% ( P < 0.05) and maximum gain by ∼95% ( P < 0.001), from that at T _b= 37°C. All parameters were restored to precooling levels on rewarming. Electrical stimulation of cardiac vagal efferents induced a voltage-related bradycardia, the magnitude of which was partially reduced during acute hypothermia, and there was a significant prolongation of the electrocardiogram intervals indicating a delay in cardiac conduction. Mild suppression of baroreflex control of RSNA could contribute to hypothermic hypotension and may primarily reflect an effect of T _b on central drive. The marked attenuation of the baroreflex control of HR during hypothermia was likely to be due to an impairment of both the central and peripheral components of the reflex arc. Baroreflex control of RSNA and HR was similar between both groups of rats, which implied that the control was non-adaptive on chronic cold exposure.     

Long-term administration of tempol attenuates postinfarct ventricular dysfunction and sympathetic activity in rats

The purpose of this study was to determine whether the long-term administration of tempol attenuates postinfarct ventricular dysfunction and sympathetic activity in rats. Myocardial infarction (MI) was induced by left descending coronary artery ligation. Tempol was orally administered in drinking water (2 mmol/L), which was initiated 4 h after infarction and continued for 6 weeks. Tempol prevented not only the increases in left ventricular end-diastolic pressure and volume but also the decreases in ejection fraction and peak velocities of contraction in MI rats. The treatment normalized the increased renal sympathetic nerve activity (RSNA) and plasma norepinephrine level, as well as the enhanced cardiac sympathetic afferent reflex (CSAR; an excitatory cardiovascular reflex partially contributing to the sympathetic activation in chronic heart failure) and the RSNA responses to microinjection of angiotensin II into paraventricular nucleus in MI rats. Furthermore, tempol prevented the increased AT₁ receptor protein expression and superoxide anion level in both paraventricular nucleus and rostral ventrolateral medulla in MI rats. In conclusion, long-term administration of tempol attenuates ventricular dysfunction and normalizes sympathetic neural control in MI rats. The normalization of the CSAR, levels of superoxide anions and AT₁ receptor expression, and the response to angiotensin II in the paraventricular nucleus and rostral ventrolateral medulla may partially contribute to the beneficial effects of tempol on central sympathetic control.     

Jaw-jerk reflex activity in relation to various clenching tasks in man

In order to investigate whether the mandibular stretch (jaw-jerk) reflex is modulated in a task-dependent manner, jaw-jerk reflexes were elicited in eight subjects during clenching with unilateral and bilateral tooth support, respectively. The reflexes were examined in the electromyographic (EMG) activity recorded by means of surface electrodes and were elicited by means of small transient jaw displacements at a constant value of 80 m. Low levels of background EMG were applied ranging from 1 to 30% maximal voluntary contraction (MVC) as controlled by means of visual feedback. Linear relationships were observed between reflex amplitude and level of background EMG. The slope in these relationships served as a measure of reflex gain. For the masseter as well as the anterior temporal muscles, the reflex gain, averaged over both sides, was larger during clenching with unilateral tooth support than with bilateral tooth support (P < 0.05). Furthermore, the gain was larger on the side without tooth support during unilateral clenching and larger on the side without visual feedback of elevator muscle activity during bilateral clenching. It can be concluded that the jaw-jerk reflex is modulated to subserve the stabilization of the mandible, with the reflex sensitivity being larger the more that alternative stabilizing factors such as mechanical tooth contact, visual feedback and feedback from periodontal pressure receptors around the teeth are lacking. The reflex modulation may be of functional importance in stabilizing the mandible during its movement in the chewing process, as the food is predominantly placed unilaterally between the antagonistic teeth during individual chewing cycles.