The effects of stimulation of the left atrial receptors on sympathetic efferent nerve activity

1. Activation of left atrial receptors by distension of balloons at the pulmonary vein-atrial junctions caused an increase in the cardiac sympathetic nerve activity, a decrease in the renal sympathetic nerve activity, and no change in the lumbar and splenic sympathetic nerve activity.2. The cardiac and renal nerve responses to balloon distension were abolished by vagal blockade in the neck.3. The results provide additional evidence that the reflex increase in the heart rate following stimulation of the left atrial receptors is mediated by selective activation of cardiac sympathetic nerve fibres.4. The inhibitory effect of atrial receptor activation on the renal sympathetic nerve activity suggests that a neural factor, possibly involving renal haemodynamics, may be a component of the diuretic response to the activation of the left atrial receptors.5. The results provide further evidence for the selective nature of the pattern of reflex responses to left atrial receptor activation and show for the first time a directionally fractionated response from sympathetic efferent neurones.     

Neuropeptides,amines and amino acids as mediators of the sympathetic effects of paraventricular nucleus activation in the rat

The aim of the present study was to determine the influence on renal sympathetic nerve activity of the different chemically coded neuronal phenotypes that project from the paraventricular nucleus (PVN) to the spinal cord. Experiments were carried out on male Wistar rats anaesthetised with chloralose and urethane. Changes in renal sympathetic nerve activity were measured following activation of neurones in the PVN with D,L-homocysteic acid (100 nl, 200 mM), before and following intrathecal application of glutamate, vasopressin, oxytocin, dopamine and their receptor antagonists. Excitatory and inhibitory effects on renal sympathetic nerve activity were elicited by PVN stimulation. PVN excitatory effects were mimicked by intrathecal administration of glutamate and vasopressin and selectively antagonised by intrathecal administration of kynurenic acid and a V1a receptor antagonist, respectively. A low dose of dopamine increased renal sympathetic activity and this was selectively antagonised by haloperidol; however, the latter was without effect on PVN excitatory responses. A high dose of dopamine decreased renal sympathetic nerve activity and this was selectively blocked by a D1 dopamine receptor antagonist (SCH 23390), which also antagonised a minority of inhibitory responses obtained from the caudal extension of the PVN. Oxytocin also had two actions in 5 rats it inhibited and in 10 rats it increased renal sympathetic nerve activity, both actions being blocked selectively by oxytocin receptor antagonists. Neither of the PVN effects on renal sympathetic nerve activity appeared to be dependent on oxytocin pathways. Tests with intrathecal administration of bicuculline showed that PVN inhibition of renal sympathetic nerve activity was not dependent on spinal GABA(A) receptor activation. The results show that PVH-induced excitation of sympathetic activity to the kidney is mainly mediated by glutamate or vasopressin neurones whereas dopamine via Dl receptors may mediate some of the PVN inhibitory effects.     

Right Atrial Stretch Induces Renal Nerve Inhibition and c-fos Expression in Parvocellular Neurones of the Paraventricular Nucleus in Rats

The paraventricular nucleus of the hypothalamus plays a pivotal role in the regulation of plasma volume. Part of the response to an increase in volume load is an inhibition of renal sympathetic nerve activity. The present experiments were designed to determine which subnuclei of the paraventricular nucleus are involved in this sympatho-inhibitory response. Experiments were performed on anaesthetised rats. Activated neurones were recognised by the expression of the early gene c-fos, identified by immunohistochemical labelling of its protein product Fos. Plasma volume loading with 4 % Ficoll 70, using an infusion-withdrawal procedure (2 ml over 1 min) repeated 15 times over 1 h revealed a total of 775 +/- 101 (n = 6) Fos-positive neurones scattered throughout both the magnocellular and parvocellular subnuclei. In comparison, sustained hypertension resulted in 452 +/- 56 (n = 3) Fos-positive neurones similarly distributed, whereas a normotensive control group (n = 3) displayed 115 +/- 18 Fos-positive neurones. Because of this lack of a specific effect we used a more selective stimulation of right atrial receptors via a balloon placed at the junction of the superior vena cava and the right atrium so it did not impede venous return. Inflation of the balloon inhibited renal sympathetic nerve activity (36 +/- 5 %, n = 7) and repetitive inflation over 1 h resulted in c-fos activation of a small number of neurones (54 +/- 14) located only in the parvocellular subnuclei. Whether these are inhibitory interneurones acting within the paraventricular nucleus, or spinally projecting neurones which inhibit or excite renal sympathetic activity by an action in the spinal cord remains to be determined.     

Role of GABA and NO in the paraventricular nucleus-mediated reflex inhibition of renal sympathetic nerve activity following stimulation of right atrial receptors in the rat

The aim of this study was to determine the site within the brain at which inhibition of renal sympathetic nerve activity (RSNA) occurs following right atrial receptor stimulation. The atrial receptors were stimulated by inflating a balloon at the right vena cava-atrium junction and the reflex effect was observed before and during application of neurotransmitter agonists and antagonists into the paraventricular nucleus (PVN), or intrathecally to the spinal cord. Balloon inflation reduced RSNA by 29.1 +/- 3 % without changing blood pressure in anaesthetised Wistar rats. Microinjection of the GABA(A) receptor antagonist bicuculline (0.025 mM, 100 nl) into the PVN increased RSNA by 42.3 +/- 5 % and this was changed little by balloon inflation when PVN increased RSNA by 50.6 +/- 6.3 %. Microinjection of the nitric oxide synthase (NOS) inhibitors L-NAME (0.1 mM, 100 nl) or L-NMMA (0.2 mM, 100 nl) into PVN elicited increases in RSNA of 36 +/- 8 % or 54 +/- 10 %, respectively. Balloon inflation during PVN stimulation plus NOS inhibition resulted in RSNA activity of 8 +/- 4 % or -1 +/- 1 %, respectively, compared to baseline control. Baseline RSNA was similar throughout this series of tests ranging from 9.1 +/- 1.3 to 11.5 +/- 1.1 spike counts s(-1). To rule out the possibility that the atrial reflex inhibition was in part dependent on a dopamine-mediated PVN-spinal projection pathway inhibiting RSNA at a spinal locus, a dopamine D1 receptor antagonist SCH 23390 was intrathecally applied to the spinal cord. The effect of subsequent balloon inflation on RSNA was not significantly reduced. It was concluded that atrial receptor activation causes an inhibition of RSNA at the PVN and that this effect is mediated by GABA.     

Paraventricular neurones elicit a volume expansion-like change of activity in sympathetic nerves to the heart and kidney in the rabbit

The role of the paraventricular nucleus (PVN) of the hypothalamus in the cardiovascular response induced by blood volume expansion was examined in anaesthetised rabbits, in which simultaneous recordings were made from a renal sympathetic nerve and one of other sympathetic nerves, the inferior cardiac nerve, a splanchnic nerve and an adrenal nerve. Activation of PVN neurones, by discrete injections (25-100 nl) of d,l-homocysteic acid (DLH, 0.2 M) produced one main pattern of sympathetic nerve activity accompanying a pressor response (57-86 % of PVN sites). This was a decrease in renal sympathetic activity (27 +/- 12 %) and an increase in splanchnic (60 +/- 12 %), adrenal (31 +/- 9 %) and cardiac (42 +/- 8 %) sympathetic activity. Sites in the PVN from which these combinations of nerve activity were obtained were not confined to a specific subnucleus. An increase in renal sympathetic activity which was reversed to a decrease by reducing the volume of DLH injected was obtained at 10 sites in the PVN. These sites were mainly located in the dorsal parvocellular subnucleus. Varying combinations of sympathetic activation were obtained at a minority of sites. It is concluded that the PVN can evoke a differential pattern of sympathetic discharge which may be functionally significant in the control of blood volume regulation, as it mimics that seen on acute volume expansion.     

Neurochemistry of the paraventricular nucleus of the hypothalamus: Implications for cardiovascular regulation

The paraventricular nucleus of the hypothalamus (PVN) is an important site for autonomic and endocrine homeostasis. The PVN integrates specific afferent stimuli to produce an appropriate differential sympathetic output. The neural circuitry and some of the neurochemical substrates within this circuitry are discussed. The PVN has at least three neural circuits to alter sympathetic activity and cardiovascular regulation. These pathways innervate the vasculature and organs such as the heart, kidney and adrenal medulla. The basal level of sympathetic tone at any given time is dependent upon excitatory and inhibitory inputs. Under normal circumstances the sympathetic nervous system is tonically inhibited. This inhibition is dependent upon GABA and nitric oxide such that nitric oxide potentiates local GABAergic synaptic inputs onto the neurones in the PVN. Excitatory neurotransmitters such as glutamate and angiotensin II modify the tonic inhibitory activity. The neurotransmitters oxytocin, vasopressin and dopamine have been shown to affect cardiovascular function. These neurotransmitters are found in neurones of the PVN and within the spinal cord. Oxytocin and vasopressin terminal fibres are closely associated with sympathetic preganglionic neurones (SPNs). Sympathetic preganglionic neurones have been shown to express receptors for oxytocin, vasopressin and dopamine. Oxytocin causes cardioacceleratory and pressor effects that are greatest in the upper thoracic cord while vasopressin cause these effects but more significant in the lower thoracic cord. Dopaminergic effects on the cardiovascular system include inhibitory or excitatory actions attributed to a direct PVN influence or via interneuronal connections to sympathetic preganglionic neurones.     

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.     

Signalling pathway of nitric oxide in synaptic GABA release in the rat paraventricular nucleus

In the paraventricular nucleus (PVN) of the hypothalamus, nitric oxide (NO) inhibits sympathetic outflow through increased GABA release. However, the signal transduction pathways involved in its action remain unclear. In the present study, we determined the role of cGMP, soluble guanylyl cyclase, and protein kinase G in the potentiating effect of NO on synaptic GABA release to spinally projecting PVN neurones. The PVN neurones were retrogradely labelled by a fluorescent tracer injected into the thoracic spinal cord of rats. Whole-cell voltage-clamp recordings were performed on labelled PVN neurones in the hypothalamic slice. Bath application of the NO donor, S -nitroso- N -acetyl-penicillamine (SNAP), reproducibly increased the frequency of miniature GABAergic inhibitory postsynaptic currents (mIPSCs) without changing the amplitude and the decay time constant. Neither replacement of Ca²⁺ with Co²⁺ nor application of Cd²⁺ to block the Ca²⁺ channel altered the effect of SNAP on mIPSCs. Also, the effect of SNAP on mIPSCs was not significantly affected by thapsigargin, a Ca²⁺-ATPase inhibitor that depletes intracellular Ca²⁺ stores. Application of a membrane-permeant cGMP analogue, pCPT–cGMP, mimicked the effect of SNAP on mIPSCs in the presence of a phosphodiesterase inhibitor, IBMX. Furthermore, both the soluble guanylyl cyclase inhibitor, ODQ, and the specific protein kinase G inhibitor, Rp pCPT cGMP, abolished the effect of SNAP on mIPSCs. Thus, these data provide substantial new information that NO potentiates GABAergic synaptic inputs to spinally projecting PVN neurones through a cGMP–protein kinase G pathway.     

Regulation of synaptic input to hypothalamic presympathetic neurons by GABA(B) receptors

The hypothalamic paraventricular (PVN) neurons projecting to the spinal cord and brainstem play an important role in the control of homeostasis and the sympathetic nervous system. Although GABA(B) receptors are present in the PVN, their function in the control of synaptic inputs to PVN presympathetic neurons is not clear. Using retrograde tracing and whole-cell patch-clamp recordings in rat brain slices, we determined the role of presynaptic GABA(B) receptors in regulation of glutamatergic and GABAergic inputs to spinally projecting PVN neurons. The GABA(B) receptor agonist baclofen (1-50 microM) dose-dependently decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and inhibitory postsynaptic currents (sIPSCs). The effect of baclofen on sEPSCs and sIPSCs was completely blocked by 10 microM CGP52432, a selective GABA(B) receptor antagonist. Baclofen also significantly reduced the frequency of both miniature excitatory and miniature inhibitory postsynaptic currents (mEPSCs and mIPSCs). Furthermore, uncoupling pertussis toxin-sensitive G(i/o) proteins with N-ethylmaleimide abolished baclofen-induced inhibition of mEPSCs and mIPSCs. However, the inhibitory effect of baclofen on the frequency of mIPSCs and mEPSCs persisted in the presence of either Cd2+, a voltage-gated Ca2+ channel blocker, or 4-aminopyridine, a blocker of voltage-gated K+ channels. Our results suggest that activation of presynaptic GABA(B) receptors inhibits synaptic GABA and glutamate release to PVN presympathetic neurons. This presynaptic action of GABA(B) receptors is mediated by the N-ethylmaleimide-sensitive G(i/o) proteins, but independent of voltage-gated Ca2+ and K+ channels.     

Influence of intravenous infusion on heart rate, sympathetic and vagal efferentation and left atrial and aortic baroreceptor activity in dogs

The influence of 42 i.v. infusions of saline on heart rate, sympathetic and vagal cardiac efferent activity and on the aortic baroreceptor and left atrial B-type nerve impulse activity was studied in 32 morphine-chloralose anesthetized dogs. The responses in heart rate were tachycardic in 31 infusions and bradycardic in 11 infusions. In tachycardia, sympathetic activity increased in a majority of the cases but also decreases and nonsignificant changes were observed. Vagal efferentation decreased in most of the cases but also nonsignificant changes or increases in activity occurred. Sympathetic efferentation mainly decreased in bradycardic responses while vagal efferentation diverged in different directions in its nerve activity rate. The ratio of sympathetic to vagal impulses significantly correlated to the heart rate in most of the cases in tachycardia but not in bradycardia. It is concluded that sympathetic and vagal cardiac efferentation plays a significant role in heart rate regulation in volume load-induced tachycardia but in bradycardia only the changes in sympathetic cardiac efferentation are important in respect to heart rate changes. The aortic baroreceptor and left atrial B-type receptor activity rate increased both in tachycardia and bradycardia. Changes in the activities of these receptors do not explain the different heart rate responses. It is supposed that bradycardic responses result from changes in cardiac contraction associated with some reflex mechanism suppressing the excitatory influence of the activity of atrial receptors on sympathetic cardiac efferentation.     

Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons

The hypothalamic paraventricular nucleus (PVN) is an important site for the regulation of sympathetic outflow. Angiotensin II (Ang II) can activate AT(1) receptors to stimulate PVN presympathetic neurons through inhibition of GABAergic input. However, little is known about the downstream pathway involved in this presynaptic action of Ang II in the PVN. In this study, using whole cell recording from retrogradely labeled PVN neurons in rat brain slices, we determined the signaling mechanisms responsible for the effect of Ang II on synaptic GABA release to spinally projecting PVN neurons. Bath application of Ang II reproducibly decreased the frequency of GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in fluorescence-labeled PVN neurons. Ang II failed to change the frequency of mIPSCs in labeled PVN neurons treated with pertussis toxin. However, Ang II-induced inhibition of mIPSCs persisted in the presence of either CdCl(2), a voltage-gated Ca(2+) channel blocker, or 4-aminopyridine, a blocker of voltage-gated K(+) channels. Interestingly, inhibition of superoxide with superoxide dismutase or Mn(III) tetrakis (4-benzoic acid) prophyrin completely blocked Ang II-induced decrease in mIPSCs. By contrast, inhibition of hydroxyl radical formation with the ion chelator deferoxamine did not significantly alter the effect of Ang II. These findings suggest that the presynaptic action of Ang II on synaptic GABA release in the PVN is mediated by the pertussis toxin-sensitive G(i/o) proteins but not by voltage-gated Ca(2+) and K(+) channels. Ang II attenuates GABAergic input to PVN presympathetic neurons through reactive oxygen species, especially superoxide anions.     

Inhibition of renal sympathetic nerve traffic from cardiac receptors in normotensive and spontaneously hypertensive rats

The reflex inhibition of the sympathetic outflow to the kidney was examined during volume load with horse plasma in 6 normotensive rats (NCR) and 6 spontaneously hypertensive rats (SHR). The rats were anesthetized with chloralose and urethane. The arterial baroreceptors were denervated. The renal nervous inhibition was mediated via the vagal nerves and was mainly due to activation of receptors in the left side of the heart. The average thresholds in mean left atrial pressure for renal nervous inhibition was 5.4 mmHg for NCR and 9.2 mmHg for SHR indicating a clear resetting of the reflex arch in the hypertensive animal: The reason is probably a decreased distensibility of the wall of the left atrium due to a chronic elevation of left atrial pressure. This resetting of the atrial receptors in the hypertensive animals is probably of importance to allow an adequate filling pressure of the hypertrophied left ventricle and might also be of importance for the reflex neural control of renal function in these animals.     

Inhibition of renal sympathetic nerve traffic from cardiac receptors in normotensive and spontaneously hypertensive rats.

The reflex inhibition of the sympathetic outflow to the kidney was examined during volume load with horse plasma in 6 normotensive rats (NCR) and 6 spontaneously hypertensive rats (SRH). The rats were anesthetized with chloralose and urethane. The arterial baroreceptors were denervated. The renal nervous inhibition was mediated via the vagal nerves and was mainly due to activation of receptors in the left side of the heart. The average thresholds in mean left artrial pressure for renal nervous inhibition was 5.4 mmHg for NCR and 9.2 mmHg for SHR indicating a clear resetting of the reflex arch in the hypertensive animal: The reason is probably a decreased distensibility of the wall of the left atrium due to a chronic elevation of left atrial pressure. This resetting of the atrial receptors in the hypertensive animals is probably of importance to allow an adequate filling pressure of the hypertrophied left ventricle and might also be of importance for the reflex neural control of renal function in these animals.     

Baroreflex inhibition of cardiac sympathetic outflow is attenuated by angiotensin II in the nucleus of the solitary tract

Homeostatic regulation of arterial pressure is maintained by arterial baroreceptors. Activation of these receptors results in an inhibition of sympathetic activity to the heart. It is known that angiotensin II in the nucleus tractus solitarii attenuates the baroreceptor reflex-evoked vagal bradycardia. Here, we determined whether the cardiac sympathetic component of the baroreceptor reflex could be modulated by angiotensin II in the nucleus of the solitary tract. An in situ, arterially perfused working heart--brainstem preparation of rat was employed and the sympathetic inferior cardiac nerve recorded. Increases in perfusion pressure caused a reflex bradycardia and inhibition of inferior cardiac nerve activity. Microinjection of angiotensin II (500 fmol) in the nucleus of the solitary tract attenuated significantly both the reflex bradycardia and inhibition of inferior cardiac nerve activity (P<0.01). The latter was reversible and sensitive to losartan, an angiotensin II type 1 receptor antagonist. In contrast, the peripheral chemoreceptor reflex evoked an increase in inferior cardiac nerve activity that was not affected by angiotensin II applied exogenously in the nucleus of the solitary tract. We conclude that within the nucleus of the solitary tract angiotensin II exerts a powerful and specific inhibitory modulation of the baroreceptor reflex control of sympathetic nerve activity destined for the heart. We suggest that our data may have clinical implications relating to hypertension, a condition when angiotensin II activity is heightened in the brain and the efficacy of the baroreflex is reduced.     

The influence of bulbospinal monoaminergic pathways on sympathetic nerve activity

1. Spontaneous and reflex activity was recorded from renal and splanchnic nerves and thoracic white rami during discrete electrical stimulation within the medulla oblongata of anaesthetized cats.2. Inhibition or excitation of spontaneous sympathetic nerve activity was obtained from several medullary regions.3. The long-circuited reflex elicited in renal nerves and the spinally mediated reflex discharge produced in white rami by single shock stimulation of intercostal nerves were inhibited by stimulation within the sympatho-inhibitory areas of the medulla.4. Activation of spontaneous sympathetic nerve activity or inhibition of spontaneous and reflex sympathetic nerve activity was obtained during electrical stimulation within the lateral funiculi of the cervical spinal cord in unanaesthetized decerebrate cats, spinalized at C1.5. There was a correlation between the position of some sympatho-inhibitory regions of the medulla and spinal cord and the position of the cell bodies and axons of descending monoamine-containing neurones.6. Intravenous administration of the precursor of noradrenaline, L-DOPA, to unanaesthetized decerebrate cats, spinalized at C1, was followed by a depression of spontaneous activity in renal nerves and reflex responses elicited in renal nerves and white rami.7. Similarly the precursor of 5-hydroxytryptamine, 5-HTP, caused a depression of reflex activity elicited in renal nerves and white rami, but had no effect on spontaneous renal nerve activity.8. It is suggested that there exist both noradrenergic and tryptaminergic pathways which descend to the spinal cord from the medulla and which are inhibitory to sympathetic outflow.     

P2X purinoceptor subtypes on paraventricular nucleus neurones projecting to the rostral ventrolateral medulla in the rat

The rostral ventrolateral medulla (RVLM) is essential for the generation of sympathetic nerve activity. The RVLM receives a substantial innervation from the hypothalamic paraventricular nucleus (PVN). Activation of P2X purinoceptors via ATP has been shown to mediate fast excitatory synaptic neurotransmission. There is mounting evidence to suggest the presence of P2X purinoceptors in hypothalamic nuclei, including the PVN. In this study, we determined whether P2X1-P2X6 purinoceptor subtypes were present on PVN neurones that projected to the RVLM. Injection of the retrogradely transported tracer, rhodamine-tagged microspheres, into the pressor region of the RVLM was used to identify the neurones in the PVN that innervated the RVLM. P2X1-P2X6 purinoceptors were detected by immunohistochemistry. Double-labelled neurones were quantified and expressed as a proportion of the retrogradely labelled neurones. The proportions of double-labelled neurones for each of the P2X purinoceptor subtypes varied, on average, from 14 to 29%. The P2X3 purinoceptor subtype was found to be the dominant purinoceptor subtype present on PVN neurones projecting to the RVLM. Additionally it was apparent that more than one P2X purinoceptor subtype was present on the PVN neurones projecting to the RVLM, since the sum of the average percentages of double-labelled neurones for each P2X purinoceptor subtype exceeded 100%. These findings highlight the presence of the P2X1-P2X6 purinoceptors on PVN neurones projecting to the RVLM. The results suggest a potential role for ATP in the PVN in the regulation of sympathetic nerve activity.     

SOD1 overexpression in paraventricular nucleus improves post-infarct myocardial remodeling and ventricular function

Excessive sympathetic activation contributes to the progression of chronic heart failure. Reactive oxygen species in paraventricular nucleus (PVN) play an important role in the enhanced sympathetic outflow. This study was designed to determine whether superoxide dismutase 1 (SOD1) overexpression in the PVN attenuated the sympathetic activation and cardiac dysfunction in rats after an episode of myocardial infarction (MI). Adenoviral vectors containing human SOD1 (Ad-SOD) or null adenoviral vectors (Ad-null) were immediately microinjected into the PVN of rats with coronary artery ligation or sham operation. At the eighth week, the SOD1 protein level and activity in the PVN increased while the superoxide anions in the PVN decreased in Ad-SOD rats. The SOD1 overexpression in the PVN prevented the increases in left ventricular end-diastolic pressure and volume, and the decreases in ejection fraction and peak velocities of contraction in MI rats. In addition, there was an attenuation of renal sympathetic nerve activity, cardiac sympathetic afferent reflex and plasma norepinephrine level in MI rats. Furthermore, the SOD1 overexpression in the PVN reduced cardiomyocyte size, collagen deposition and the TUNEL-positive cardiomyocytes in MI rats. These results indicate that the SOD1 overexpression in the PVN attenuates the excessive sympathetic activation, myocardial remodeling, cardiomyocyte apoptosis and ventricular dysfunction in MI rats.     

Renal nerve activity and exaggerated natriuresis in conscious spontaneously hypertensive rats

Exaggerated natriuresis upon volume loading occurs in both human and animal hypertension and is mainly due to suppressed tubular reabsorption. To explore whether altered renal sympathetic activity contributes to this response, conscious male spontaneously hypertensive rats (SHR) were exposed to isotonic saline loading in comparison with normotensive male Wistar Kyoto rats (WKR). After a 60 min control hydropenic period, during which mean arterial pressure, heart rate, renal sympathetic nerve activity and urinary sodium excretion were followed, a 60 min period of intravenous volume expansion with isotonic saline (0.2 ml/minx 100 g b. w.) was started followed by a 60 min hydropenic recovery period. Already during the control period sodium excretion was significantly higher in SHR. During the volume load and subsequent recovery period a clearly exaggerated natriuresis occurred in SHR compared with WKR. Further, volume loading reduced renal sympathetic nerve activity in all animals, but significantly more in SHR. Moreover, volume loading reduced mean arterial pressure and heart rate in both groups. It is suggested that the accentuated reflex inhibition of renal sympathetic activity in SHR upon volume loading emanates from cardiac mechanoreceptors and partly explains the exaggerated natriuresis in SHR. This augmented ‘volume’ reflex response is probably due to reduced systemic venous compliance in SHR with a consequently increased central filling and cardiac receptor activation.     

The role of supraspinal vasopressin and glutamate neurones in an increase in renal sympathetic activity in response to mild haemorrhage in the rat

This study investigated the importance of supraspinal vasopressin and glutamate neurones in regulating renal sympathetic activity as part of the response to an acute reduction in blood volume. Wistar rats anaesthetized with chloralose and urethane were instrumented to record arterial blood pressure, heart rate and left renal sympathetic nerve activity. Pharmacological agonists and antagonists to glutamate and vasopressin were applied to the renal outflow of the spinal cord via an intrathecal catheter inserted at the foramen magnum and with the tip at the level of T10. Both glutamate and vasopressin increased renal sympathetic activity, and these actions were shown to be selectively blocked by their respective antagonists. Removing 1 ml of venous blood from a femoral venous catheter elicited an increase of 26 +/- 2% in renal sympathetic activity. This response to mild haemorrhage was halved to 13 +/- 4% by prior intrathecal application of a selective V1a antagonist. Similarly, prior intrathecal application of kynurenic acid reduced the response to the mild haemorrhage from 28 +/- 2 to 12.6 +/- 2.8%. Intrathecal application of both antagonists together reduced the haemorrhage response even further to 8 +/- 3%. All the changes were statistically significant at P < 0.01. It is concluded that a small reduction in blood volume induces an increase in renal sympathetic activity dependent on vasopressin and glutamate release from terminals of supraspinal neurones. It is suggested that the vasopressin neurones most probably originate from the paraventricular nucleus of the hypothalamus.     

Reflex effects on the heart of stimulating left atrial receptors

1. Stimulation of left atrial receptors, by distension of the pulmonary vein/left atrial junctions, is known to cause a reflex increase in heart rate; the efferent pathway is known to be solely in the sympathetic nerves.2. In expectation of a concomitant positive inotropic response the effect of stimulating the left atrial receptors on the inotropic state of the left ventricle was studied, using as a known sensitive index of inotropic changes the maximal rate of rise of pressure in the left ventricle (dP/dt max).3. Stimulation of left atrial receptors resulted in an increase in heart rate but there were no significant concomitant changes in dP/dt max.4. It is concluded that activity in this discrete efferent pathway does not include an inotropic effect on the left ventricle and therefore the reflex involves only those sympathetic nerves which innervate the sinu-atrial node.5. The possible function of atrial receptors in the regulation of heart volumes is discussed.