Opioid signalling in the rat rostral ventrolateral medulla

1. The present article reviews several aspects of opioid signalling in the rostral ventrolateral medulla (RVLM) and their implications for the neural control of blood pressure. 2. In the RVLM, preproenkephalin (PPE) mRNA is expressed by bulbospinal cells that are strongly barosensitive. These putative presympathetic neurons includes C1 and non-C1 neurons. 3. In the RVLM, PPE mRNA is also present in GABAergic neurons that do not project to the thoracic spinal cord. 4. Rostral ventrolateral medulla presympathetic cells receive enkephalinergic inputs and express mu-opioid receptors (MOR). Some of their synaptic inputs also contain MOR. 5. Pre- and post-synaptic modulation of RVLM presympathetic neurons by MOR agonists has been demonstrated in slices of neonate brain. The post-synaptic effect is inhibitory (increased gK). Presynaptic effects include disfacilitation (reduction of glutamate release) and possibly dishinhibition (reduction of GABA release). 6. In conclusion, opioid signalling plays a pervasive role in the medullospinal network that controls sympathetic tone and arterial pressure. Opioid peptides are made by the presympathetic, presumably excitatory, cells of the RVLM and by local GABAergic inhibitory neurons. In addition, RVLM presympathetic neurons are also controlled by opioid peptides at the pre- and post-synaptic level. mu-Opioid receptors are found post-synaptically, whereas presynaptic receptors probably include both mu and delta subtypes. Conditions that trigger the release of opioid peptides by presympathetic neurons or by inputs to these cells are not fully understood and may include decompensated haemorrhage and certain types of peripheral sensory stimulation related to acupuncture.     

NMDA受体机制在动脉压力反射中的介导作用(英文)

目的:研究N-甲基-D-天门冬氨酸(NMDA)受体机制在动脉压力反射中的作用。方法:头端延髓腹外侧区(RVLM)前交感神经元(presympathetic neuron)与动脉压力反射相关,它们可被电刺激主动脉神经或升高动脉血压所抑制,其自发放电具有心性节律。根据这一特性,本研究用电生理学方法在17只雄性SD大鼠鉴定了27个假想的(putative)RVLM前交感神经元。以这些神经元对电刺激主动脉神经的反应为指标,观察在同侧孤束核(NTS)或尾端延髓腹外侧区(CVLM)微注射选择性NMDA受体拮抗剂CPP(0.1μL,50mmol/L)的作用。结果:在NTS微注射CPP可完全阻断或减弱电刺激主动脉神经引起的神经元抑制,但血压升高引起的神经元抑制不能完全被消除,神经元放电的心性节律仍然存在;在CVLM,CPP不仅完全阻断电刺激主动脉神经引起的神经元抑制,而且阻断血压升高引起的神经元抑制,神经元放电的心性节律消失。结论:NMDA受体机制在动脉压力反射中起着重要的介导作用;单侧孤束核的压力敏感神经元向单侧RVLM投射。     

氯胺酮对大鼠头端延髓腹外侧区前交感神经元的作用(英文)

目的:研究氯胺酮在中枢交感心血管活动中的调节作用。方法:在25只氨基甲酸乙酯麻醉、三碘季铵酚制动并人工通气的雄性SD大鼠中,共细胞外记录到32个头端延髓腹外侧区前交感神经元的自发放电,这些神经元具有压力敏感性和向脊髓投射的特点。观察选择性NMDA受体拮抗剂氯胺酮对前交感神经元放电的影响。结果:静脉注射不同剂量的氯胺酮(3,6,12mg/kg)能增加RVLM前交感神经元的放电频率,同时能阻断这些神经元的压力敏感性,且具有剂量依赖性的特点。结论:氯胺酮通过阻断RVLM前交感神经元压力感受反射的紧张性抑制,从而调节交感心血管活动。     

大鼠尾端延髓腹外侧区非NMDA受体参与压力反射传导

目的:探讨大鼠尾端延髓腹外侧区(CVLM)非N-甲基-D-天门冬氨酸(non-NMDA)受体在介导压力反射中的作用。方法:在戊巴比妥钠和氨基甲酸乙酯麻醉、制动和人工呼吸的SD大鼠,观察CVLM内局部给予non-NMDA受体选择性阻断剂CNQX对刺激主动脉神经导致的减压反应和头端延髓腹外侧区(RVLM)神经元的压力敏感性的作用。结果:双侧CVLM微量注射CNQX(每侧200 pmol/100 nL)后明显(P<0.01)地增高基础血压(BP)和心率,而且显著(P<0.01)地减弱刺激主动脉神经导致的降压反应。单侧CVLM内给予CNQX(200 pmol/100 nL)明显(P<0.01)增高同侧RVLM压力敏感性神经元的基础放电频率,但显著(P<0.01)减弱刺激主动脉神经和升高血压导致的神经元活动的抑制效应和部分抑制神经元的心性节律。结论:大鼠尾端延髓腹外侧区non-NMDA受体在维持紧张性兴奋的心血管活动和传递压力感受器信息中具有重要的意义。     

Role of angiotensin II receptors in the regulation of vasomotor neurons in the ventrolateral medulla

1. There is a high density of angiotensin type 1 (AT1) receptors in various brain regions involved in cardiovascular regulation. The present review will focus on the role of AT1 receptors in regulating the activity of sympathetic premotor neurons in the rostral part of the ventrolateral medulla (VLM), which are known to play a pivotal role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial pressure. 2. Microinjection of angiotensin (Ang) II into the rostral VLM (RVLM) results in an increase in arterial pressure and sympathetic vasomotor activity. These effects are blocked by prior application of losartan, a selective AT1 receptor antagonist, indicating that they are mediated by AT1 receptors. However, microinjection of AngII into the RVLM has no detectable effect on respiratory activity, indicating that AT1 receptors are selectively or even exclusively associated with vasomotor neurons in this region. 3. Under normal conditions in anaesthetized animals, AT1 receptors do not appear to contribute significantly to the generation of resting tonic activity in RVLM sympathoexcitatory neurons. However, recent studies suggest that they contribute significantly to the tonic activity of these neurons under certain conditions, such as salt deprivation or heart failure, or in spontaneously hypertensive or genetically modified rats in which the endogenous levels of AngII are increased or in which AT1 receptors are upregulated. 4. Recent evidence also indicates that AT1 receptors play an important role in mediating phasic excitatory inputs to RVLM sympathoexcitatory neurons in response to activation of some neurons within the hypothalamic paraventricular nucleus. The physiological conditions that lead to activation of these AT1 receptor-mediated inputs are unknown. Further studies are also required to determine the cellular mechanisms of action of AngII in the RVLM and its interactions with other neurotransmitters in that region.     

DIFFERENCES IN THE DENSITY OF BAROSENSITIVE NEURONS IN THE MEDULLA OF SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

1. The density of barosensitive neurons in the medulla was examined in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. In control experiments, rats were sham-operated, while in test experiments arterial baroreceptors were stimulated by pressor responses to i.v. administration of phenylephrine and the density of c-Fos-labelled neurons was immunocytologically examined. 2. In both control and test experiments, c-Fos-labelled neurons were distributed in cardiovascular control sites: the nucleus trac-tus solitarii (NTS) and the caudal and rostral ventrolateral medullas (CVLM/RVLM). 3. In both WKY rats and in SHR, the total density of labelled neurons in test experiments was significantly higher than in control experiments. 4. In control experiments, no significant difference was found in the distribution and density of labelled neurons in the NTS and in the CVLM/RVLM between WKY rats and SHR. 5. In test experiments, no significant difference was found in the distribution and density of labelled neurons in the NTS between WKY rats and SHR. 6. In test experiments in SHR, the density of labelled neurons in the CVLM just caudal to the obex level was significantly higher than that in WKY rats, whereas the density of labelled neurons in WKY rats in the RVLM just rostral to the obex level was significantly higher than that in SHR. 7. These results indicate that stimulation of the arterial baro-receptor induces strain-specific differences in the density of barosensitive neurons in the CVLM/RVLM near the obex level.     

TONIC CONTROL OF SUBRETROFACIAL VASOMOTOR NEURONS IN THE ROSTRAL VENTROLATERAL MEDULLA

1. Vasomotor pressor neurons in the subretrofacial nucleus of the rostral ventrolateral medulla receive afferent inputs from different sources that utilize different neurotransmitters. This paper briefly reviews recent studies on the role of inputs releasing: (i) GABA, and (ii) angiotensin II (AII) in the subretrofacial nucleus. 2. There are two types of tonic GABAergic inhibitory inputs: one arises from peripheral baroreceptors, while the second is independent of peripheral baroreceptors. 3. Blockade of receptors for AII elicits a decrease in blood pressure and sympathetic vasomotor activity, indicating that subretrofacial neurons are also tonically excited by AII. It is likely that the AII is released from nerve terminals in the subretrofacial nucleus, but the origin of the pathway is unknown.     

Role of excitatory amino acid inputs to the rostral ventrolateral medulla in cardiovascular regulation

1. Excitatory amino acid (EAA)-mediated neural transmission in the rostral ventrolateral medulla (RVLM) is important for many cardiovascular reflexes, although the receptor subtypes involved vary depending on the specific response. 2. Although injection of the EAA ionotropic receptor antagonist kynurenic acid into the RVLM has no effect on baseline arterial pressure, this lack of effect appears to result from EAA inputs to RVLM exciting both excitatory and inhibitory mechanisms within the RVLM. 3. The balance between EAA-mediated excitation and inhibition of RVLM neurons may be shifted to excitation in experimental models of hypertension. 4. The excitatory influence that EAA inputs to the RVLM have on vasomotor neurons in the RVLM may involve a sarthran-sensitive intermediary in the RVLM.     

Ipsilateral but not contralateral blockade of excitatory amino acid receptors in the caudal ventrolateral medulla inhibits aortic baroreceptor reflex in rats

Summary The caudal ventrolateral medulla (CVLM) contains vasodepressor neurons which, when activated, decrease vasomotor tone. To investigate whether excitatory amino acid receptors in the CVLM of the rat are involved in mediation of the aortic baroreceptor reflex, we microinjected amino acid antagonists unilaterally into the CVLM and examined their effects on the depressor response to electrical stimulation of the aortic nerve which contains mainly baroreceptor afferent fibers in rats. Male Wistar rats were anaesthetized with urethane, paralyzed and artificially ventilated. To block reflex vagal effects, methylatropine (1 mg/kg) was given intravenously. Kynurenate (227 ng), an excitatory amino acid antagonist, injected ipsilaterally but not contralaterally into the CVLM markedly inhibited the depressor response to aortic nerve stimulation, while both injections produced a similar small increase in basal blood pressure. Muscimol (1 ng), a GABA receptor agonist, injected ipsilaterally into the CVLM partly inhibited the baroreflex response, while it produced a moderate increase in basal blood pressure. 2-Amino-5-phosphonovalerate (APV) (10 ng), a N-methyl-d-aspartate (NMDA) receptor antagonist, and MK-801 (30 ng), a NMDA receptor channel blocker, partly inhibited the baroreflex response. MK-801 (30 ng) injected into the CVLM reduced the depressor response to the NMDA receptor agonist NMDA (0.3 ng) but not to the quisqualate receptor agonist quisqualate (0.1 ng) and the kainate receptor agonist kainate (0.1 ng), while kynurenate (227 ng) inhibited the depressor response to all three excitatory amino acid receptor agonists. These findings provide further evidence for the presence of excitatory amino acid receptors involved in mediating the aortic baroreceptor reflex in the rat CVLM. It appears that neurons other than the vasodepressor neurons in the CVLM, at least in part, play a role in transmitting the aortic baroreceptor reflex. In addition, both NMDA and non-NMDA receptors may be responsible for the mediation of the reflex. Send offprint requests to T. Kubo at the above address     

Role of AT1 receptors in the central control of sympathetic vasomotor function

1. In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits. 2. In conscious rabbits, fourth ventricular infusions of AngII produced dose-dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000-fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction. 3. The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms. 4. In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased. 5. The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT(1) antagonist losartan injected into the 4V. These results suggest that mainly AT(1) receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex. 6. Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes. 7. Our studies suggest that there are sympathoexcitatory AT(1) receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT(1) receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.     

Benzodiazepine inhibits hypothalamic presympathetic neurons by potentiation of GABAergic synaptic input

Presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus receive inputs from gamma-aminobutyric acid (GABA)-containing neurons, which regulate sympathetic outflow and cardiovascular function. Benzodiazepines can decrease blood pressure and sympathetic nerve activity when used for induction of anesthesia, but the sites and mechanisms of action are uncertain. In this study, we determined the effect of the benzodiazepine agonist diazepam on GABAergic inhibitory postsynaptic currents (IPSCs) and the firing activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons. RVLM-projecting PVN neurons were retrogradely labeled by fluorescent microspheres injected into the RVLM in rats. Whole-cell and cell-attached recordings were performed on labeled PVN neurons in the hypothalamic brain slice. Bath application of 1-10 microM diazepam significantly increased the decay time constants of the GABAergic miniature IPSCs and evoked IPSCs in a dose-dependent manner. Also, diazepam significantly increased the amplitude of evoked IPSCs but not of miniature IPSCs. Pretreatment with the benzodiazepine antagonist flumazenil completely blocked the diazepam-induced increases in the amplitude and decay time constants of the evoked IPSCs. Furthermore, diazepam significantly decreased the firing activity of PVN-RVLM neurons that responded with increased firing to the GABA(A) receptor antagonist bicuculline. In contrast, diazepam had no significant effect on the firing activity of bicuculline-unresponsive PVN-RVLM neurons. This study provides new information that the benzodiazepine suppresses the firing activity of PVN presympathetic neurons by potentiation of GABAergic inputs.     

Role of I1-imidazoline receptors within the caudal ventrolateral medulla in cardiovascular responses to clonidine in rats

Although it is recognized that imidazoline receptors play an important role in the central regulation of cardiovascular activities, little is known about their role in the caudal ventrolateral medulla. In male Sprague-Dawley rats anesthetized with urethane, we used antagonists of I1-imidazoline receptor or alpha2-adrenoceptor to assess the function of these receptors in the caudal ventrolateral medulla in controlling the cardiovascular effects of clonidine. Unilateral microinjection of clonidine (6 nmol/50 nl) into the caudal ventrolateral medulla significantly (P<0.01) increased blood pressure and the discharge of the rostral ventrolateral medulla presympathetic neurons, while heart rate remained unchanged. Microinjection of yohimbine (a selective alpha2-adrenoceptor antagonist, 500 pmol/50 nl) into the caudal ventrolateral medulla did not modify blood pressure, heart rate, or the discharge of the rostral ventrolateral medulla presympathetic neurons, and failed to attenuate the local caudal ventrolateral medulla clonidine-induced blood pressure elevation. However, unilateral microinjection of idazoxan (a mixed antagonist of imidazoline receptor and alpha2-adrenoceptor, 2 nmol/50 nl) into the caudal ventrolateral medulla significantly (P<0.01) decreased mean arterial pressure, heart rate, and the discharge of the rostral ventrolateral medulla presympathetic neurons, and completely abolished the pressor effect of clonidine. In addition, bilateral microinjection of idazoxan (4 nmol in 100 nl for each side) into the caudal ventrolateral medulla effectively (P<0.01) blocked the depressor effects of clonidine administered intravenously (5 and 50 microg/kg). These results confirm that I1-imidazoline receptors within the caudal ventrolateral medulla are involved in maintaining the tonic cardiovascular activities and in the pressor effect of clonidine in the caudal ventrolateral medulla. In addition, it seems that the caudal ventrolateral medulla plays an important role in the antihypertensive effects of systemically administered clonidine in rats.     

Role of the central nucleus of the amygdala in the control of blood pressure: descending pathways to medullary cardiovascular nuclei

1. One of the key areas that links psychologically induced stress with the blood pressure-regulatory system is the central nucleus of the amygdala (CeA). This is an integratory forebrain nucleus that receives input from higher centres in the forebrain and has extensive connections with the hypothalamus and the medulla oblongata, areas involved in the regulation of the cardiovascular reflexes. 2. Based on studies using electrical or chemical stimulation or electrolytic lesions of the CeA, it has become clear that the CeA plays an important role in the regulation of blood pressure in response to stressful or fearful stimuli. 3. Two important medullary areas known to receive projections from the CeA are the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). The NTS is the site of the first synapse for afferent fibres originating from baroreceptors, chemoreceptors and the heart, whereas the RVLM contains neurons that maintain resting blood pressure and sympathetic nerve activity via projections to sympathetic preganglionic neurons in the intermediolateral cell column of the thoracolumbar spinal cord. 4. Electron microscopic studies using combined anterograde tracing and pre- and post-embedding immunogold labelling have shown that the pathways originating from the CeA to the NTS are inhibitory and may use GABA as a neurotransmitter. The results of these studies suggest that blood pressure changes produced by activation of the CeA may be mediated by attenuation of baroreceptor reflexes through a GABAergic mechanism at the level of the NTS. 5. Neuronal tract tracing combined with neurofunctional studies using the Fos protein as a marker of activated neurons indicate that the CeA projects directly to baroreceptive neurons in the NTS and RVLM that are activated by changes in blood pressure. 6. In conclusion, studies that have examined the efferent pathways of the CeA suggest that CeA neurons with projections to medullary baroreceptive neurons may play a vital role in the reflex changes in sympathetic nerve activity that are involved in blood pressure regulation in response to stress or anxiety.     

INVOLVEMENT OF NON-NMDA AND NMDA RECEPTORS IN GLUTAMATE-INDUCED PRESSOR OR DEPRESSOR RESPONSES OF THE PONS AND MEDULLA

1. Fifty-five intact and six baroreceptor denervated and vagotomized cats of either sex were anaesthetized intraperito-neally with urethane (400 mg/kg) and a-chloralose (40 mg/kg). Responses of the systemic arterial pressure (SAP), mean SAP (MSAP) and sympathetic vertebral nerve (VNA) and renal nerve activities (RNA) were recorded. 2. In intact animals, monosodium L-glutamate (Glu, 0.1 mol/L, 50 nL) was microinjected into pressor areas of the locus coeruleus (LC), gigantocellular tegmental field (GTF), rostral ventrolateral medulla (RVLM) and dorsomedial medulla (DM), and the depressor areas of caudal ventrolateral medulla (CVLM). The induced actions were compared before and after microinjection of either glutamate antagonists, glutamate diethylester (GDEE, 0.5 mol/L, 50–100nL), a competitive AMPA receptor blocker, or 2-amino-5-phosphonovaleric acid (D-AP5, 0.025 mol/L, 50–100 nL), a competitive N-methyl-D-aspartate (NMDA) receptor blocker. GDEE completely blocked the increases of SAP and VNA elicited from all pressor areas. D-AP5 only partially blocked the pressor but slightly blocked VNA and RNA responses from LC, GTF and DM, particularly those from RVLM. Neither GDEE nor D-AP5 blocked the depressor responses of SAP and two nerve activities elicited from CVLM. 3. In baroreceptor denervated animals, NMDA (2 mmol/L, 50–100 nL) and AMPA (0.2 mmol/L, 50–100 nL) were micro-injected into the same pressor areas of GTF, RVLM and DM and the depressor area of CVLM responsive to Glu activation (0.1 mol/L, 30 nL). In RVLM, DM and CVLM, the results of either NMDA or AMPA were similar to those induced by Glu. However, in GTF, microinjection of either NMDA or AMPA did not induce similar responses to Glu. This suggests that the nature of GTF may differ from RVLM and DM. 4. The above results suggest that the Glu-induced pressor responses from LC, GTF, DM and especially RVLM, are primarily mediated through AMPA receptors. The Glu-induced depressor responses from CVLM may not be predominantly mediated by either AMPA or NMDA receptors. 5. In both baroreceptor-intact and -denervated cats stimulation of the pressor areas often produced an increase of VNA and a decrease of RNA, while in the depressor CVLM decreased both VNA and RNA. The VNA, but not RNA were positively correlated with the pressor responses, while both VNA and RNA were positively correlated with the depressor responses. This may suggest that neurons of the sympathetic vertebral and renal nerves are topographically organized in the brain.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ROLE OF AT1 RECEPTORS IN THE CENTRAL CONTROL OF SYMPATHETIC VASOMOTOR FUNCTION

• 1 In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits.
• 2 In conscious rabbits, fourth ventricular infusions of AngII produced dose-dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000-fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction.
• 3 The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms.
• 4 In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased.
• 5 The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT₁ antagonist losartan injected into the 4V. These results suggest that mainly AT₁ receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex.
• 6 Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes.
• 7 Our studies suggest that there are sympathoexcitatory AT₁ receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT₁ receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.

     

Differential control of cardiac and sympathetic vasomotor activity from the dorsomedial hypothalamus

1. The dorsomedial hypothalamus (DMH) plays a crucial role in mediating the cardiovascular responses to different stressors, including acute psychological stress and cold stress. Activation of neurons in the DMH evokes increases in arterial pressure and in the activity of sympathetic nerves innervating the heart, blood vessels and brown adipose tissue. The descending pathways from the DMH to the spinal sympathetic outflow include synapses with neurons in medullary nuclei and possibly other brain stem regions. 2. Recent studies from our and other laboratories have indicated that neurons in the rostral ventrolateral medulla (RVLM) and in the region of the raphe pallidus (RP) in the medulla are important components of the descending pathways that mediate the cardiovascular response to activation of the DMH. Neurons in the RP primarily mediate the sympathetic cardiac components of the DMH-evoked response, whereas the RVLM neurons primarily mediate the sympathetic vasomotor component. 3. Activation of DMH neurons not only increases heart rate and sympathetic vasomotor activity, but also resets the baroreceptor reflex such that it remains effective, without any decrease in sensitivity, over a higher operating range of arterial pressure. 4. Activation of 5-hydroxytryptamine 5-HT(1A) receptors in the medulla oblongata leads to a selective suppression of cardiac and sympathetic vasomotor components of the DMH-evoked response, but does not affect sympathetic reflex responses evoked from baroreceptors or chemoreceptors. Thus, central 5-HT(1A) receptors modulate cardiovascular responses evoked from the DMH in a highly potent but selective fashion.     

Roles for CCK1 and 5-HT3 receptors in the effects of CCK on presympathetic vasomotor neuronal discharge in the rat

1 The role of peripheral 5-hydroxytryptamine (5-HT(3)) receptors and cholecystokinin type 1 (CCK(1)) receptors in the inhibitory effects of phenylbiguanide (PBG) and CCK on arterial blood pressure, heart rate and the discharge of presympathetic vasomotor neurones of the rostral ventrolateral medulla (RVLM) was studied in alpha-chloralose-anaesthetized rats. 2 CCK (1 and 4 micro g kg(-1), i.v.) and PBG (2 and 10 micro g kg(-1), i.v.) reduced arterial blood pressure and heart rate, and inhibited the discharge of single RVLM presympathetic vasomotor neurones in a dose-related manner. 3 Devazepide (0.5 mg kg(-1), i.v.), a selective CCK(1) receptor antagonist, blocked the effects of CCK on arterial blood pressure, heart rate and neuronal discharge but did not significantly alter these responses to PBG. MDL72222 (0.1 mg kg(-1), i.v.), a selective 5-HT(3) receptor antagonist, blocked the effects of PBG on arterial blood pressure, heart rate and presympathetic neuronal discharge. MDL72222 attenuated the effects of CCK on arterial blood pressure, heart rate and RVLM presympathetic neuronal discharge. Vehicle did not significantly alter any of the responses to CCK or PBG. 4 These experiments suggest that systemically administered CCK acts directly through CCK(1) receptors to modulate sympathetic vasomotor function. In addition, the actions of CCK also are partly dependent on activation of 5-HT(3) receptors. CCK may release 5-HT which then acts at 5-HT(3) receptors to produce sympathetic vasomotor inhibition. In contrast, the actions of PBG are entirely dependent on 5-HT(3) receptors and are independent of any actions at the CCK(1) receptor.     

What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla?

1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla. 2. Experimental evidence is reviewed that indicates that these neurons receive both tonic excitatory and tonic inhibitory synaptic inputs. The former appear to be mediated, at least in part, by glutamate receptors and the latter appear to be mediated by GABA receptors. 3. There is also evidence that these neurons have the capacity to generate action potentials in the absence of synaptic inputs. However, at present, there is not clear evidence that such an intrinsic pacemaker-like mechanism contributes to the tonic activity of these neurons under normal resting conditions. 4. These neurons are also chemosensitive and this may contribute to their tonic activation under conditions of hypoxia or hypercapnia.     

Differential regulation of brown adipose and splanchnic sympathetic outflows in rat: roles of raphe and rostral ventrolateral medulla neurons

1. The medullary premotor neurons determining the sympathetic outflow regulating cardiac function and vasoconstriction are located in the rostral ventrolateral medulla (RVLM). The present study sought evidence for an alternative location for the sympathetic premotor neurons determining the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis. 2. The tonic discharge on sympathetic nerves is determined by the inputs to functionally specific sympathetic preganglionic neurons from supraspinal populations of premotor neurons. Under normothermic conditions, BAT SNA was nearly silent, while splanchnic (SPL) SNA, controlling mesenteric vasoconstriction, exhibited sustained large-amplitude bursts. 3. The rostral raphe pallidus (RPa) contains potential sympathetic premotor neurons that project to the region of sympathetic preganglionic neurons in the thoracic spinal cord. Disinhibition of neurons in RPa elicited a dramatic increase in BAT SNA, with only a small rise in SPL SNA. 4. Splanchnic SNA was strongly influenced by the baroreceptor reflex, as indicated by a high coherence with the arterial pressure wave, a significant amplitude modulation over the time-course of the cardiac cycle and a marked inhibition of SPL SNA during a sustained increase in arterial pressure. When activated, the bursts in BAT SNA exhibited no correlation with arterial pressure and were not affected by increases in arterial pressure. 5. Because these characteristics and reflex responses in sympathetic outflow have been shown to arise from the on-going or altered discharge of sympathetic premotor neurons, the marked differences between SPL and BAT SNA provide strong evidence supporting the hypothesis that vasoconstriction and thermogenesis (metabolism) are controlled by distinct populations of sympathetic premotor neurons, the former in the RVLM and the latter, potentially, in the RPa.     

Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat

We evaluated the contribution of peroxynitrite to the fatal cardiovascular depression induced by overproduction of nitric oxide (NO) after activation of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the origin of sympathetic vasomotor tone. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of E. coli lipopolysaccharide (LPS) bilaterally into the RVLM elicited significant hypotension, bradycardia, reduction in sympathetic vasomotor tone and mortality. There was also a discernible elevation of iNOS expression in the ventrolateral medulla, followed by a massive production of nitrotyrosine, an experimental index for peroxynitrite. Co-administration bilaterally into the RVLM of the selective iNOS inhibitor, S-methylisothiourea (50, 100 or 250 pmol), an active peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis- (N-methyl-4'-pyridyl)-porphyrinato iron (III) (10 or 50 pmol), a peroxynitrite scavenger, L-cysteine (5, 50 or 100 pmol), or a superoxide dismutase mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (1 or 10 pmol), significantly prevented mortality, reduced nitrotyrosine production and reversed the NO-induced cardiovascular suppression after application of LPS into the RVLM. We conclude that the formation of peroxynitrite by a reaction between superoxide anion and NO is primarily responsible for the fatal cardiovascular depression induced by overproduction of NO after activation of iNOS at the RVLM.