Rostral Ventrolateral Medulla: An Integrative Site for Muscle Vasodilation During Defense-Alerting Reactions

1. Evidence gathered over the last 30 years has firmly established that the rostral ventrolateral medulla (RVLM) is a major vasomotor center in the brainstem, harboring sympathetic premotor neurons responsible for generating and maintaining basal vasomotor tone and resting levels of arterial blood pressure. Although the RVLM has been almost exclusively classified as a vasopressor area, in this report we review some evidence suggesting a prominent role of the RVLM in muscle vasodilation during defense-alerting responses.2. Defense-alerting reactions are a broad class of behavior including flexion of a limb, fight/flight responses, apologies, etc. They comprise species-distinctive motor and neurovegetative adjustments. Cardiovascular responses include hypertension, tachycardia, visceral vasoconstriction, and muscle vasodilation. Since defense-alerting reactions generally involve intense motor activation, muscle vasodilation is regarded as a key feature of these responses.3. In anesthetized or unanesthetized-decerebrate animals, natural or electrical stimulation of cutaneous and muscle afferents produced hypertension, tachycardia, and vasodilation restricted to the stimulated limb.4. Unilateral inactivation of the RVLM contralateral to the stimulated limb abolished cardiovascular adjustments to stimulation of cutaneous and muscle afferents. Within the RVLM glutamatergic synapses mediate pressor responses, whereas GABAergic synapses mediates muscle vasodilation.5. In urethane-anesthetized rats, electrical stimulation of the hypothalamus elicited hypertension, tachycardia, visceral vasoconstriction, and hindlimb vasodilation. The hindlimb vasodilation induced by hypothalamic stimulation is a complex response, involving reduction of sympathetic vasoconstrictor tone, release of catecholamines by the adrenal medulla, and a still unknown system that may use nitric oxide as a mediator.6. Blockade of glutamatergic transmission within the RVLM selectively blocks muscle vasodilation induced by hypothalamic stimulation.7. The results obtained suggest that, besides its role in the generation and maintenance of the sympathetic vasoconstrictor drive, the RVLM is also critical for vasodilatory responses during defense reactions. The RVLM may contain several, distinctive mechanisms for muscle vasodilation. Anatomical and functional characterization of these pathways may represent a breakthrough in our understanding of cardiovascular control in normal and/or pathological conditions.     

Cardiovascular responses to microinjection of ATP into the nucleus tractus solitarii of awake rats

Microinjection of increasing doses of ATP (0.31, 0.62, 1.25, and 2.5 nmol/50 nl) into the nucleus tractus solitarii (NTS) produced a dose-dependent pressor response. Prazosin abolished the pressor response and produced no change in the bradycardic response to ATP. Microinjection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (0.25 nmol/50 nl), a nonselective P2 receptor antagonist into the NTS, reduced the bradycardic response but had no effect on the pressor response to microinjection of ATP (1.25 nmol/50 nl) into the NTS. Microinjection of suramin (2 nmol/50 nl), another nonselective P2 receptor antagonist, had no effect on the pressor and bradycardic responses to microinjection of ATP (1.25 nmol/50 nl) into the NTS. Antagonism of A1 receptors of adenosine with 1,3-dipropyl-8-cyclopentylxanthine also produced no changes in the cardiovascular responses to microinjection of ATP into the NTS. The involvement of excitatory amino acid (EAA) receptors in the pressor and bradycardic responses to microinjection of ATP into the NTS was also evaluated. Microinjection of kynurenic acid, a nonselective EAA receptor antagonist (10 nmol/50 nl), into the NTS reduced the bradycardic response and had no effect on the pressor response to microinjection of ATP into the NTS. The data show that 1) microinjection of ATP into the NTS of awake rats produced pressor and bradycardic responses by independent mechanisms, 2) the activation of parasympathetic component may involve an interaction of P2 and EAA receptors in the NTS, and 3) the sympathoexcitatory response to microinjection of ATP into the NTS was not affected by the blockade of P2, A1, or EAA receptors.     

Both α1- and α2-adrenoceptors in the Insular Cortex Are Involved in the Cardiovascular Responses to Acute Restraint Stress in Rats

The insular cortex (IC) is a limbic structure involved in cardiovascular responses observed during aversive threats. However, the specific neurotransmitter mediating IC control of cardiovascular adjustments to stress is yet unknown. Therefore, in the present study we investigated the role of local IC adrenoceptors in the cardiovascular responses elicited by acute restraint stress in rats. Bilateral microinjection of different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective α₁-adrenoceptor antagonist WB4101 into the IC reduced both the arterial pressure and heart rate increases elicited by restraint stress. However, local IC treatment with different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective α₂-adrenoceptor antagonist RX821002 reduced restraint-evoked tachycardia without affecting the pressor response. The present findings are the first direct evidence showing the involvement of IC adrenoceptors in cardiovascular adjustments observed during aversive threats. Our findings indicate that IC noradrenergic neurotransmission acting through activation of both α₁- and α₂-adrenoceptors has a facilitatory influence on pressor response to acute restraint stress. Moreover, IC α₁-adrenoceptors also play a facilitatory role on restraint-evoked tachycardiac response.     

Effects of angiotensin II on the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in spontaneously hypertensive rats

The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesthetized spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar Kyoto rat (WKY). It was found that Ang II elicited dose-dependent excitatory responses in a subpopulation of RVL cardiovascular neurons, followed by a subsequent increase in blood pressure. These effects of Ang II were significantly greater in SHR than in WKY. The effects were attenuated or abolished by co-administration of Ang II antagonist, [Sar¹, Ile⁸]-Ang II. Pre-administration of [Sar¹, Ile⁸]-Ang II to RVL using bilateral microinjection attenuated the blood pressure effects of intracerebroventricularly administered Ang II by as much as 70%. These results indicated that spinal projecting RVL cardiovascular neurons are important in mediating the pressor action of Ang II. The enhanced sensitivity and responsiveness of RVL cardiovascular neurons to Ang II may be pertinent to the genesis of hypertension in adult SHR.     

Contribution of infralimbic cortex in the cardiovascular response to acute stress

The infralimbic region of the medial prefrontal cortex (IL) modulates autonomic and neuroendocrine function via projections to subcortical structures involved in the response to stress. We evaluated the contribution of the IL to the cardiovascular response evoked by acute stress. Under anesthesia (80 mg/kg ketamine-11.5 mg/kg xylazine), rats were implanted with telemetry probes or arterial lines for recording heart rate and blood pressure. Guide cannulas were implanted to target the IL for microinjection of muscimol (100 pmol/100 nl), N-methyl-d-aspartate (NMDA) (6 pmol/100 nl), or vehicle (100 nl). Microinjection of muscimol, an agonist of GABA(A) receptors, into the IL had no effect on stress-evoked cardiovascular and thermogenic changes in any of the paradigms evaluated (cage switch, restraint plus air-jet noise, or air-jet stress). However, microinjection of the excitatory amino acid NMDA into the IL attenuated the pressor and tachycardic response to air-jet stress. Pretreatment with the selective NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP-5, 100 pmol/100 nl) blocked the effect of NMDA on the cardiovascular response to air-jet stress. We conclude that 1) the IL region is not tonically involved in cardiovascular or thermogenic control during stress or under baseline conditions, and 2) activation of NMDA receptors in the IL can suppress the cardiovascular response to acute stress exposure.     

Bradykinin microinjection in the paratrigeminal nucleus triggers neuronal discharge in the rat rostroventrolateral reticular nucleus

A small collection of neurons in the dorsal lateral medulla, the paratrigeminal nucleus (Pa5), projects directly to the rostroventrolateral reticular nucleus (RVL). Bradykinin (BK) microinjections in the Pa5 produce marked pressor responses. Also, the Pa5 is believed to be a component of the neuronal substrates of the somatosensory response and the baroreflex arc. Considering the developing interest in the functional physiology of the Pa5, the present study was designed to characterize RVL neuronal activity in response to BK microinjections in the Pa5 as well as to phenylephrine-induced blood pressure increases in freely behaving rats. Of the 46 discriminated RVL neurons, 82% responded with a 180% mean increase in firing rate after BK application to the paratrigeminal nucleus, before the onset of the blood pressure increase. Thirty (79%) of the RVL BK-excited neurons were baroreceptor-inhibited units that responded with a 30% decrease in firing rate in response to a phenylephrine-produced increase of blood pressure. Twenty-seven (71%) units of the latter population displayed cardiac-cycle-locked rhythmic activity. The findings demonstrate a BK-stimulated functional connection between the Pa5 and RVL that may represent the neural pathway in the BK-mediated pressor response. This pathway may be relevant to baroreflex mechanisms since it relates to cardiovascular pressure-sensitive neurons.     

Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging

Adult aging in humans is associated with marked and sustained increases in sympathetic nervous system (SNS) activity to several peripheral tissues, including the heart, the gut-liver circulation, and skeletal muscle. This chronic activation of the peripheral SNS likely is, at least in part, a primary response of the central nervous system to stimulate thermogenesis to prevent further fat storage in the face of increasing adiposity with aging. However, as has been proposed in obesity hypertension, this tonic activation of the peripheral SNS has a number of adverse secondary cardiovascular consequences. These include chronic reductions in leg blood flow and vascular conductance, increased tonic support of arterial blood pressure, reduced limb and systemic alpha-adrenergic vasoconstrictor responsiveness, impaired baroreflex buffering, large conduit artery hypertrophy, and decreased vascular and cardiac responsiveness to beta-adrenergic stimulation. These effects of chronic age-associated SNS activation on the structure and function of the cardiovascular system, in turn, may have important implications for the maintenance of physiological function and homeostasis, as well as the risk of developing clinical cardiovascular and metabolic diseases in middle-aged and older adults.     

Mechanisms underlying the cardioinhibitory and pressor responses elicited from the medullary neurons in the gigantocellular tegmental field of cats

A stimulation of the gigantocellular tegmental field (FTG) in the medulla oblongata often increases systemic arterial blood pressure (SAP) and decreases heart rate (HR). We investigated if the cardioinhibitory/depressor areas, including the nucleus ambiguus (NA), the dorsal motor nucleus of vagus (DMV) and the caudal ventrolateral medulla (CVLM), underlied the functional expression of FTG neurons in regulating cardiovascular responses. In 73 chloralose-urethane anesthetized cats, the HR, SAP and vertebral nerve activity (VNA) were recorded. Neurons in the FTG, NA, DMV and CVLM were stimulated by microinjection of sodium glutamate (25 mM Glu, 70 nl). To study if the NA, DMV, and CVLM relayed the cardioinhibitory messages from the FTG, 24 mM kainic acid (KA, 100 nl) was used as an excitotoxic agent to lesion neurons in the NA, DMV or CVLM. We found that the cardioinhibition induced by FTG stimulation was significantly reduced by KA lesioning of the ipsilateral NA or DMV. Subsequently, a bilateral KA lesion of NA or DMV abolished the cardioinhibitory responses of FTG. Compared to the consequence of KA lesion of the DMV, only a smaller bradycardia was induced by FTG stimulation after KA lesion of the NA. The pressor response induced by Glu stimulation of the FTG was reduced by the KA lesion of the CVLM. Such an effect was dominant ipsilaterally. Our findings suggested that both NA and DMV mediated the cardioinhibitory responses of FTG. The pressor message from the FTG neurons might be partly working via a disinhibitory mechanism through the depressor neurons located in the CVLM.     

Mechanisms mediating regional sympathoactivatory responses to stimulation of NTS A(1) adenosine receptors

Selective activation of adenosine A(1) and A(2a) receptors in the subpostremal nucleus tractus solitarius (NTS) increases and decreases mean arterial pressure (MAP), respectively, and decreases heart rate (HR). We have previously shown that the decreases in MAP evoked by NTS A(2a) receptor stimulation were accompanied with differential sympathetic responses in renal (RSNA), lumbar (LSNA), and preganglionic adrenal sympathetic nerve activity (pre-ASNA). Therefore, now we investigated whether stimulation of NTS A(1) receptors via unilateral microinjection of N(6)-cyclopentyladenosine (CPA) elicits differential activation of the same sympathetic outputs in alpha-chloralose-urethane-anesthetized male Sprague-Dawley rats. CPA (0.33-330.0 pmol in 50 nl) evoked dose-dependent increases in MAP, variable decreases in HR, and differential increases in all recorded sympathetic outputs: upward arrow pre-ASNA > upward arrow RSNA > or = upward arrow LSNA. Sinoaortic denervation + vagotomy abolished the MAP and LSNA responses, reversed the normal increases in RSNA into decreases, and significantly attenuated increases in pre-ASNA. NTS ionotropic glutamatergic receptor blockade with kynurenate sodium (4.4 nmol/100 nl) reversed the responses in MAP, LSNA, and RSNA and attenuated the responses in pre-ASNA. We conclude that afferent inputs and intact glutamatergic transmission in the NTS are necessary to mediate the pressor and differential sympathoactivatory responses to stimulation of NTS A(1) receptors.     

Activation of neurons in the rostral ventrolateral medulla increases bronchomotor tone in dogs.

Previous work from this laboratory has demonstrated that the chemical activation of cell bodies in the caudal ventrolateral medulla of chloralose-anesthetized dogs decreased bronchomotor tone by withdrawing cholinergic input to airway smooth muscle. In the present study we determined the bronchomotor responses to microinjection of DL-homocysteic acid (100 mM; 25-50 nl) into the rostral ventrolateral (RVL) medulla of chloralose-anesthetized dogs. Total lung resistance was used as a functional index of bronchomotor tone. Microinjection of DL-homocysteic acid into the 20 sites located in the lateral aspect of the RVL medulla increased both total lung resistance [from 6.5 +/- 0.4 to 9.1 +/- 0.8 (SE) cmH2O.l-1.s; P less than 0.05] and mean arterial pressure (from 125 +/- 5 to 148 +/- 8 mmHg; P less than 0.05). Microinjection of this amino acid into nine sites located in the medial aspect of the RVL medulla increased mean arterial pressure (from 130 +/- 6 to 153 +/- 6 mmHg; P less than 0.05) but had no effect on total lung resistance. We confirmed in three sites that the increase in total lung resistance evoked by microinjection of DL-homocysteic acid was accompanied by an increase in tracheal smooth muscle tension. The increase in total lung resistance evoked by DL-homocysteic acid was not affected by beta-adrenergic blockade but was abolished by muscarinic blockade.     

臂旁核和延髓头端腹外侧区在黑质升压效应中的作用

本实验室观察到黑质具有升压效应。用L-谷氨酸钠微量注入黑质可使血压升高,此效应可被DA受体阻断剂氟哌啶醇(Halo)微量注入臂旁核加压区基本阻断。我们过去的工作证明延髓头端腹外侧区(RVL)及其内的α-受体中介臂旁核的加压效应,本实验将酚妥拉明注入RVL能明显衰减黑质的加压效应,而将Halo注入RVL加压区对黑质加压效应无明显影响。以上结果提示臂旁核-RVL(α-受体)加压系统参与黑质加压效应。     

脑内P物质在谷氨酸兴奋腹内侧核引起的升压反应中之作用

目的：分析谷氨酸兴奋下兵脑腹内侧核（NVM）引起升压反应的机制。方法：大鼠脑内或静脉注射不同药物,记录血压和心率的变化。结果：①L－谷氨酸（Glu)兴奋NVM、P物质（SP）注入背内侧核（NDM）室旁核（NPV）或延髓头端腹外侧区（RVL）均引起升压反应;②NVM升压反应可被双侧NDM、NPV或PVL内预先注射[D-Pro^2,D-Phe^7,D-Trp^9]-P物质（SP拮抗剂）衰减,但RVL内注射阿托品无此效应;③酚妥拉明（i.v.）也能使NVM升压反应减小,而心得安或甲基阿托品（i.v.）对该升压反应无影响。结论：兴奋NVM可通过NDM（SP受体）,作用于NPV（SP受体）升压区和RVL（SP受体）－交感缩血管神经系统产生升压反应。心交感和心迷走神经不参与该反应。     

Contribution of AMPA/kainate receptors in the rostral ventrolateral medulla to the hypotensive and sympathoinhibitory effects of clonidine

The depressor and sympathoinhibitory effect of the imidazoline drug clonidine is reported to be associated with functional states of the central glutamate receptors. The rostral ventrolateral medulla (RVLM) has been recognized as a specific target area for mediating the central depressor mechanism of clonidine. The objective of this study was to determine the role of the glutamate receptor subtype alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor within the RVLM in clonidine-induced depressor and sympathoinhibitory action in anesthetized normotensive rats. Unilateral microinjection of 200 pmol of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a potent AMPA/kainate receptor antagonist, into the RVLM completely abolished the pressor action evoked by AMPA (5 pmol) without affecting the pressor action of N-methyl-D-aspartate (20 pmol). Pretreatment with intra-RVLM injection of CNQX (20 and 200 pmol) dose dependently attenuated the reduction in blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) elicited by intra-RVLM clonidine (5 nmol) or intravenous clonidine (10 microg/kg), while 2 pmol of CNQX did not alter clonidine-induced cardiovascular action. Furthermore, the decreases in BP, HR, and RSNA evoked by intravenous clonidine (10 microg/kg) or intra-RVLM clonidine (5 nmol) were reversed when CNQX (20 and 200 pmol) was subsequently injected into the RVLM. In conclusion, these data show that blockade of AMPA/kainate receptors in the RVLM significantly antagonizes decreases in BP, HR, and sympathetic activity induced by clonidine, suggesting that the AMPA/kainate receptors within the RVLM contribute to the depressor and sympathoinhibitory effect of clonidine.     

兴奋大鼠延髓A1区引起降压、降心率效应的机制

在水合氯醛麻醉、箭毒化、人工呼吸的大鼠,观察到:(1) A_1区注入谷氨酸钠引起明显的血压下降和心率减慢。(2) 切断双侧颈迷走神经明显衰减A_1区的降压,降心率效应。(3) 延髓头端腹外侧区(RVL)预先注射酚妥拉明或心得安,均能明显衰减谷氨酸钠兴奋A_1区的降压效应,A_1区的降心率作用基本不受影响,将纳洛酮注入RVL后,A_1区的降压和降心率效应均无明显变化;注射荷包牡丹碱入RVL则使A_1区的降压、降心率效应反转。(4) RVL内注入酚妥拉明或心得安本身使基础血压降低,注射荷包牡丹碱入RVL则使基础血压升高(提示RVL内的α-,β-受体中介对RVE加压神经元的紧张性兴奋作用,GABA受体中介紧张性抑制作用);另一方面,RVL内注入心得安使基础心率减慢、注入纳洛酮或荷包牡丹碱使基础心率加快(说明β-受体中介紧张性心加速效应,阿片受体和GABA受体中介紧张性心抑制效应)。     

Cardiovascular mechanisms activated by microinjection of baclofen into NTS of conscious rats

The peripheral mechanisms responsible for pressor response produced by microinjections of baclofen (GABA(B) agonist) into the nucleus tractus solitarii (NTS) of conscious rats were studied. Bilateral microinjections of baclofen (10-1,000 pmol/100 nl) produced a dose-related increase in mean arterial pressure (MAP) and heart rate. The maximal response was observed after 15 min. Intravenous injection of prazosin decreased MAP to control levels. Subsequent treatment with Manning compound (vasopressin receptor antagonist; iv) produced an additional decrease in MAP. In a different group of rats, vasopressin antagonist was injected first and MAP was significantly decreased; however, it remained elevated compared with prebaclofen injection levels. Subsequent treatment with prazosin abolished the baclofen-induced pressor response. Reductions in baclofen-induced pressor response with prazosin treatment were followed by a reflex tachycardia in animals that received a 100 pmol/100 nl dose of baclofen. The tachycardia was not observed with a dose of 1,000 pmol/100 nl. The pressor response induced by microinjection of baclofen into the NTS of conscious rats may be produced by both increases in sympathetic tonus and vasopressin release.     

Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia

Mu-opioid receptor activation increases body temperature and affects cardiovascular function. In the present study, fentanyl was administered intravenously [100 mug/kg (300 nmol/kg) iv] and intracerebroventricularly [3.4 mug (10 nmol) in 10 microl icv] in urethane-chloralose-anesthetized, artificially ventilated rats. Increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA) (peak, +326% of control), BAT temperature (peak, +0.8 degrees C), renal SNA (peak, +146% of control), and heart rate (HR; peak, +32 beats/min) produced by intravenous fentanyl were abolished by premamillary transection of the neuraxis but were mimicked by intracerebroventricular administration of fentanyl, which also increased arterial pressure (AP; peak, +12 mmHg). Pretreatment with the opioid antagonist naloxone (100 nmol in 10 microl icv) eliminated the intracerebroventricular fentanyl-evoked responses. Microinjection of glycine (0.5 M, 60 nl) to inhibit local neurons in the rostral raphe pallidus (RPa) selectively reversed the intracerebroventricular fentanyl-evoked increases in BAT SNA and HR, while the fentanyl-evoked excitation in RSNA, the pressor responses, and the tachycardic responses were reversed by inhibition of neurons in the rostral ventrolateral medulla (RVLM). Prior inhibition of neurons in the dorsomedial hypothalamus eliminated the intracerebroventricular fentanyl-evoked increases in BAT SNA, BAT temperature, and HR, but not those in RSNA or AP. These results indicate that activation of central mu-opioid receptors with fentanyl can elicit BAT thermogenesis and cardiovascular stimulation through excitation of the sympathetic outflows to BAT, kidney, and heart. Activation of neurons in the rostral RPa and RVLM are essential for the increases in BAT thermogenesis and renal sympathoexcitation, respectively, induced by activation of central mu-opioid receptors. BAT thermogenesis could contribute to fentanyl-evoked hyperthermia, particularly in infants where BAT plays a significant role in thermoregulation.     

谷氨酸钠兴奋尾侧导水管周围灰质腹外侧部的升压反应及其在脑干内的传出通路

实验用乌拉坦麻醉、箭毒化、人工呼吸的大鼠,观察到:(1) 胞体兴奋剂L-谷氨酸钠(Glu)注入尾侧导水管周围灰质腹外侧部(PAG)引起明显的加压反应,(2) 该效应可被双侧延髓头端腹外侧(RVL)加压区内注射酚妥拉明或心得安衰减,但不受阿托品注入RVL影响;表明此升压反应是通过RVL及其内的α-及β-受体实现的。(3) RVL内注入心得安也可衰减电刺激腹侧臂旁核(NPV)的加压作用,却不影响Glu注入NPV的升压效应;结合以往的实验结果,提示尾侧PAG腹外侧部的神经元发出的轴突,可能一方面路过臂旁核直接作用于RVL内的β-受体,另一方面可能在臂旁核内换元,然后作用于RVL内的α-受体,而起升压作用。     

Cardiovascular responses to central administration of mu and kappa opioid receptor agonist and antagonist in normal rats

The response to centrally administered beta-endorphin has been characterized by decreasing sympathetic nervous activity and decreased cardiovascular tone. We investigated the effect of the central administration of both mu and kappa opioid receptor agonist and antagonists on cardiovascular responses. The administration of the mu agonist, DAMGO (0.2nmol) increased the mean arterial pressure (MAP) and stimulated iliac vasoconstriction while higher doses (2 and 20nmol) decreased MAP and stimulated iliac vasodilation. The administration of the kappa receptor agonist, Dynorphin decreased the MAP and stimulated superior mesenteric vasodilation. beta-Funaltrexamine reduced MAP and superior mesenteric vasodilation while nor-binaltorphimine increased MAP and iliac and superior mesenteric vasoconstriction. We conclude that mu receptor activation decrease or increase MAP depending on the mu agonist concentration. However, kappa receptor activation is consistently associated with a decrease in MAP.     

AT1 receptors in the paraventricular nucleus mediate the hyperthermia-induced reflex reduction of renal blood flow in rats

Increasing body core temperature reflexly decreases renal blood flow (RBF), and the hypothalamic paraventricular nucleus (PVN) plays an essential role in this response. ANG II in the brain is involved in the cardiovascular responses to hyperthermia, and ANG II receptors are highly concentrated in the PVN. The present study investigated whether ANG II in the PVN contributes to the cardiovascular responses elicited by hyperthermia. Rats anesthetized with urethane (1-1.4 g/kg iv) were microinjected bilaterally into the PVN (100 nl/side) with saline (n = 5) or losartan (1 nmol/100 nl) (n = 7), an AT1 receptor antagonist. Body core temperature was then elevated from 37°C to 41°C and blood pressure (BP), heart rate (HR), RBF, and renal vascular conductance (RVC) were monitored. In separate groups losartan (n = 4) or saline (n = 4) was microinjected into the PVN, but body core temperature was not elevated. Increasing body core temperature in control rats elicited significant decreases in RBF (-48 ± 5% from a resting level of 14.3 ± 1.4 ml/min) and MVC (-40 ± 4% from a resting level of 0.128 ± 0.013 ml/min·mmHg), and these effects were entirely prevented by pretreatment with losartan. In rats in which body core temperature was not altered, losartan microinjected into the PVN had no significant effects on these variables. The results suggest that endogenous ANG II acts on AT1 receptors in the PVN to mediate the reduction in RBF induced by hyperthermia.     

Cardiovascular regulation by skeletal muscle reflexes in health and disease

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.