The Gigantocellular Depressor Area Revisited

1. In studies conducted with Dr Donald Reis we described a functionally distinct region of the rat medullary reticular formation that we called the Gigantocellular Depressor Area (GiDA). The GiDA was defined as a region from which vasodepressor and sympathoinhibitory responses were evoked by nanoinjections of glutamate. We later showed that cells in the GiDA project to autonomic nuclei in the medulla, brainstem, and spinal cord, including the intermediolateral cell column. We also showed that kainic acid lesions of the GiDA induce hypertension and block the baroreceptor reflex evoked by electrical stimulation of the aortic depressor nerve. The present studies describe the effects of muscimol nanoinjections into the GiDA.2. Nanoinjections of muscimol were made in the GiDA of anesthetized rats and changes in arterial pressure, heart rate, and responses to aortic depressor nerve stimulation were measured.3. Bilateral nanoinjections of muscimol into the GiDA evoke an increase in arterial pressure and lead to fulminating hypertension. Unilateral injections of muscimol into the GiDA block the baroreflex response evoked by electrical stimulation of the ipsilateral aortic depressor nerve. However, these unilateral injections of muscimol into the GiDA evoked profound falls in arterial pressure to nearly spinal levels. In spite of this fall in blood pressure, heart rate also decreased significantly and there was not a compensatory tachycardia. Both the arterial pressure and baroreceptor responses required several hours to recover following the muscimol injections.4. Although these data are consistent with the proposal that the GiDA is critical for the baroreflex, the opposing effects on blood pressure of unilateral and bilateral injections of muscimol are difficult to reconcile with our current models of central sympathetic regulation.     

Cardiorespiratory responses to chemical activation of right ventricular receptors

Previous reports have shown that activation of left ventricular receptors with sympathetic afferents elicits increases in respiratory output and arterial pressure. The purpose of the present study was to determine whether similar responses are produced by chemical activation of epicardial receptors in the right ventricle. Receptors were stimulated by applying either capsaicin (10 micrograms) or bradykinin (500 ng) to the epicardial surface of the right ventricle in anesthetized cats. Application of either chemical evoked an increase in respiratory output (phrenic nerve activity), a decrease in heart rate, and a nonsignificant increase in arterial pressure in intact cats. However, capsaicin and bradykinin produced significant increases in arterial pressure, heart rate, and respiratory output after bilateral cervical vagotomy. In contrast, a fall in both heart rate and arterial pressure with only small increases in respiratory output were evoked after bilateral removal of the stellate ganglia in cats with intact vagi. Only small responses to the chemical stimulation of right ventricular receptors persisted after combined vagotomy and stellate ganglionectomy. These findings suggest that 1) activation of epicardial receptors with sympathetic afferents originating in the right ventricle causes an increase in cardiorespiratory function, and 2) activation of right ventricular receptors with vagal afferents produces decreases in heart rate and arterial pressure.     

Spinal GABA(A) receptors do not mediate the sympathetic baroreceptor reflex in the rat

Activation of baroreceptors causes efferent sympathetic nerve activity (SNA) to fall. Two mechanisms could account for this sympathoinhibition: disfacilitation of sympathetic preganglionic neurons (SPN) and/or direct inhibition of SPN. The roles that spinal GABA and glycine receptors play in the baroreceptor reflex were examined in anesthetized, paralyzed, and artificially ventilated rats. Spinal GABA(A) receptors were blocked by an intrathecal injection of bicuculline methiodide, whereas glycine receptors were blocked with strychnine. Baroreceptors were activated by stimulation of the aortic depressor nerve (ADN), and a somatosympathetic reflex was used as control. After an intrathecal injection of vehicle, there was no effect on any measured variable or evoked reflex. In contrast, bicuculline caused a dose-dependent increase in arterial pressure, SNA, phrenic nerve discharge, and it significantly facilitated the somatosympathetic reflex. However, bicuculline did not attenuate either the depressor response or sympathoinhibition evoked after ADN stimulation. Similarly, strychnine did not affect the baroreceptor-induced depressor response. Thus GABA(A) and glycine receptors in the spinal cord have no significant role in baroreceptor-mediated sympathoinhibition.     

Effects of pituitary adenylate cyclase-activating polypeptide on cardiovascular and respiratory responses in anaesthetised dogs

This study examines some of the cardiovascular and respiratory effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in anaesthetised dogs. Intravenous injection of PACAP 27 caused an increase in arterial blood pressure and an increase in heart rate. The blood pressure response was significantly reduced by adrenoceptor blockade suggesting a mechanism of action mediated in part via catecholamines. The heart rate increase was unaltered by adrenoceptor blockade suggesting a direct effect of PACAP 27. PACAP 27 also caused potentiation of cardiac slowing caused by stimulation of the vagus nerve. In addition, PACAP 27 powerfully stimulated breathing. This was probably evoked by stimulation of arterial chemoreceptors, because bilateral section of the carotid sinus nerves abolished this effect. PACAP 27 had no effect on the ability of the cardiac sympathetic nerve to increase heart rate, nor on the interaction between the sympathetic and parasympathetic systems in the heart.     

Effect of gamma-aminobutyric acid and phenibut on the central links of the vascular reflexes with chemo- and mechanoreceptors of the aorto-carotid zone]

Experiments were conducted on decerebrated cats. A depressive effect of gamma-aminobutyruc acid (GABA)--100--200 mg/kg and its phenyl derivative phenibut--20 mg/kg--on depressive reactions of the systemic arterial pressure and on the inhibition of spontaneous bioelectrical activity in the renal nerve occurring in stimulation of the mechanoreceptors of the carotid sinus and of the sinus and depressor nerve afferents (having a mechanoreceptor modality) was demonstrated. Pressor reactions of the systemic arterial pressure and evoked bioelectrical activity were enhanced in the renal nerve in stimulation of chemoreceptors of the carotid sinus following administration of the same GABA and phenibut doses. The data obtained are interpreted from the aspect of a deprimating action of GABA and phenibut in the area of the paramedian reticular nuclei of the medulla oblongata.     

刺激家兔腹部迷走神经外周端降压效应中枢机制的研究

应用电解损毁和脑室内注射药物的方法研究了刺激家兔腹部迷走神经外周端所致降压效应的中枢机制。结果表明:1.电刺激延脑闩部尾侧1.5—2mm、中线旁开0.25mm、深1—2mm 处主要引起降压反应。2.电解损毁该部位可以使刺激腹部迷走神经外周端所引起的降压效应显著减弱(n=20,P<0.001),但对刺激减压神经所致降压反应无影响。3.在延脑闩部水平电解损毁减压神经纤维在孤束核的主要投射区可以使刺激减压神经所致降压反应显著减弱,而对刺激腹部迷走神经外周端所致降压反应无影响。4.第四脑室注射5,6-双羟色胺的动物较之注射人工脑脊液的动物颈、胸髓5-羟色胺含量明显降低、动物动脉压增高、心率明显增快、刺激减压神经所致降压反应未见减弱,而刺激腹部迷走神经外周端所致降压反应却明显减小。因此,我们认为家兔腹部迷走神经外周端所致降压效应依赖于延脑闩下部的中缝隐核及连合核等结构,而与减压神经的投射部位无关。延脑中缝核至脊髓的下行性5-HT能神经纤维抑制脊髓交感节前神经元的活动,是这个降压效应的中枢机制之一。     

Protective influence of phosphocreatine (Neoton) on the neural structures of the heart and brain

In acute experiments on dogs, we demonstrated that local immunogenic injury to the heart resulting from injection of anticardial cytotoxic serum is accompanied by suppression of a vagus-mediated depressor reflex evoked by intracoronary injection of 5 μg veratrine. Preliminary i.v. injection of 250 mg/kg phosphocreatine to a significant extent prevented the development of immunogenic heart injury and served to normalize the cardiogenic depressor reflex (we measured the heart rate, systemic arterial pressure, pressure in the left ventricle, and its first derivative, and also recorded the afferent activity in the cardial branches of the vagus nerve). These data are indicative of a protective effect of phosphocreatine on the receptor and afferent structures in the heart. At the same time, a parallel study of the effects of application of phosphocreatine on the spike activity of single neurons and on evoked potentials in the neocortex of rats showed that phosphocreatine increases the excitability of cortical neurons by facilitating the processes of synaptic transmission. This was manifested in an increase in the frequency of background spike activity of the neurons and in facilitation of the development of epileptiform reactions evoked by surface application of penicillin after preliminary applications of phosphocreatine.     

Central inhibition of the aortic baroreceptors-heart rate reflex at the onset of spontaneous muscle contraction.

Animals decerebrated at the precollicular-premammillary body level exhibit spontaneous locomotion without any artificial stimulation. Our laboratory reported that the cardiovascular and autonomic responses at the onset of spontaneous locomotor events are evoked by central command, generated from the caudal diencephalon and the brain stem (Matsukawa K, Murata J, and Wada T. Am J Physiol Heart Circ Physiol 275: H1115-H1121, 1998). In this study, we examined whether central command and/or a reflex resulting from muscle afferents modulates arterial baroreflex function using a decerebrate cat model. The baroreflex was evoked by stimulating the aortic depressor nerve (ADN) at the onset of spontaneous muscle contraction (to test the possible influence of central command) and during electrically evoked contraction or passive stretch (to test the possible influence of the muscle reflex). When the ADN was stimulated at rest, heart rate and arterial blood pressure decreased by 40 +/- 2 beats/min and 11 +/- 1 mmHg, respectively. The baroreflex bradycardia was attenuated to 55 +/- 4% at the onset of spontaneous contraction. The attenuating effect on the baroreflex bradycardia was not observed at the onset and middle of electrically evoked contraction or passive stretch. The depressor response to ADN stimulation was identical among resting and any muscle interventions. The inhibition of the baroreflex bradycardia during spontaneous contraction was seen after beta-adrenergic blockade but abolished by muscarinic blockade, suggesting that the bradycardia is mainly evoked through cardiac vagal outflow. We conclude that central command, produced within the caudal diencephalon and the brain stem, selectively inhibits the cardiac component, but not the vasomotor component, of the aortic baroreflex at the onset of spontaneous exercise.     

刺激家兔腹部迷走神经外周端引起的降压作用

本文对电刺激家兔腹部的迷走神经外周端所引起的降压反应进行了研究。在121只家兔中的实验结果表明:电刺激腹部迷走神经外周端可引起动脉压、小肠和后肢的灌流压同时降低,而心率则无明显变化。这一降压反应发生时,小肠静脉血中的组织胺含量较刺激前明显升高,然后恢复;将小剂量的组织胺 H_1受体阻断剂扑尔敏、非乃根和 H_2受体阻断剂甲氰咪胍(Cimetidine)分别注入肠系膜上动脉均能减弱刺激腹部迷走神经外周端引起的动脉压和小肠灌流压的降低。心得安能削弱此降压反应,而阿托品无效;切断两侧内脏大神经能显著削弱刺激腹部迷走神经外周端引起的降压反应。此残余的降压反应在注入抗组织胺剂后完全消失。由此推论,刺激家兔腹部迷走神经外周端引起的降压反应是通过中枢和外周两方面因素的作用,使血管舒张,外周阻力降低而实现的。     

An inhibitory role of beta-endorphin in central cardiovascular regulation

The cardiovascular effects of beta-endorphin after administration directly into the nucleus tractus solitarii (NTS) of urethane anaesthetised rats were investigated. Unilateral injection resulted in a dose related fall in mean arterial pressure and heart rate. No change in respiratory frequency was prevented and the bradycardia reduced by pretreatment with locally applied naloxone (10 ng). This dose of the opiate antagonist had no effect on mean arterial pressure or heart rate when administered alone. Antiserum to beta-endorphin (1:50 dilution) caused a rise in pressure and a tendency towards tachycardia on injection into the NTS, while it completely blocked the depressor response and bradycardia induced by beta-endorphin. These results are consistent with the view that a beta-endorphin-like peptide has a depressor role in the central nervous system. The hypotension may result from an effect within the central connections of the baroreceptor reflex arc, probably at the level of the NTS.     

Differential cardiovascular effects of central clonidine and B-HT 920 in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of the alpha 2-adrenoceptor agonists clonidine and B-HT 920 on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of noradrenaline and adrenaline was examined in conscious unrestrained rats. The injection of 1.0 microgram clonidine significantly decreased MAP and slightly decreased HR. Plasma noradrenaline and adrenaline levels were slightly but not significantly decreased after the injection of 1 microgram clonidine. In contrast, the injection of 0.1-10.0 micrograms B-HT 920 increased MAP and decreased HR. Plasma noradrenaline and adrenaline levels were slightly increased after the injection of the 1- and 10-micrograms doses. The i.c.v. injection of the alpha 2-antagonist rauwolscine slightly but not significantly increased MAP and plasma noradrenaline and adrenaline levels. The responses to i.c.v. injection of clonidine and B-HT 920 were not changed by prior administration of rauwolscine. Neither the pressor response to B-HT 920 nor the depressor response to clonidine was abolished by rauwolscine, suggesting that neither response was mediated by alpha 2-adrenoceptors.     

Modulation of cardiopulmonary depressor reflex in nucleus ambiguus by electroacupuncture: roles of opioids and γ-aminobutyric acid

Stimulation of cardiopulmonary receptors with phenylbiguanide (PBG) elicits depressor cardiovascular reflex responses, including decreases in blood pressure and heart rate mediated in part by the brain stem parasympathetic cardiac neurons in the nucleus ambiguus (NAmb). The present study examined NAmb neurotransmitter mechanisms underlying the influence of electroacupuncture (EA) on the PBG-induced hypotension and bradycardia. We hypothesized that somatic stimulation during EA modulates PBG responses through opioid and γ-aminobutyric acid (GABA) modulation in the NAmb. Anesthetized and ventilated cats were studied during repeated stimulation with PBG or cardiac vagal afferents while low-frequency EA (2 Hz) was applied at P5-6 acupoints overlying the median nerve for 30 min and NAmb neuronal activity, heart rate, and blood pressure were recorded. Microinjection of kainic acid into the NAmb attenuated the PBG-induced bradycardia from -60 ± 11 to -36 ± 11 beats/min. Likewise, EA reduced the PBG-induced depressor and bradycardia reflex by 52 and 61%, respectively. Cardiac vagal afferent evoked preganglionic cellular activity in the NAmb was reduced by EA for about 60 min. Blockade of opioid or GABA(A) receptors using naloxone and gabazine reversed the EA-related modulation of the evoked cardiac vagal activity by 73 and 53%, respectively. Similarly, naloxone and gabazine reversed EA modulation of the negative chronotropic responses from -11 ± 5 to -23 ± 6 and -13 ± 4 to -24 ± 3 beats/min, respectively. Thus EA at P5-6 decreases PBG evoked hypotension and bradycardia as well as the NAmb PBG-sensitive preganglionic cardiac vagal outflow through opioid and GABA neurotransmitter systems.     

电刺激猫小脑顶核对动脉血压和肾交感神经放电的影响

在38只麻醉及人工呼吸的猫,观察到电刺激小脑顶核嘴侧部能引起动脉血压显著升高;肾交感神经放电于刺激期间显著增加。去缓冲神经对刺激顶核所引起的血压反应的幅度和肾交感神经放电均无明显影响,但可明显延长血压反应升高相以及血压恢复期的时间。静脉注射氯庄定引起血压降低、心率减慢及肾交感神经放电的抑制,并能减弱刺激顶核引起的血压反应,但增强了刺激顶核引起的肾神经放电的变化。电解损毁延髓腹外侧面引起血压降低及肾交感神经放电的抑制,然而无论单侧还是双侧损毁延髓腹外侧面都不能阻断刺激顶核所引起的血压和肾交感神经放电的反应。以上结果表明,电刺激顶核能引起明显的心血管反应,其反应的下行性通路可能不通过延髓腹外侧面。     

Noradrenaline suppression of the spinal efferent component of the pressor reflexes

Noradrenaline applied to the dorsal surface of spinal cord segments C6-T1 suppressed the pressor components of the blood pressure reflexes evoked by stimulation of radial nerve afferents in anesthetized cats. Noradrenaline applied to spinal cord segments L4-S1 suppressed pressor reflexes elicited by stimulation of tibial nerve afferents. The increase in noradrenaline concentration from 0.05 to 0.2% enhanced the duration and intensity of this effect.     

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

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

Cardiovascular responses to electrical stimulation of the recurrent laryngeal nerve in conscious toads (Bufo marinus)

Summary Cardiovascular responses to electrical stimulation of the cut central end of the recurrent laryngeal nerve (rLN) were recorded in 19 conscious toads (Bufo marinus). Low intensity stimulation of the rLN (3.4±0.5 V, 1 ms, 10 Hz) elicited a slow 18–22% fall in heart rate and systolic and diastolic aortic arterial blood pressures (N=18), but had little or no effect upon ventilation (N=6). This low threshold depressor response (LTDR) was considered to represent the expression of the previously demonstrated pulmocutaneous baroreflex. Bilateral stimulation of the rLNs elicited greater LTDRs than did either left or right unilateral rLN stimulation. Blood pressure and heart rate responses to bilateral stimulation were 69–77% of the sum of responses to unilateral stimulation, and the mean summation was significant for the reduction in heart rate. Stimulus intensities of >4.7±0.7 V caused an immediate cessation of cardiac activity for up to 6.5±1.3 s (N=17) and a concomitant apnoea (N=6), which were followed by a lesser bradycardia and hypotension. This response was termed a high threshold depressor response (HTDR). During continued stimulation at intensities of >9.1±1.4 V, aortic blood pressure (Pa) and ventilation were rapidly restored, and aortic blood pressure continued to rise above control values (N=14). In some cases this high threshold pressor response (HTPR) was associated with an increase in heart rate. All responses to rLN stimulation were abolished by pithing (N=9) or by pentobarbital (40 mg/kg, i.p.,N=4), but LTDS and HTPRs could be elicited in urethanized (1.5–2.0 g/kg,N=4) toads.During depressor responses, aortic arterial resistance fell by 18% in 18 of 20 trials in 5 toads, whereas pulmocutaneous arterial resistance increased by 76% in 12 of 15 trials in 4 toads. During the HTPR, aortic arterial resistance increased 40%, while pulmocutaneous arterial resistance remained unchanged. We suggest that depressor responses may actively redistribute blood flow from the pulmocutaneous to the aortic circulation, whereas the reverse should occur during HTPRs.Abbreviations HTDR high threshold depressor response - HTPR high threshold pressor response - rLN recurrent laryngeal nerve - LTDR low threshold depressor response - Pa aortic blood pressure - PCA pulmocutaneous artery - Pd diastolic aortic pressure - Ppca pulmocutaneous blood pressure - PRU peripheral resistance unit - Ps systolic aortic pressure - Pv venous blood pressure - Ra aortic arterial resistance - Rpca pulmocutaneous arterial resistance     

Baroreceptor afferent discharge in the pregnant rat

Pregnancy is associated with blunted reflex responses to cardiac and arterial baroreceptor stimulation. We tested the hypothesis that arterial baroreceptor afferent discharge is attenuated in response to a pressure stimulus in pregnant rats. Multifiber aortic depressor nerve activity (ADNA), mean arterial pressure (MAP), and heart rate were measured in anesthetized (pentobarbital sodium, 35 mg/kg ip) late-pregnant and virgin rats in response to increases ?phenylephrine (PE), 1.5-24 microg. kg(-1). min(-1) and 1-16 microg/kg and decreases ?sodium nitroprusside (SNP), 5-80 microg. kg(-1). min(-1) and 0.05-16 microg/kg in MAP. Resting MAP was lower in pregnant rats, but changes in MAP were similar to those in virgin rats during both PE and SNP administration. ADNA was significantly attenuated in pregnant animals during both PE and SNP infusions (P < 0.05) due to a more rapid adaptation to the pressure stimulus. Bolus drug administration evoked similar changes in MAP and ADNA in both groups; however, the maximum decrease in ADNA was achieved at the lowest dose of SNP in pregnant rats. Thus baroreceptor afferent discharge is attenuated in pregnant rats, and this involves a more rapid adaptation to a pressure stimulus.     

Blood pressure responsiveness to sympathetic agonists in anaesthetised diabetic rats

Chronic diabetes alters sympathetic modulation of the cardiovascular system. In the present work, we examined if the cardiovascular system also demonstrates an impaired responsiveness to sympathetic control. The effects of streptozotocin-induced diabetes on pressure responses to noradrenaline or isoproterenol infusion of diabetic rats in vivo are studied. Systolic and diastolic pressures were recorded through a cannula implanted in the right carotid artery. Increasing doses of noradrenaline or isoproterenol were infused through a catheter implanted in the left jugular vein. The dose-response curves for the effects of noradrenaline on blood pressure were altered in streptozotozin-induced diabetic rats. Noradrenaline induced a statistically significant higher increase of both systolic and diastolic pressure in control than in diabetic rats. The maximum depressor response of systolic pressure to isoproterenol was lower in diabetic than in control animals. Diabetes fully abolishes the effect of beta-adrenoceptor stimulation on diastolic blood pressure. The present results demonstrate that streptozotocin-induced diabetes reduces systolic and diastolic arterial pressure, and diminishes the arterial pressure reactivity to sympathetic stimulation.     

迷走神经兴奋性对HRV的影响及其机制的初步分析

实验在氯醛糖加氨基甲酸乙酯麻醉的新西兰兔上进行。记录血压,心率,心电图和心率变异性频谱分析。电刺激减压神经,疑核和右侧迷走神经外周端,均引起心率和血压下降,总变异性,低频成分,高频成分,ＬＦ／ＨＦ比值和极代频成分增大。静脉注射阿托品可使上述反应显著减小,而静脉注射心得安仅可阻断ＤＮ和ＮＡ所致ＬＦ的增大。     

Exercise pressor reflex in decerebrate and anesthetized rats

I investigated whether muscular contraction evokes cardiorespiratory increases (exercise pressor reflex) in alpha-chloralose- and chloral hydrate-anesthetized and precollicular, midcollicular, and postcollicular decerebrated rats. Mean arterial pressure (MAP), heart rate (HR), and minute ventilation (Ve) were recorded before and during 1-min sciatic nerve stimulation, which induced static contraction of the triceps surae muscles, and during 1-min stretch of the calcaneal tendon, which selectively stimulated mechanosensitive receptors in the muscles. Anesthetized rats showed various patterns of MAP response to both stimuli, i.e., biphasic, depressor, pressor, and no response. Sciatic nerve stimulation to muscle in precollicular decerebrated rats always evoked spontaneous running, so the exercise pressor reflex was not determined from these preparations. None of the postcollicular decerebrated rats showed a MAP response or spontaneous running. Midcollicular decerebrated rats consistently showed biphasic blood pressure response to both stimulations. The increases in MAP, HR, and Ve were related to the tension developed. The static contractions in midcollicular decerebrated rats (381 +/- 65 g developed tension) significantly increased MAP, HR, and Ve from 103 +/- 12 to 119 +/- 24 mmHg, from 386 +/- 30 to 406 +/- 83 beats/min, and from 122 +/- 7 to 133 +/- 25 ml/min, respectively. After paralysis, sciatic nerve stimulation had no effect on MAP, HR, or Ve. These results indicate that the midcollicular decerebrated rat can be a model for the study of the exercise pressor reflex.