Baroreceptor Reflex Activation Research Articles

Reduced responses to glutamate receptor agonists follow loss of astrocytes and astroglial glutamate markers in the nucleus tractus solitarii.

Saporin (SAP) or SAP conjugates injected into the nucleus tractus solitarii (NTS) of rats kill astrocytes. When injected in its unconjugated form, SAP produces no demonstrable loss of or damage to local neurons. However bilateral injections of SAP significantly attenuate responses to activation of baroreceptor reflexes that are mediated by transmission of signals through glutamate receptors in the NTS. We tested the hypothesis that SAP would reduce cardiovascular responses to activation of NTS glutamate receptors despite its recognized ability to spare local neurons while killing local astrocytes. In animals treated with SAP and SAP conjugates or, as a control, with the toxin 6‐hydroxydopamine (6‐OHDA), we sought to determine if dose‐related changes of arterial pressure (AP) or heart rate (HR) in response to injection into NTS of N‐methyl‐d‐aspartate (NMDA) or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) were attenuated. Also we quantified changes in immunoreactivity (IR) for EAAT2, EAAC1, and VGluT2 in NTS after SAP and SAP conjugates. Our earlier studies showed that IR for NMDA and AMPA receptors was not changed after injection of SAP. We found that EAAT2 and EAAC1, both found in astrocytes, were reduced by SAP or its conjugates but not by 6‐OHDA. In contrast, VGluT2‐IR was increased by SAP or conjugates but not by 6‐OHDA. AP and HR responses to NMDA and AMPA were attenuated after SAP and SAP conjugate injection but not after 6‐OHDA. Results of this study are consistent with others that have shown interactions between astroglia and neurons in synaptic transmission mediated by glutamate receptor activation in the NTS.

Cardiovascular afferents cause the release of 5-HT in the nucleus tractus solitarii; this release is regulated by the low- (PMAT) not the high-affinity transporter (SERT).

The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5-HT has also been shown to play a role in their actions. Using fast-cyclic voltammetry, an increase in 5-HT concentrations (range 12-50 nm) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo- and baroreceptor reflexes. This 5-HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg(-1) ). However, decynium-22 (600 μg kg(-1) ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5-HT signal by 111 ± 21% from 29 ± 10 nm. The effectiveness of these inhibitors was tested against the removal time of 5-HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium-22 attenuated the removal of 5-HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg(-1) ) had no effect. Blockade of glutamate receptors with topical kynurenate (10-50 nm) reduced the vagally evoked 5-HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5-HT release is under the regulation of the high-capacity, low-affinity transporter PMAT, not the low-capacity, high-affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5-HT transmission and this could indicate that 5-HT is acting, in part, as a volume transmitter within the NTS.

Plasma leptin inhibits the response of nucleus of the solitary tract neurons to aortic baroreceptor stimulation

Leptin receptors have been identified within the nucleus of the solitary tract (NTS) and leptin injections into the caudal NTS inhibit the baroreceptor reflex. However, whether plasma leptin alters the discharge of NTS neurons mediating aortic baroreceptor reflex activity is not known. A series of electrophysiological single unit recording experiments was done in the urethane-chloralose anesthetized, paralyzed and artificially ventilated Wistar and Zucker obese rat with either their neuroaxis intact or with mid-collicular transections. Single units in NTS antidromically activated by electrical stimulation of depressor sites in the caudal ventrolateral medulla (CVLM) were found to display a cardiac cycle-related rhythmicity. These units were tested for their responses to stimulation of the aortic depressor nerve (ADN) and intra-carotid injections of leptin (50-200ng/0.1ml). Of 63 single units tested in NTS, 33 were antidromically activated by stimulation of CVLM depressor sites and 18 of these single units responded with a decrease in discharge rate after intracarotid injections of leptin. Thirteen of these leptin responsive neurons (∼72%) were excited by ADN stimulation. Furthermore, the excitatory response of these single units to ADN stimulation was attenuated by about 50% after the intracarotid leptin injection. Intracarotid injections of leptin (200ng/0.1ml) in the Zucker obese rat did not alter the discharge rate of NTS-CVLM projecting neurons. These data suggest that leptin exerts a modulatory effect on brainstem neuronal circuits that control cardiovascular responses elicited during the reflex activation of arterial baroreceptors.

The effect of heart rate on the heart rate variability response to autonomic interventions

Heart rate variability (HRV), the beat-to-beat variation in either heart rate (HR) or heart period (R-R interval), has become a popular clinical and investigational tool to quantify cardiac autonomic regulation. However, it is not widely appreciated that, due to the inverse curvilinear relationship between HR and R-R interval, HR per se can profoundly influence HRV. It is, therefore, critical to correct HRV for the prevailing HR particularly, as HR changes in response to autonomic neural activation or inhibition. The present study evaluated the effects of HR on the HRV response to autonomic interventions that either increased (submaximal exercise, n = 25 or baroreceptor reflex activation, n = 20) or reduced (pharmacological blockade: β-adrenergic receptor, muscarinic receptor antagonists alone and in combination, n = 25, or bilateral cervical vagotomy, n = 9) autonomic neural activity in a canine model. Both total (RR interval standard deviation, RRSD) and the high frequency (HF) variability (HF, 0.24–1.04 Hz) were determined before and in response to an autonomic intervention. All interventions that reduced or abolished cardiac parasympathetic regulation provoked large reductions in HRV even after HR correction [division by mean RRsec or (mean RRsec)2 for RRSD and HF, respectively] while interventions that reduced HR yielded mixed results. β-adrenergic receptor blockade reduced HRV (RRSD but not HF) while both RRSD and HF increased in response to increases in arterial blood (baroreceptor reflex activation) even after HR correction. These data suggest that the physiological basis for HRV is revealed after correction for prevailing HR and, further, that cardiac parasympathetic activity is responsible for a major portion of the HRV in the dog.

Is Antiarrhythmic Treatment in the Elderly Different?

Aging is associated with electrical and structural changes of the myocardium. The response to catecholamines is also reduced and the baroreceptor reflex activity is blunted. These aspects conceivably affect the response to antiarrhythmic drugs in the elderly. Furthermore, physiological parameters change in older age, affecting the pharmacokinetics of drugs. In this article, the literature on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs in elderly subjects is reviewed with the purpose of improving their optimal and safe prescription. Pharmacokinetic studies of antiarrhythmic drugs in the elderly are sparse, and there are no data available for procainamide and propafenone. Mean dose reductions calculated for elderly patients relative to younger patients are 60% for digoxin, 19% for diltiazem, 32% for disopyramide, 31% for flecainide, 40% for metoprolol, 35% for quinidine, 29% for sotalol and 26% for verapamil. No dose reductions are required for dofetilide or dronedarone. The clearance of dofetilide is not affected by age after correction for renal function. The dosage of dofetilide is individualized according to an algorithm based on the corrected QT (QTc) interval and renal function. Although the area under the plasma concentration-time curve (AUC) for dronedarone is larger in elderly patients, the dose should not be reduced because the registered dose has specifically been studied in an elderly population. In elderly patients with renal insufficiency, hepatic impairment, heart failure or certain genetic variants, the pharmacokinetics of antiarrhythmic drugs might be affected to an even greater extent, meaning additional dosage adjustments are necessary. With increasing age, the number of prescribed drugs increases because of co-morbidity, making interactions between drugs more likely. Several drugs interact with antiarrhythmic drugs, leading to clinically relevant changes in drug concentrations or AUC values. Furthermore, several drugs with non-cardiovascular indications appear to have QTc prolonging effects. The combination of these drugs with antiarrhythmic drugs that affect the QTc interval increases the risk of developing torsades de pointes and should therefore be avoided. Altered effects of drugs in the elderly can also be the result of age-related changes in the cardiovascular system. For example, atenolol and sotalol show greater effects, i.e. reductions in heart rate and increased probability of adverse effects, at a given plasma concentration in older subjects compared with younger subjects. It remains unclear whether old age as such is a determinant for reduced or modified efficacy of antiarrhythmic drugs. In a randomized study it was found that patients aged ≥65 years with atrial fibrillation had better survival with rate control than with rhythm control. However, different treatment strategies were compared and the results cannot be extrapolated to indicate better survival with a specific antiarrhythmic drug. Antiarrhythmic drugs will remain the first-line approach in most patients for the prevention or suppression of atrial and ventricular arrhythmias. As a rule of thumb, a 50% reduction in the starting dose of antiarrhythmic drugs compared with younger patients appears a wise approach in elderly patients. However, this does not apply to dofetilide and dronedarone. The selection of antiarrhythmic drugs in the elderly is predominantly determined by factors such as the treatment target, assumed patient compliance, possible drug interactions, co-morbidity, and renal and liver function. Efficacy and safety monitoring should take into account symptoms, ECG findings, rhythm recordings, plasma drug concentrations and other laboratory parameters.

Tonic and reflex control of the cardio-respiratory system by neurons in the ventral medulla

To investigate the channels and neurotransmitters in the ventrolateral medulla (VLM) oblongata that are responsible for the maintenance of sympathetic tone and cardio-respiratory reflex regulation. Microinjections of excitant amino acid (glutamate, 100 nl, 100 mM), calcium channel blockers, agonists and antagonists were made throughout the VLM in anaesthetized rats. Arterial blood pressure, sympathetic nerve activity and phrenic nerve discharge was recorded. Responses to activation of the baroreceptor, somatosympathetic, and chemoreceptor reflexes were recorded. Injection sites were marked with albumin-colloidal gold or methylene blue. At the end of recording, brains were removed, fixed, sectioned and stained for gold spots, and counterstained to localize injection sites. Bilateral microinjection of calcium channel antagonists into the rostral VLM (RVLM) had little effect on arterial blood pressure with the exception of Ni++ (an agent that blocks low voltage T-type calcium channels). Ni++ caused a profound fall in arterial blood pressure and sympathetic nerve activity, but did not affect reflex function. By contrast the high voltage channel (P, Q, L, N) blockers increased blood pressure and sympathetic activity following injection into the caudal VLM (CVLM). The agents applied were 8-OHDPAT; 5HT1a agonist, DAMGO; mu opioid agonist, DPDPE; delta opioid agonist and sar9-substance P; substance P agonist. In addition, the effect of changing the inhaled concentration of carbon dioxide was tested. In all cases except injection DAMGO, there was an attenuation of the somato-sympathetic reflex. DAMGO attenuated the baroreceptor reflex. None of these agents affected the chemoreceptor reflex. The data suggest that tonic maintenance of sympathetic activity is mediated, at least in part, by a Ni++ sensitive conductance in RVLM and that the neurochemical heterogeneity found within the inputs to sympathoexcitatory and inhibitory neurons in the RVLM has functional significance, with different neurotransmitters affecting cardiorespiratory reflexes differentially. Further functional studies are required to determine the precise connectivity between different neuronal populations that are subserving different functions in the RVLM.

Cannabinoid Receptor Activation in the Nucleus Tractus Solitaries Produces Baroreflex-Like Responses in the Rat

The effects of cannabinoids on the baroreflex have been investigated in the nucleus tractus solitarii (NTS). In urethane-anesthetized rats, microinjection of the cannabinoid (CB) receptor agonist WIN 55212-2 (100 mM) into the NTS produced a short lasting decrease in arterial pressure (from 95.2 ± 2.9 to 76.2 ± 1.5, n=5, P<0.05) but no change in the heart rate. Another cannabinoid agonist, CP 55940 (100 mM) also caused hypotensive responses (from 90.2 ± 11.3 to 66.4 ± 12.3 mmHg, n=5, P<0.05). Simultaneous sympathetic nerve discharge recordings showed suppression prior to the arterial pressure lowering effect of these agonists. Microinjection of the cannabinoid receptor antagonist, AM 281 (70 mM) did not cause any significant change in arterial pressure (from 100.8 ± 12 mmHg to 108.1 ± 12.8 mmHg, n=5, P>0.05) though it inhibited the agonist-induced responses. The non-NMDA receptor antagonist, DNQX (4 mM) microinjections antagonized the actions of CB agonist WIN 55212-2. Furthermore, sinoaortic denervation attenuated the responses to CB agonists suggesting an intact baroreflex arc is necessary to elicit CB-mediated effects. Neither WIN 55212-2 nor AM 281, altered baroreceptor reflex activation by bolus phenylephrine (25 microg/kg) injections. These data suggest that cannabinoid receptors in the NTS are not involved in the tonic regulation of the arterial pressure but may have a modulatory role in the baroreceptor reflex integration.

Comparative cardiovascular and pulmonary effects of sedatives and anesthetic agents and anesthetic drug selection for the trauma patient

AbstractObjective: To integrate and compare the effects of tranquilizer/sedatives and anesthetic drugs on various parameters of cardiovascular function in normal dogs and in dogs stressed by hypovolemia, anemia, and endotoxemia, and to discuss the relative merits and appropriate precautions of anesthetic drugs with respect to specific patient physiologic complications.Data sources: Personal data and experiences in conjunction with veterinary and human clinical and research studies.Human and veterinary data synthesis: Drugs that produce calming, sedation, muscle relaxation, analgesia, and loss of consciousness have the potential to produce marked cardiorespiratory effects particularly in hemorrhaged, hypovolemic‐traumatized animals. Acute but key cardiovascular components that are affected by sedative and anesthetic drugs include heart rate and rhythm, venous return (preload), systemic vascular resistance (afterload), and myocardial contractile (inotropic) and relaxation (lusitropic) properties. In addition, all sedative and anesthetic drugs alter or depress normal baroreceptor reflex activity, thereby inhibiting or eliminating the animal's normal physiologic response to decreases in arterial blood pressure and predisposing to tissue hypoperfusion, decreased oxygen delivery, and oxygenation. Oxygen delivery needs to be adequate to meet the metabolic (oxygen) requirements of the patient. Decreases in oxygen delivery to tissues increases oxygen extraction, thereby maintaining tissue oxygenation (supply‐independent oxygen consumption phase) until compensatory processes reach their limit and any further decrease in oxygen delivery causes a decrease in oxygen consumption (supply‐dependent oxygen consumption phase). The critical oxygen delivery that defines the transition between these 2 phases is generally higher in the anesthetized state than in the awake state. The effect of anesthetics on critical oxygen delivery at comparable anesthetic dosages is pentobarbital=ketamine>alfentanil>etomidate=propofol>inhalational anesthetics. Anesthetics generally decrease oxygen consumption from the awake, baseline state; exceptions are ketamine and ether. Ketamine, however, increases oxygen delivery and oxygen extraction.Conclusions: The transition from the awake to the anesthetized state is a huge imposition on the physiology of animals and, therefore, should be accomplished with great care and proper vigilance. Rapid, ‘crash’ induction of anesthesia should be avoided in hypotension‐prone animals and slow, prolonged induction should be avoided in animals with respiratory disorders. It is not recommended to implement an unfamiliar protocol in critical patients, even if it might be pharmacologically preferable. Familiarity with an anesthetic drug is a very important reason for its selection.

Maturation of the autonomic nervous system: differences in heart rate variability in premature vs. term infants

Aims Heart rate variability (HRV) reveals information on the functional state of the autonomic nervous system (ANS). This study was initiated to assess the physiological- and maturational development of the ANS by comparing HRV data of healthy prematures with term infants. Methods Short-term recordings of HRV in 39 premature healthy infants (29-35 weeks' gestation) were performed and compared with normative data of term infants. Frequency domain HRV parameters are computed in three frequency bands. Results Gestational age of newborn infants is correlated with HRV. Prematures showed significant lower HRV parameters than term infants. The most significant differences were discerned for HRV parameters reflecting parasympathetic activity, whereas the pulse of the baro-receptor reflex was similar for prematures and term infants at 0.07 Hz (0.1 Hz adults). A respiratory peak in the HF-band according to respiratory sinus arrhythmia (RSA), as is common in adults, was not detected for prematures as it is not detected in term infants. Conclusions Maturation of the ANS is accompanied by increasing HRV with a pronounced increase of parasympathetic activity. These changes are measurable by short-term recordings. The physiological pulses concerning baroreceptor reflex activity and respiratory modulation were similar in prematures and term infants.

The Hypo-Osmolality of Pregnancy Does Not Alter Baroreceptor Responses to Acute Changes in Osmolality

Reducing extracellular osmolality by 10-12 mOsm/L reduces baroreceptor firing in vitro in tissues from male rats. Pregnancy is associated with a similar reduction in plasma osmolality (pOsm) as well as with alterations in baroreceptor firing and reduced baroreceptor reflex activity. Mechanisms for reduced baroreflex activity are not yet understood, but they have important implications for maintenance of cardiovascular homeostasis in the pregnant female. Thus, this study was designed to test whether changes in plasma osmolality alter baroreceptor discharge during pregnancy. Late-gestation pregnant and virgin control rats were anesthetized, femoral vessels were cannulated for measurement of arterial pressure and drug infusion, and the aortic depressor nerve, containing baroreceptor afferents, was isolated and prepared for recording. Plasma osmolality was measured before and 30 min after graded intraperitoneal injections of NaCl (50-1500 mOsm/L). Arterial pressure, heart rate, and aortic depressor nerve activity (ADNA) were measured continuously before and after injections. A 50 mOsm/L NaCl injection significantly decreased pOsm but did not alter ADNA in either group. Likewise, 1200 mOsm/L NaCl injections significantly increased pOsm and had no effect on ADNA in either group. The 1500 mOsm salt load significantly increased pOsm and ADNA in pregnant rats, and in virgin animals, it increased pOsm but evoked a paradoxical decrease in ADNA. The authors' studies indicate that pOsm has minimal effects on baroreceptor activity, which are not significantly different during gestation. Their findings suggest that in vitro data from male rats indicating a correlation between pOsm and baroreceptor discharge are not applicable in anesthetized intact female animals.

Baroreceptor reflex sensitivity in human neonates: the effect of postmenstrual age

We performed a cross-sectional study in human infants to determine if indices of R-R interval variability, systolic blood pressure (SBP) variability, and baroreceptor reflex sensitivity change with postmenstrual age (PMA: gestational age+postnatal age). The electrocardiogram, arterial SBP and respiration were recorded in clinically stable infants (PMA, 28-42 weeks) in the quiet sleep state in the first days after birth. (Cross-)spectral analyses of R-R interval series and SBP series were performed to calculate the power of low-frequency (LF, indicating baroreceptor reflex activity, 0.04-0.15 Hz) and high-frequency (HF, indicating parasympathetic activity, individualized between the p-10 and p-90 values of respiratory frequency) fluctuations, and transfer function phase and gain. The mean R-R interval, and LF and HF spectral powers of R-R interval series increased with PMA. The mean SBP increased with PMA, but not the LF and HF spectral powers of SBP series. In the LF range, cross-spectral analysis showed high coherence values (>0.5) with a consistent negative phase shift between R-R interval and SBP, indicating a approximately 3 s lag in R-R interval changes in relation to SBP. Baroreceptor reflex sensitivity, calculated from LF transfer gain, increased significantly with PMA, from 5 (preterm) to 15 ms mmHg-1 (term). Baroreceptor reflex sensitivity correlated significantly with the (LF and) HF spectral powers of R-R interval series, but not with the LF and HF spectral powers of SBP series. The principal conclusions are that baroreceptor reflex sensitivity and spectral power in R-R interval series increase in parallel with PMA, suggesting a progressive vagal maturation with PMA.

Kainic acid seizure-evoked parasympathetic and sympathetic nerve activity and altered baroreceptor reflex responses in urethane-anesthesized rats

Kainic acid (KA) can cause limbic cortical seizure activity that generalizes to produce severe convulsions. Limbic seizures can spread to subcortical structures, producing severe autonomic consequences. We recorded from the vagus nerves in the neck region, renal sympathetic nerves, splanchnic nerves, and cervical sympathetic ganglia. In each animal, two or three nerves were recorded simultaneously. A femoral arterial catheter was used for blood pressure monitoring. Limb electrodes were used for electrocardiogram (ECG), and electroencephalogram (EEG) was recorded from the dorsal or ventral hippocampus. Vagus nerves were cut bilaterally (distally) to prevent fatal arrhythmias. KA (10 mg/kg, i.a.) was given to rats anesthesized with urethane or ketamine/xylazine. Baroreceptor reflex activity was assessed by recording nerve and ECG responses to nitroprusside (0.1 mg, i.a.) or phenylephrine (0.25 mg, i.a.). Modest sustained increases in vagus and sympathetic nerve activity were seen after KA when seizure activity was seen ventral hippocampus. A transient blood pressure decrease occurred in rats anesthesized with urethane but not ketamine/xylazine. After KA, neither sympathetic nor parasympathetic nerve activity changed in response to nitroprusside or phenylephrine challenges. EEG seizure discharges in dorsal hippocampus were associated with substantial additional sustained increases in firing, plus evidence of phasic seizure-related activity, in the vagus and sympathetic nerves. We conclude that KA alters sympathetic and parasympathetic neural activity by acting initially at ventral hippocampal regions. Limbic seizure discharges increase activity in both divisions of the autonomic nervous system, profoundly disrupting blood pressure regulation and heart rhythms.

Impairment of cardiovascular autonomic control in patients early after cardiac surgery.

Impairment of the baroreceptor reflex activity reflects an alteration of the autonomous regulation of the cardiovascular system and has proven to predict fatal outcome in patients after acute myocardial infarction. The following study was performed to analyse the baroreceptor sensitivity, heart rate variability and blood pressure variability in patients early after coronary surgery. Twenty-five male patients undergoing coronary artery bypass were examined in a prospective study; normal values were obtained from healthy volunteers. Arterial pressure signals were recorded from a radial artery catheter for 30 min preoperatively and in short intervals after surgery. Mechanical manipulations and pharmacological interventions were avoided during the sampling periods. Baroreflex function was calculated according to the dual sequence method, heart rate variability and blood pressure variability were calculated including nonlinear methods. Initial values of the patients did not differ from healthy volunteers. The strength of baroreflex sensitivity (increase in blood pressure causing a synchronous decrease of heart rate) is low 2 h postoperatively. The number of delayed tachycardic changes of heart rate, which are caused by sympathetic activation, is only moderately reduced as compared to values obtained from healthy volunteers. Heart rate variability is widely unchanged as compared to preoperative values; blood pressure variability showed an increase of low-frequency components, again indicating sympathetic predominance. Nonlinear analyses revealed reduced system complexity at the beginning of the postoperative course. Obviously, there is a vagal suppression 20 h after surgery, while the sympathetic tonus works in a normal range. This unbalanced interaction of the autonomous systems is similar to findings in patients after myocardial infarction. The predictive value of these markers has to be elucidated in further clinical studies.

Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation.

The sequence of neural responses to exogenous arterial pressure manipulation remains unclear, especially for extramedullary sites. We used functional magnetic resonance imaging procedures to visualize neural responses during pressor (phenylephrine) and depressor (sodium nitroprusside) challenges in seven isoflurane-anesthetized adult cats. Depressor challenges produced signal-intensity declines in multiple cardiovascular-related sites in the medulla, including the nucleus tractus solitarius, and caudal and rostral ventrolateral medulla. Signal decreases also emerged in the cerebellar vermis, inferior olive, dorsolateral pons, and right insula. Rostral sites, such as the amygdala and hypothalamus, increased signal intensity as arterial pressure declined. In contrast, arterial pressure elevation elicited smaller signal increases in medullary regions, the dorsolateral pons, and the right insula and signal declines in regions of the hypothalamus, with no change in deep cerebellar areas. Responses to both pressor and depressor challenges were typically lateralized. In a subset of animals, barodenervation resulted in rises and falls of blood pressure that were comparable to these resulting from the pharmacological challenges but different regional neural responses, indicating that the regional signal intensity responses did not derive from global perfusion effects but from baroreceptor mediation of central mechanisms. The findings demonstrate widespread lateralized distribution of neural sites responsive to blood pressure manipulation. The distribution and time course of neural responses follow patterns associated with early and late compensatory reactions.

Evidence for glutamatergic mechanisms in the vagal sensory pathway initiating cardiorespiratory reflexes in the shorthorn sculpin Myoxocephalus scorpius.

Glutamate is a major neurotransmitter of chemoreceptor and baroreceptor afferent pathways in mammals and therefore plays a central role in the development of cardiorespiratory reflexes. In fish, the gills are the major sites of these receptors, and, consequently, the terminal field (sensory area) of their afferents (glossopharyngus and vagus) in the medulla must be an important site for the integration of chemoreceptor and baroreceptor signals. This investigation explored whether fish have glutamatergic mechanisms in the vagal sensory area (Xs) that could be involved in the generation of cardiorespiratory reflexes. The locations of the vagal sensory and motor (Xm) areas in the medulla were established by the orthograde and retrograde axonal transport of the neural tract tracer Fast Blue following its injection into the ganglion nodosum. Glutamate was then microinjected into identified sites within the Xs in an attempt to mimic chemoreceptor- and baroreceptor-induced reflexes commonly observed in fish. By necessity, the brain injections were performed on anaesthetised animals that were fixed by 'eye bars' in a recirculating water system. Blood pressure and heart rate were measured using an arterial cannula positioned in the afferent branchial artery of the 3rd gill arch, and ventilation was measured by impedance probes sutured onto the operculum. Unilateral injection of glutamate (40-100 nl, 10 mmol l(-1)) into the Xs caused marked cardiorespiratory changes. Injection (0.1-0.3 mm deep) in different rostrocaudal, medial-lateral positions induced a bradycardia, either increased or decreased blood pressure, ventilation frequency and amplitude and, sometimes, an initial apnea. Often these responses occurred simultaneously in various different combinations but, occasionally, they appeared singly, suggesting specific projections into the Xs for each cardiorespiratory variable and local determination of the modality of the response. Response patterns related to chemoreceptor reflex activation were predominantly located rostral of obex, whereas patterns related to baroreceptor reflex activation were more caudal, around obex. The glutamate-induced bradycardia was N-methyl-D-aspartate (NMDA) receptor dependent and atropine sensitive. Taken together, our data provide evidence that glutamate is a putative player in the central integration of chemoreceptor and baroreceptor information in fish.

Antinociceptive effect of cardiopulmonary chemoreceptor and baroreceptor reflex activation in the rat

The effect on the nociceptive tail-flick (TF) reflex of cardiopulmonary chemoreceptor and arterial baroreceptor activation, producing Bezold–Jarisch like- and baro-reflex responses, respectively, was analysed in lightly halothane-anaesthetized rats. Intra-cardiac administration of phenylbiguanide (5–100 μg/kg, into the right atrium) or veratrine (30–150 μg/kg, into the left ventricle), which both elicited the characteristic Bezold–Jarisch-like cardiovascular reflex responses (hypotension and bradycardia), produced a dose-dependent increase in TF latency. A similar inhibitory influence on the TF reflex was noted upon baroreflex activation by acute administration of phenylephrine (15–50 μg/kg i.v.) or aortic depressor nerve stimulation (100–400 μA). As expected from the involvement of local excitatory amino acid receptors in both vagally mediated cardiovascular reflex responses and inhibition of the TF reflex, microinjections of kynurenic acid (3 nmol/0.1 μl), an N-methyl- d-aspartate (NMDA) and non-NMDA receptor antagonist, into the nucleus tractus solitarius, prevented the cardiovascular responses as well as the concomitant increase in TF latency produced by cardiopulmonary chemoreceptor and baroreceptor stimulations. The present data show that induction of the cardiopulmonary chemoreceptor and baroreceptor reflexes produces an antinociceptive effect which can be assessed using the TF test, and that glutamate ionotropic receptors within the nucleus tractus solitarius mediate this effect.

Vasoregulatory function of the heme-heme oxygenase-carbon monoxide system

Arterial vessels express one or more heme oxygenase (HO) isoenzymes that catalyze the metabolism of heme to carbon monoxide (CO) and biliverdin. Carbon monoxide promotes vasorelaxation through mechanisms that, depending on the vessels, involve activation of soluble guanylate cyclase, stimulation of calcium-activated potassium channels, or diminished synthesis of constrictor mediators, such as, endothelin and 20-HETE. Inhibitors of HO elicit vasoconstriction in vivo and in isolated pressurized arterioles. Inhibitors of HO also enhance myogenic vasoconstriction, as well as the constriction induced by phenylephrine in several vessels. The blood pressure of awake rats is increased by acute treatment with HO inhibitors, a response that is accompanied by attenuation of baroreflex activity. All in all, it would appear that a product of HO activity manufactured by arterial vessels, presumably CO, promotes vasodilation and decreases the reactivity of vascular smooth muscle to myogenic stimuli and constrictor agonists. In doing so, CO of vascular origin may contribute to the implementation of antihypertensive mechanisms. Carbon monoxide produced in central nervous system structures, for example, the nucleus tractus solitarii, also appears to support a blood pressure-lowering mechanism linked to inhibitory modulation of baroreceptor reflex activity.

Differential regulation of sympathetic outflows to vasoconstrictor and thermoregulatory effectors.

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 differential characteristics and baroreceptor reflex sensitivities between the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis and cardiovascular SNA such as that controlling mesenteric vasoconstriction via the splanchnic (SPL) nerve. The tonic discharge of 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 SPL SNA exhibited sustained, large-amplitude bursts. Disinhibition of neurons in the rostral raphe pallidus (RPa), a potential site of sympathetic premotor neurons controlling BAT SNA, or icv injection of prostaglandin E2, a pyrogenic stimulus, elicited a dramatic increase in BAT SNA. SPL SNA was strongly influenced by the baroreceptor reflex as indicated by a high coherence to the arterial pressure, while activated BAT SNA exhibited no correlation with the arterial pressure. Since these characteristics and reflex responses in sympathetic outflow have been shown to arise from the ongoing or altered discharge of sympathetic premotor neurons, the marked differences between SPL SNA 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 strongly baroreceptor-modulated and the latter potentially in the RPa exhibiting little influence of baroreceptor reflex activation.

Different adrenal sympathetic preganglionic neurons regulate epinephrine and norepinephrine secretion.

Brain stimulation or activation of certain reflexes can result in differential activation of the two populations of adrenal medullary chromaffin cells: those secreting either epinephrine or norepinephrine, suggesting that they are controlled by different central sympathetic networks. In urethan-chloralose-anesthetized rats, we found that antidromically identified adrenal sympathetic preganglionic neurons (SPNs) were excited by stimulation of the rostral ventrolateral medulla (RVLM) with either a short (mean: 29 ms) or a long (mean: 129 ms) latency. The latter group of adrenal SPNs were remarkably insensitive to baroreceptor reflex activation but strongly activated by the glucopenic agent 2-deoxyglucose (2-DG), indicating their role in regulation of adrenal epinephrine release. In contrast, adrenal SPNs activated by RVLM stimulation at a short latency were completely inhibited by increases in arterial pressure or stimulation of the aortic depressor nerve, were unaffected by 2-DG administration, and are presumed to govern the discharge of adrenal norepinephrine-secreting chromaffin cells. These findings of a functionally distinct preganglionic innervation of epinephrine- and norepinephrine-releasing adrenal chromaffin cells provide a foundation for identifying the different sympathetic networks underlying the differential regulation of epinephrine and norepinephrine secretion from the adrenal medulla in response to physiological challenges and experimental stimuli.

Peculiarities of heart rate reaction to passive head-up tilt and carotid baroreceptor reflex activation in patients with essential hypertension

Peculiarities of heart rate reaction to passive head-up tilt and carotid baroreceptor reflex activation in patients with essential hypertension