Baroreceptor Afferent Activity Research Articles

Aortic baroreceptor afferent activity during systemic inflammation

Objective: Neuroimmune interactions have been extensively explored to find new therapeutic targets for inflammatory diseases. We postulated that baroreceptors (essential for arterial pressure control) might be susceptible to systemic inflammation. Thus, the present study investigated the effect of early-stage systemic inflammation on aortic baroreceptor afferent activity. Hypothesis: Aortic depressor nerve activity is increased during systemic inflammation. Methods: Anesthetized (urethane; 1 g/kg; i.p.) male Sprague-Dawley rats (7-8 weeks old) were used, and lipopolysaccharide (LPS; 1.5 mg/kg; i.v.) injected to induce systemic inflammation. The femoral artery and vein were cannulated for pulsatile arterial pressure recording and LPS administration, respectively. Following 30 min since injections of either saline (control; n = 10) or LPS (n = 16), pulsatile arterial pressure and aortic depressor nerve activity were recorded. Nerve activity recordings were rectified and integrated on a time basis. Body temperature was measured via rectal thermometer. The results are presented as mean ± standard error of the mean. Results: Compared to saline-treated rats, there was an increase in aortic depressor nerve activity (LPS: 1.04 ± 0.02 vs saline: 0.98 ± 0.01 a.u.; p = 0.007); this was accompanied by increases in diastolic arterial pressure (LPS: 83 ± 2 vs saline: 73 ± 4 mmHg; p = 0.031), mean arterial pressure (LPS: 102 ± 3 vs saline: 91 ± 4 mmHg; p = 0.035) but not systolic pressure (LPS: 140 ± 6 vs saline: 122 ± 6 mmHg; p = 0.057; strong trend) or heart rate (LPS: 425 ± 11 bpm vs saline: 393 ± 14; p = 0.085). Importantly, in the LPS-injected rats, a reduction in body temperature was noted compared to saline-treated rats (LPS: 36.7 ± 0.1 vs saline: 37.2 ± 0.2°C; p = 0.005), an indicative of systemic inflammation. Conclusions: Since the diastolic and mean arterial pressures increased after LPS administration, it remains unclear whether the elevated aortic depressor nerve activity reflects this increased pressure or results from the inflammatory mediated sensitization. However, our preliminary data support the notion that aortic baroreceptor afferents participate in the neuroimmune communication response in the early stages of inflammation. Funding sources: FAPESP (protocols #2021/03764-8 and #2021/05554-0). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypothesis: Pulmonary Afferent Activity Patterns During Slow, Deep Breathing Contribute to the Neural Induction of Physiological Relaxation.

Control of respiration provides a powerful voluntary portal to entrain and modulate central autonomic networks. Slowing and deepening breathing as a relaxation technique has shown promise in a variety of cardiorespiratory and stress-related disorders, but few studies have investigated the physiological mechanisms conferring its benefits. Recent evidence suggests that breathing at a frequency near 0.1 Hz (6 breaths per minute) promotes behavioral relaxation and baroreflex resonance effects that maximize heart rate variability. Breathing around this frequency appears to elicit resonant and coherent features in neuro-mechanical interactions that optimize physiological function. Here we explore the neurophysiology of slow, deep breathing and propose that coincident features of respiratory and baroreceptor afferent activity cycling at 0.1 Hz entrain central autonomic networks. An important role is assigned to the preferential recruitment of slowly-adapting pulmonary afferents (SARs) during prolonged inhalations. These afferents project to discrete areas in the brainstem within the nucleus of the solitary tract (NTS) and initiate inhibitory actions on downstream targets. Conversely, deep exhalations terminate SAR activity and activate arterial baroreceptors via increases in blood pressure to stimulate, through NTS projections, parasympathetic outflow to the heart. Reciprocal SAR and baroreceptor afferent-evoked actions combine to enhance sympathetic activity during inhalation and parasympathetic activity during exhalation, respectively. This leads to pronounced heart rate variability in phase with the respiratory cycle (respiratory sinus arrhythmia) and improved ventilation-perfusion matching. NTS relay neurons project extensively to areas of the central autonomic network to encode important features of the breathing pattern that may modulate anxiety, arousal, and attention. In our model, pronounced respiratory rhythms during slow, deep breathing also support expression of slow cortical rhythms to induce a functional state of alert relaxation, and, via nasal respiration-based actions on olfactory signaling, recruit hippocampal pathways to boost memory consolidation. Collectively, we assert that the neurophysiological processes recruited during slow, deep breathing enhance the cognitive and behavioral therapeutic outcomes obtained through various mind-body practices. Future studies are required to better understand the physio-behavioral processes involved, including in animal models that control for confounding factors such as expectancy biases.

Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg-1·min-1, n = 13) or PE (0.2-1.0 µg·kg-1·min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Relationship between cardioventilatory coupling and pulmonary gas exchange

Cardioventilatory coupling (CVC) is a temporal alignment between the heartbeat and inspiratory activity caused by pulsatile baroreceptor afferent activity. However, although first described over a century ago, the functional significance of CVC has yet to be established. One hypothesis is that baroreceptor triggering of inspiration positions heartbeats into phases of the respiratory cycle that may optimize pulmonary gas exchange efficiency. To test this hypothesis, we recruited ten patients with permanently implanted fixed-rate cardiac pacemakers and instructed them to pace breathe at heart rate-to-respiratory rate (HR/f) ratios of 3·8, 4·0 and 4·2. This breathing protocol enabled us to simulate heartbeat distributions similar to those seen in the presence (4·0) and complete absence (3·8, 4·2) of CVC. Results showed that heart rate, mean arterial pressure, end-tidal carbon dioxide and tidal volume remained unchanged across the three conditions (P> 0·05). Pulmonary gas exchange efficiency, as determined by the ventilatory equivalents of carbon dioxide (V·E/V·CO2) and oxygen (V·E/V·O2) did not differ significantly by HR/f ratio (P = 0·29 and P = 0·70, respectively). These data suggest that CVC does not play a significant role in optimizing pulmonary gas exchange efficiency in humans.

Modulation of baroreceptor afferent terminal excitability and reflex responses by phospholipase D‐coupled metabotropic glutamate receptors

We have demonstrated glutamate released from clear synaptic‐like vesicles (SLVs) modulates mechanoreceptor excitability in Ia primary afferent endings of rat muscle spindles acting on phospholipase D‐linked metabotropic glutamate receptors (PLD‐mGluRs; Bewick et al. 2005 J. Physiol 562, 381‐). We have tested whether the SLVs in baroreceptor endings (Krauhs, 1979 J. Neurocytol. 8:401‐) show a similar mechanism that modulates both afferent discharge and reflex‐evoked responses. Baroreceptors were stimulated by ramp increases in arterial pressure while either afferent discharge or reflex changes in heart rate and sympathetic nerve activity were measured after superfusion of the aortic arch with either the PLD‐mGluR antagonist PCCG‐13 (20μM) or glutamate (10mM) in situ. PCCG‐13 decreased baroreceptor afferent activity by 35% (P&lt;0.05) and glutamate increased discharge by 42% (P&lt;0.05) relative to control levels. Cardiac baroreceptor reflex gain was was attenuated reversibly by PCCG‐13 by 51% from 2.8+0.4 bpm/mmHg (P&lt;0.05). Baroreceptor reflex‐mediated sympathoinhibition was also depressed. Glutamate applied to the aortic arch mimicked a baroreflex response. These data indicate autogenic glutamate release from baroreceptor terminals regulate afferent discharge through PLD‐mGluRs to modulate reflex cardiac and sympathomotor responses. MRC funded research.

Rostral ventrolateral medullary (RVLM) but not medullary lateral tegmental field (LTF) neurons are in the pathway mediating sympathoexcitatory (SE) responses elicited by activation of cardiac and splanchnic sympathetic afferents

The LTF is involved in mediating sympathetic responses to activation of baroreceptor, arterial chemoreceptor, and vagal afferents but not trigeminal or sciatic afferents (Orer et al, Am J Physiol 286: R451‐64, 2004). In the current study, we tested the hypothesis that the LTF is an element of the sympatho‐sympathetic reflex pathway. We studied the effects of blockade of NMDA or non‐NMDA receptors bilaterally in the LTF on the area under the curve of the computer‐averaged SE potential in the right inferior cardiac nerve elicited by trains of stimuli applied at 0.5 Hz to afferents in left inferior cardiac and splanchnic nerves (lCN, lSN) of Dial‐urethane anesthetized cats. SE responses to lCN stimulation were unchanged by microinjection of either D‐AP5 (101±5% of control; n = 5) or NBQX (98±8% of control; n = 5). Responses to lSN stimulation were similarly unaffected: 92 ± 4 (n = 6) and 90 ± 5 (n = 4) % of control after D‐AP5 and NBQX. Thus, LTF is not a part of these reflex pathways. However, microinjection of NBQX into RVLM significantly (P ≤ 0.05) reduced SE responses to stimulation of lCN (37± 11% of control; n = 6) and lSN (35 ± 11 % of control; n = 5). D‐AP5 microinjection into RVLM did not significantly effect SE responses to stimulation of lCN or lSN (79 ± 13 and 72 ± 17 % of control; n = 5 each). These data show that activation of non‐NMDA receptors in RVLM contribute to SE responses to activation of sympathetic afferents. (Supported by HL33266)

S7.2 Altered autonomic control of cardiovascular function in obesity: Insights from obese Zucker rats

Human obesity is associated with the development of hypertension and exaggerated cardiovascular responses to stress. Underlying these attributes are elevated sympathetic nerve activity (SNA) and impaired baroreflexes. To begin to determine mechanisms underlying obesity-associated deficits in autonomic control we studied obese Zucker rats (OZR), which are hyperphagic due to a mutated leptin receptor. Compared to lean Zucker rats (LZR), which have functional leptin receptors, the OZR become obese shortly after weaning and develop autonomic deficits as they approach adulthood. Adult OZR have elevated arterial pressure (AP) and SNA compared to LZR. In addition, OZR have exaggerated sympatho-excitatory responses (somatic and diving reflexes) but blunted sympathetic baroreflexes compared to LZR. The following studies were performed in adult OZR and LZR (14–16 wks old) that were anesthetized with urethane (1.7 g/kg LZR weight, iv), ventilated, and paralyzed. Direct recordings of baroreceptor afferent nerve activity (aortic depressor nerve, ADN) showed that ADN responses to evoked changes in AP were comparable in OZR and LZR. In contrast, electrical stimulation of the ADN evoked blunted inhibitions of SNA and AP in OZR compared to LZR. This deficit appears to extend to other sympatho-inhibitory reflexes initiated by the vagus nerve, because stimulation of the vagal afferents (electrical or by iv injection of phenybiguanide, 1–16 µg) elicited smaller decreases in SNA in OZR compared to LZR. These data suggest that impaired baroreflexes in OZR are not due to the ability to sense changes in AP, but altered central mechanisms that regulate SNA.

Hydrogen Peroxide Mediates Post‐Excitatory Depression of Baroreceptor Afferent Activity in Vivo

Acute hypertension leads to 'post‐excitatory depression' (PED) of baroreceptor (BR) activity after the period of elevated blood pressure (BP), a phenomenon that contributes to BR resetting. The molecular mechanism of PED is not fully understood. We recently demonstrated that electrical stimulation of isolated BR neurons in vitro generates reactive oxygen species that cause PED of action potential firing after the period of neuronal activation (Hypertension 43(6):1349, 2004). In the present study, we tested the hypothesis that the reactive oxygen species hydrogen peroxide (H2O2) mediates BR PED in vivo. The left aortic depressor nerve (ADN) was draped over a recording/stimulating electrode and crushed centrally to prevent reflex changes in BP in anesthetized C57BL/6 mice. Afferent ADN (BR) activity was recorded before and after a brief period of ADN stimulation (3V, 2ms pulses at 20Hz for 10s). Afferent BR activity was markedly inhibited after the 10s period of electrical stimulation, averaging 50±5% and 80±8% of baseline levels 5 and 60s after the stimulation was terminated (n=7). This PED was abolished after administration of the membrane permeable H2O2 scavenger PEG‐catalase (4000 U, IV) with activity averaging 100±4 and 126±7% of baseline 5 and 60s after ADN stimulation (n=7). PED was unaffected by administration of the saline vehicle in a separate group of mice (n=6). We conclude that H2O2 generated during activation of BR afferents causes PED. This autocrine‐feedback inhibition of BR activity may contribute to rapid BR resetting in acute hypertension. (HL14388, VA)

Acute and chronic electrical activation of baroreceptor afferents in awake and anesthetized subjects

Electrical stimulation of baroreceptor afferents was used in the 1960's in several species, including human beings, for the treatment of refractory hypertension. This approach bypasses the site of baroreceptor mechanosensory transduction. Chronic electrical stimulation of arterial baroreceptors, particularly of the carotid sinus nerve (Hering's nerve), was proposed as an ultimate effort to treat refractory hypertension and angina pectoris due to the limited nature of pharmacological therapy available at that time. Nevertheless, this approach was abandoned in the early 1970's due to technical limitations of implantable devices and to the development of better-tolerated antihypertensive medications. More recently, our laboratory developed the technique of electrical stimulation of the aortic depressor nerve in conscious rats, enabling access to hemodynamic responses without the undesirable effect of anesthesia. In addition, electrical stimulation of the aortic depressor nerve allows assessment of the hemodynamic responses and the sympathovagal balance of the heart in hypertensive rats, which exhibit a well-known decrease in baroreflex sensitivity, usually attributed to baroreceptor ending dysfunction. Recently, there has been renewed interest in using electrical stimulation of the carotid sinus, but not the carotid sinus nerve, to lower blood pressure in conscious hypertensive dogs as well as in hypertensive patients. Notably, previous undesirable technical outcomes associated with electrical stimulation of the carotid sinus nerve observed in the 1960's and 1970's have been overcome. Furthermore, promising data have been recently reported from clinical trials that evaluated the efficacy of carotid sinus stimulation in hypertensive patients with drug resistant hypertension.

Baroreflex responsiveness during ventilatory acclimatization in humans

We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n=2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA (DeltaSNA)/change of diastolic blood pressure (DeltaDBP)], mechanical (Deltadiastolic diameter/DeltaDBP), and neural (DeltaSNA/Deltadiastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, -8.3+/-1.2; 1-h Hx, -7.2+/-1.0; 7-h Hx, -4.9+/-1.0; and post-Hx: -4.1+/-0.9 arbitrary integrated units (AIU) x min(-1) x mmHg(-1); P<0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, -2.70+/-0.53; 1-h Hx, -2.59+/-0.53; 7-h Hx, -1.60+/-0.34; and post-Hx, -1.34+/-0.27 AIU x min(-1) x microm(-1); P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.

Differential long‐term cardiovascular compensations to sustained activation of carotid baroreceptor afferents

Prolonged baroreflex activation (PBA) by electrical stimulation of the carotid sinuses produces sustained reductions in mean arterial pressure (MAP) and sympathetic activity. This technique bypasses mechanotransduction at the level of the baroreceptors producing controlled electrical activation of baroreceptor afferents. We used this technique to determine whether there are compensations that diminish the chronic blood pressure lowering effects of the baroreflex during activation with continuous trains of impulses. This was studied in 4 normotensive dogs using 24 hour recordings of MAP and heart rate (HR). Control values for MAP and HR were 93±4 mmHg and 54±2 bpm, respectively. Values for MAP after 1, 2 and 3 weeks of PBA were 64±1, 72±1, and 72±1 mmHg, respectively; the corresponding values for HR were 44±2, 44±1, and 44±1 bpm. Thus, during week 2, there was ~ a 30% reduction in the blood pressure lowering response to PBA, with no effect on PBA induced bradycardia. MAP did return to control levels after cessation of PBA, but only after a modest increase above control during the initial 7 days following discontinuation of PBA. These findings indicate that while PBA produces substantial sustained reductions in MAP, slowly developing central and/or peripheral mechanisms act differentially to partially restore MAP towards control levels without attenuating reflex‐induced decreases in HR. (HL‐51971).

Structural Remodeling of Baroreceptor Afferent Innervation of Aortic Arch in Transgenic Type 1 Diabetic Mice (OVE 26)

Baroreflex control of heart rate is impaired in OVE26 mice (Lin et al. 2008, EB abstract). The location and the nature of such a neurally‐mediated change are not clear. TMR‐D was injected into the left nodose ganglion to anterogradely label baroreceptor afferent in the aortic arch of OVE 26 diabetic and FVB control mice (6–9 months, n = 9/group). A confocal microscope and a Neurolucida 3‐D digitization system were used to examine baroreceptor axons and terminals. In the aortic arch of FVB and OVE26 mice, we found large and small baroreceptor afferent axons which formed 4 different types of baroreceptor afferent terminals: large and small axons formed large and small flower‐sprays and end‐nets, respectively. In addition, the size of baroreceptor afferent terminals (flower‐sprays and end‐nets) in OVE26 mice was decreased (p&lt;0.01) compared to FVB mice. The overall baroreceptor afferent innervation of the aortic arch appeared sparser in OVE26 than in FVB mice. Our observation demonstrates that diabetes induces a significant structural remodeling of baroreceptor afferent innervation of the aortic arch. Since baroreceptor afferent activity in response to the arterial pressure increase is not changed (Gu et al., 2008, EB abstract), we postulate that morphological remodeling precedes the functional deficit of baroreceptor afferent axons. *The first two authors equally contributed to the present work. NIH HL‐79636.

Exercise and cardiovascular risk reduction: time to update the rationale for exercise?

although it is generally accepted that the promotion of exercise accords with clinical best practice, the anecdotal experience of many primary care physicians, cardiologists, and exercise physiologists is that, even when exercise prescriptions are adhered to, risk factors often fail to demonstrate

The cardiac-related rhythm in preganglionic sympathetic activities of developing piglets

This investigation was performed to determine whether partial spectral analysis of preganglionic sympathetic nerve discharges would reveal age-related differences in the distribution of baroreceptor afferent information to brainstem sympathetic-related neurons. Any influence of baroreceptor afferent activity on ordinary spectra of cervical sympathetic and splanchnic nerves was removed by partialization using the arterial blood pressure signal which represented baroreceptor activity. An absence of statistically significant coherence in partialized nerve spectra would indicate that sympathetic-related neurons receive peripheral baroreceptor afferent input, but are not interconnected, whereas the presence of significant coherence would mean that these neurons are interconnected. Ordinary spectral analysis did not demonstrate age-related differences in the relationship between nerve activity and baroreceptor afferent input. In many animals, large peaks, located at cardiac frequencies (range 2.75–5.6 Hz), were noted in ordinary nerve autopower spectra, and were significantly correlated in ordinary coherence spectra. Partialization of nerve spectra eliminated or reduced cardiac-related peaks in autopower spectra regardless of age, and, in 8 of 10 animals, reduced coherence estimates to non-significant values. In two animals, 19 and 36 days old, significant coherence values remained after partialization. These results demonstrated that cardiac-related peaks in coherence in spectra of preganglionic splanchnic and cervical sympathetic nerves were dependent upon peripheral afferent baroreceptor input in most animals. Further, the finding that significant residual coherence was absent in most cases suggested a paucity of intrabulbar pathways connecting brainstem sympathetic-related neurons.

Structural changes in AMPA-receptive neurons in the nucleus of the solitary tract of spontaneously hypertensive rats.

The baroreceptor reflex is critical for homeostatic regulation of blood pressure and is initiated centrally by glutamate release from baroreceptive afferents onto neurons in the nucleus of the solitary tract that activates AMPA-type glutamate receptors. The GluR1 subunit of the AMPA receptor is located at postsynaptic sites within the nucleus of the solitary tract, particularly in dendritic spines, which are important sites for synaptic plasticity. We tested whether the distribution of GluR1 changes after sustained hypertension, which alters baroreceptor afferent activity. We examined the distribution of GluR1 in the nucleus of the solitary tract of both hypertensive (spontaneously hypertensive) and normotensive (Wistar-Kyoto) rats at the light microscopic and electron microscopic levels. There were more GluR1-containing dendritic spines in the nucleus of the solitary tract of hypertensive rats compared with normotensive rats, which was attributable to an increase in the proportion of dendritic spines containing GluR1 as well as an increase in the total number of dendritic spines. The differences were only seen after the development of hypertension and were not seen in rostral regions of the nucleus of the solitary tract. In the spontaneously hypertensive rat, many synapses on GluR1-containing dendrites had the morphological features of synapses undergoing dynamic changes, including the presence of perforated synapses. These results suggest that changes in afferent activity to the nucleus of the solitary tract during sustained hypertension alter both the dendritic structure and AMPA receptor content of some neurons. These structural changes may be a substrate for central resetting of the baroreceptor reflex.

Induction of immunoreactive prostaglandin H synthases 1 and 2 and fos in response to cerebral hypoperfusion in late-gestation fetal sheep

The goal of the present study was to localize and quantify immunoreactive prostaglandin H synthase 1 (PGHS-1), PGHS-2, and Fos expression by immunohistochemistry in the fetal brain 30 minutes and 2 hours after the onset of a 10-minute period of cerebral hypoperfusion in barodenervated and chemodenervated fetal sheep. Fetal sheep of known gestational age were studied intact or sinoaortic denervated. Fetuses were sacrificed and tissues recovered for immunohistochemistry or real-time polymerase chain reaction measurements of protein and mRNA, respectively. Some fetuses were subjected to brachiocephalic occlusion, produced by inflation of an extravascular balloon occluder around the brachiocephalic artery. Immunohistochemistry results were quantified using image analysis, and mRNA was quantified by estimation of cycle threshold in generation of PGHS-1 or PGHS-2 amplicons. Sinoaortic denervation by itself did not alter the abundance of PGHS-1 or PGHS-2 protein in any brain region, although the denervation did reduce the abundance of PGHS-1 mRNA in hypothalamus. We assessed PGHS-1, PGHS-2, and Fos immunoreactive protein abundance by image analysis of histologic sections stained for the respective proteins using immunohistochemistry. Cerebral hypoperfusion increased the intensity of staining of immunoreactive PGHS-1, PGHS-2, and Fos in the anterior pituitary, hippocampus, and cerebellum. In the cerebral microvasculature, the intensity of PGHS-1 and Fos was significantly greater, and in the cerebral cortex, the intensity of PGHS-2 was significantly greater. Changes in the amount of immunostaining in the nucleus of tractus solitarius and paraventricular nucleus were not statistically significant. Cerebral hypoperfusion altered the expression and distribution of prostaglandin biosynthetic enzymes in ovine fetal brain by a mechanism that is independent of baroreceptor and chemoreceptor afferent activity.

C-Fos expression in the midbrain periaqueductal gray after chemoreceptor and baroreceptor activation.

The pattern of Fos-like immunoreactivity (FLI) in the periaqueductal gray (PAG) associated with activation of arterial chemoreceptors versus baroreceptor afferents was examined in urethane-anesthetized rats. Chemoreflex responses elicited by repeat intravenous injections of potassium cyanide (KCN; 90 microg/kg) significantly increased FLI in all columns of the PAG relative to saline-injected animals. Pressor responses elicited by intravenous phenylephrine (PE) produced a similar pattern of increased FLI throughout the PAG except in the dorsomedial and lateral columns of the caudal PAG, where FLI was minimal. Chemoreflex responses were unaltered by blockade of excitatory amino acid receptors in the dorsomedial PAG, and < 10% of the neurons of the caudal PAG that expressed FLI after KCN stimulation were retrogradely labeled from the A5 region of the caudal ventrolateral pons. These results indicate that integration of chemoreceptor inputs occurs primarily in the dorsal and lateral columns of the caudal PAG, but these neurons have little direct descending influence over lower brain stem regions integral to the central arterial chemoreflex arc.

Frequency response of renal sympathetic nervous activity to aortic depressor nerve stimulation in the anaesthetized rat.

1. The contribution of central baroreceptor reflex pathways to the dynamic regulation of sympathetic nervous activity (SNA) has not been properly examined thus far. The aim of this study was to characterize the transfer function of the central arc of the baroreceptor reflex (from baroreceptor afferent activity to SNA) over a wide range of frequencies. 2. In nine baroreceptor-intact and six sino-aortic baroreceptor-denervated rats anaesthetized with urethane, the renal SNA was recorded while applying sinusoidal stimulation to the aortic depressor nerve at 26 discrete frequencies ranging from 0.03 to 20 Hz. At each modulation frequency, cross-power spectrum analysis using a fast Fourier transform algorithm was performed between the stimulation and renal SNA, which provided the transfer function of the central arc. 3. In both baroreceptor intact and denervated rats, the transfer gain increased by a factor of about three between 0.03 and 1 Hz. At higher frequencies, the gain decreased but remained above the static gain of the system up to 12 Hz. There was a slight phase lead up to 0.4 Hz, then a continuously increasing phase lag. A three-element linear model satisfactorily described the experimental transfer function. The model combined a derivative gain (corner frequency approximately 0.15 Hz), an overdamped second-order low-pass filter (natural frequency approximately 1 Hz) and a fixed time delay (approximately 100 ms). 4. These results indicate that the central arc of the baroreceptor reflex shows derivative properties that are essential for compensating the filtering of fast oscillations of baroreceptor afferent activity and thus for the generation of fast oscillations of renal SNA (e.g. those related to the cardiac cycle).

Regulation of sympathetic nervous system function after cardiovascular deconditioning.

Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.

Chemosensory activity from single or few-fibres of the carotid sinus nerve in the guinea-pig

Humans who are born and raised at high altitude possess a blunted breathing response to hypoxia. The guinea-pig also has a blunted breathing response to hypoxia [1], which may be linked to its high altitude origin in South America. Our laboratory has shown that the carotid bodies of the guinea-pig are not required for the breathing response to hypoxia [1]. Whether the carotid bodies can actually detect hypoxia is uncertain because the central depressive effects associated with hypoxia may attenuate the breathing response to an otherwise potent carotid body stimulant. In a recent study, we looked for evidence of chemoreceptor activity in the whole carotid sinus nerve (CSN), but found that the whole CSN activity was dominated by baroreceptor afferent activity [2]. In this study activity was recorded from single or few-fibre CSN filaments during application of the chemoreceptor stimulants NaCN (200 μgkg-1 i.v.), 8% CO2 (60 s) and 8% O2 (60 s), from guinea-pigs (n = 10; ~420 g; ~50 days old) that were anaesthetised with ketamine/xylazine (20/1 mgkg-1). Of the 10 guinea-pigs, only 8 fibre preparations containing chemoreceptor activity were successfully obtained from 4 guinea-pigs. In general, most of the isolated nerve filaments were multi-fibre preparations. Basal chemoreceptor activity could not be detected. However, NaCN and hypercapnia increased activity in 5 of the fibre preparations that were otherwise silent, or that contained 1 or 2 baroreceptor fibres. The magnitude of response varied considerably between filaments because of the different number of individual fibres in each preparation and, thus, the difference in the actual count of action potentials. Only one of the fibre preparations responded to hypoxia with an increase in activity; no fibres responded with a decrease in activity. The physiological relevance of the latter results could be similar to that of the aortic depressor nerve (ADN) in the rat. Brophy et al. revealed that, in contrast to the general consensus, the rat ADN does contain chemoreceptor afferent fibres, and that such fibres are stimulated by chemoreceptor stimulants [3]. Kobayashi et al. agreed that chemoreceptor fibres were present, but concluded that the rat ADN does not contain a functionally significant number of chemoreceptor afferent fibres that could appreciably contribute to the generation of chemoreflexes [4]. The present study has shown that the carotid bodies of the guinea-pig can detect NaCN and hypercapnia, as expected, and also hypoxia, although the latter was a comparatively weak stimulant. In conclusion, the physiological relevance of the carotid body of the guinea-pig for the ventilatory responses to hypoxia remains uncertain.