-
Experimental Physiology Nov 2020What is the central question of this study? Do endoperoxide 4 and thromboxane A receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on...
NEW FINDINGS
What is the central question of this study? Do endoperoxide 4 and thromboxane A receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF-rEF)? What is the main finding and its importance? The data do not support a role for endoperoxide 4 receptors or thromboxane A receptors in the chronic mechanoreflex sensitization in HF-rEF rats.
ABSTRACT
We investigated the role of cyclooxygenase metabolite-associated endoperoxide 4 receptors (EP4-R) and thromboxane A receptors (TxA -R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the EP4-R antagonist L-161,982 (1 µg) or the TxA -R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF-rEF rats but not sham-operated control rats (SHAM). Ejection fraction was significantly reduced in HF-rEF (45 ± 11%) compared to SHAM (83 ± 6%; P < 0.01) rats. In SHAM and HF-rEF rats, we found that the EP4-R antagonist had no effect on the peak increase in mean arterial pressure (peak ΔMAP SHAM n = 6, pre: 15 ± 7, post: 15 ± 9, P = 0.99; HF-rEF n = 9, pre: 30 ± 11, post: 32 ± 15 mmHg, P = 0.84) or peak increase in RSNA (peak ΔRSNA SHAM pre: 33 ± 14, post: 47 ± 31%, P = 0.94; HF-rEF, pre: 109 ± 47, post: 139 ± 150%, P = 0.76) response to stretch. Similarly, in SHAM and HF-rEF rats, we found that the TxA -R antagonist had no effect on the peak ΔMAP (SHAM n = 7, pre: 13 ± 7, post: 19 ± 14, P = 0.15; HF-rEF n = 14, pre: 24 ± 13, post: 21 ± 13 mmHg, P = 0.47) or peak ΔRSNA (SHAM pre: 52 ± 43, post: 57 ± 67%, P = 0.94; HF-rEF, pre: 108 ± 93, post: 88 ± 72%, P = 0.30) response to stretch. The data do not support a role for EP4-Rs or TxA -Rs in the chronic mechanoreflex sensitization in HF-rEF.
Topics: Animals; Blood Pressure; Heart Failure; Muscle Contraction; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Reflex; Thromboxanes
PubMed: 32954541
DOI: 10.1113/EP088835 -
American Journal of Physiology. Heart... Feb 2018Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor... (Comparative Study)
Comparative Study
Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease in which a femoral artery is chronically (~72 h) ligated, the mechanically sensitive component of the exercise pressor reflex during 1-Hz dynamic contraction is exaggerated compared with that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats, we tested the hypothesis that the increases in mean arterial blood pressure and renal sympathetic nerve activity during 1-Hz dynamic stretch are larger when evoked from a previously "ligated" hindlimb compared with those evoked from the contralateral "freely perfused" hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that closely replicated the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in mean arterial blood pressure (freely perfused: 14 ± 1 and ligated: 23 ± 3 mmHg, P = 0.02) and renal sympathetic nerve activity were significantly greater during dynamic stretch of the ligated hindlimb compared with the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated peripheral artery disease involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization. NEW & NOTEWORTHY We found that the pressor and sympathetic nerve responses during dynamic stretch were exaggerated in rats with a ligated femoral artery (a model of peripheral artery disease). Our findings provide mechanistic insights into the exaggerated exercise pressor reflex in this model and may have important implications for peripheral artery disease patients.
Topics: Animals; Arterial Pressure; Decerebrate State; Disease Models, Animal; Femoral Artery; Hindlimb; Kidney; Ligation; Male; Muscle Contraction; Muscle Spindles; Muscle, Skeletal; Peripheral Arterial Disease; Rats, Sprague-Dawley; Reflex; Sympathetic Nervous System; Time Factors
PubMed: 29054973
DOI: 10.1152/ajpheart.00498.2017 -
American Journal of Physiology.... Feb 2023We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce...
We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce simulated peripheral artery disease (PAD). We hypothesized that in decerebrate, unanesthetized rats with a ligated femoral artery, hindlimb arterial injection of HOE-140 (100 ng, B2 receptor antagonist) would reduce the pressor response to 30 s of electrically induced 1 Hz hindlimb skeletal muscle contraction, and 30 s of 1 Hz hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). We hypothesized no effect of HOE-140 in sham-operated "freely perfused" rats. In both freely perfused ( = 4) and "ligated" ( = 4) rats, we first confirmed efficacious B2 receptor blockade by demonstrating that HOE-140 injection significantly reduced ( < 0.05) the peak increase in mean arterial pressure (peak ΔMAP) in response to hindlimb arterial injection of bradykinin. In subsequent experiments, we found that HOE-140 reduced the peak ΔMAP response to muscle contraction in ligated ( = 14; control: 23 ± 2; HOE-140: 17 ± 2 mmHg; = 0.03) but not freely perfused rats ( = 7; control: 17 ± 3; HOE-140: 18 ± 4 mmHg; = 0.65). Furthermore, HOE-140 had no effect on the peak ΔMAP response to stretch in ligated rats ( = 14; control: 37 ± 4; HOE-140: 32 ± 5 mmHg; = 0.13) but reduced the integrated area under the blood pressure signal over the final ∼20 s of the maneuver. The data suggest that B2 receptors contribute to the exaggerated exercise pressor reflex in rats with simulated PAD, and that contribution includes a modest role in the chronic sensitization of the mechanically activated channels/afferents that underlie mechanoreflex activation.
Topics: Rats; Animals; Reflex; Muscle, Skeletal; Receptors, Bradykinin; Rats, Sprague-Dawley; Bradykinin; Muscle Contraction; Peripheral Arterial Disease; Blood Pressure; Femoral Artery; Hindlimb
PubMed: 36534589
DOI: 10.1152/ajpregu.00274.2022 -
Frontiers in Neural Circuits 2015In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in...
In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO2) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage-dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9-104 s, mean 39 ± 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co-activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated.
Topics: Animals; Blood Pressure; Cats; Decerebrate State; Electrophysiology; Hindlimb; Motor Activity; Motor Neurons; Neural Pathways; Respiration
PubMed: 25713515
DOI: 10.3389/fncir.2015.00001 -
Journal of Neuroscience Methods Aug 2017Genetic techniques rendering murine models a popular choice for neuroscience research has led to important insights on neural networks controlling locomotor function....
BACKGROUND
Genetic techniques rendering murine models a popular choice for neuroscience research has led to important insights on neural networks controlling locomotor function. Using genetically altered mouse models for in vivo, electrophysiological studies in the adult state could validate key principles of locomotor network organization that have been described in neonatal, in vitro preparations.
NEW METHOD
The experimental model presented here describes a decerebrate, in vivo adult mouse preparation in which focal, electrical midbrain stimulation was combined with monitoring lumbar neural activity and motor output after pre-collicular decerebration and neuromuscular blockade.
RESULTS
Lumbar cord dorsum potentials (in 9/10 animals) and motoneuron output (in 3/5 animals) including fictive locomotion, was achieved by focal midbrain stimulation. The stimulation electrode locations could be reconstructed (in 6/7 animals) thereby allowing anatomical identification of the stimulated supraspinal regions.
COMPARISON WITH EXISTING METHODS
This preparation allows for concomitant recording or stimulation in the spinal cord and in the mid/hindbrain of adult mice. It differs from other methods used in the past with adult mice as it does not require pharmacological manipulation of neural excitability in order to generate motor output.
CONCLUSIONS
Midbrain stimulation can consistently be used for inducing lumbar neural activity in adult mice under neuromuscular blockade. This model is suited for examination of brain-spinal connectivity and it may benefit a wide range of fields depending on the features of the genetically modified mouse models used in combination with the presented methods.
Topics: Animals; Decerebrate State; Electric Stimulation; Evoked Potentials; Lumbosacral Region; Mesencephalon; Mice; Motor Activity; Motor Neurons; Neural Pathways; Spinal Cord
PubMed: 28648715
DOI: 10.1016/j.jneumeth.2017.06.015 -
Experimental Brain Research Aug 2014Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO4) alters the responses to vestibular stimulation of a large fraction of neurons...
Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO4) alters the responses to vestibular stimulation of a large fraction of neurons in brainstem regions that mediate nausea and vomiting, thereby affecting motion sickness susceptibility. Other studies suggested that the processing of vestibular inputs by cerebellar neurons plays a critical role in generating motion sickness and that neurons in the cerebellar fastigial nucleus receive visceral inputs. These findings raised the hypothesis that stimulation of gastrointestinal receptors by a nauseogenic compound affects the processing of labyrinthine signals by fastigial nucleus neurons. We tested this hypothesis in decerebrate cats by determining the effects of intragastric injection of CuSO4 on the responses of rostral fastigial nucleus to whole-body rotations that activate labyrinthine receptors. Responses to vestibular stimulation of fastigial nucleus neurons were more complex in decerebrate cats than reported previously in conscious felines. In particular, spatiotemporal convergence responses, which reflect the convergence of vestibular inputs with different spatial and temporal properties, were more common in decerebrate than in conscious felines. The firing rate of a small percentage of fastigial nucleus neurons (15%) was altered over 50% by the administration of CuSO4; the firing rate of the majority of these cells decreased. The responses to vestibular stimulation of a majority of these cells were attenuated after the compound was provided. Although these data support our hypothesis, the low fraction of fastigial nucleus neurons whose firing rate and responses to vestibular stimulation were affected by the administration of CuSO4 casts doubt on the notion that nauseogenic visceral inputs modulate motion sickness susceptibility principally through neural pathways that include the cerebellar fastigial nucleus. Instead, it appears that convergence of gastrointestinal and vestibular inputs occurs mainly in the brainstem.
Topics: Action Potentials; Analysis of Variance; Animals; Biophysics; Blood Pressure; Cats; Cerebellar Nuclei; Copper Sulfate; Decerebrate State; Disease Models, Animal; Electric Stimulation; Emetics; Male; Motion Sickness; Neural Pathways; Neurons; Rotation; Vestibule, Labyrinth
PubMed: 24677139
DOI: 10.1007/s00221-014-3898-9 -
American Journal of Physiology.... Sep 2019Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex...
Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex independent of contraction-induced metabolite production. Cyclooxygenase (COX) metabolites, however, are produced by skeletal muscle stretch in vitro and have been found to impact various models of mechanoreflex activation. Whether COX metabolites influence the decerebrate rat triceps surae muscle stretch mechanoreflex model remains unknown. We examined the effect of rat triceps surae muscle stretch on the interstitial concentration of the COX metabolite prostaglandin E (PGE). Interstitial PGE concentration was increased above baseline values by 4 min of both static (38% increase, = 0.01) and dynamic (56% increase, < 0.01) triceps surae muscle stretch ( = 10). The 4-min protocol was required to collect enough microdialysis fluid for PGE detection. The finding that skeletal muscle stretch in vivo was capable of producing COX metabolites prompted the hypothesis that intra-arterial administration of the COX inhibitor indomethacin (1 mg/kg) would reduce the pressor and cardioaccelerator responses evoked during 30 s (the duration most commonly used in the rat mechanoreflex model) of static and dynamic rat triceps surae muscle stretch. We found that indomethacin had no effect ( > 0.05, = 9) on the pressor or cardioaccelerator response during 30 s of either static or dynamic stretch. We conclude that, despite the possibility of increased COX metabolite concentration, COX metabolites do not activate or sensitize thin-fiber muscle afferents stimulated during 30 s of static or dynamic hindlimb skeletal muscle stretch in healthy rats.
Topics: Animals; Blood Pressure; Cyclooxygenase Inhibitors; Decerebrate State; Dinoprostone; Heart Rate; Indomethacin; Male; Mechanoreceptors; Rats; Rats, Sprague-Dawley; Reflex, Stretch
PubMed: 31241976
DOI: 10.1152/ajpregu.00080.2019 -
Mechanism of physical stress-induced inhibition of ovarian estradiol secretion in anesthetized rats.Autonomic Neuroscience : Basic &... Sep 2017This study examined the site of main integration center in the physical stress-induced inhibition of ovarian estradiol secretion because of ovarian sympathetic nerve...
This study examined the site of main integration center in the physical stress-induced inhibition of ovarian estradiol secretion because of ovarian sympathetic nerve (superior ovarian nerve: SON) activation in anesthetized rats. In central nervous system-intact rats, electrical stimulation of the tibial afferent nerve at 10V increased the efferent activity of the SON by 39±13% and reduced the ovarian secretion of estradiol by 34±7%. These responses were observed in decerebrate rats but were abolished in spinal rats. Thus, the main integration center for this ovarian hormonal response is located in the brain stem.
Topics: Afferent Pathways; Anesthesia; Animals; Brain Stem; Decerebrate State; Efferent Pathways; Electric Stimulation; Estradiol; Female; Ovary; Rats, Wistar; Stress, Physiological; Sympathetic Nervous System; Synaptic Transmission; Tibial Nerve
PubMed: 28579284
DOI: 10.1016/j.autneu.2017.05.011 -
BMC Infectious Diseases Jul 2020Pertussis is a highly contagious disease of public health interest caused by the bacterium Bordetella pertussis. Although its incidence has decreased substantially after...
BACKGROUND
Pertussis is a highly contagious disease of public health interest caused by the bacterium Bordetella pertussis. Although its incidence has decreased substantially after the introduction of a vaccination, the burden of the disease remains high. Although the paroxysmal phase is highly disabling, complications are uncommon and more prevalent in children than in adults. The most frequent neurological complication is encephalopathy, but seizures, paresis, paraplegia, ataxias, aphasias, and decerebration postures have also been described. The complication of decerebration postures has not been previously reported in adults.
CASE PRESENTATION
We present a video case of an adult HIV patient with severe coughing paroxysms, post-tussive emesis and syncope, whose workup confirmed the diagnosis of a B. pertussis respiratory infection. During hospitalization, he had fluctuant encephalopathy and post-tussive decerebration postures following paroxysms. He was treated with antibiotic therapy and finally sent home without residual neurological deficits.
CONCLUSION
This case illustrates the biological plausibility of neurologic complications of pertussis in adults, which, albeit rare, can cause important morbidities. Future research should explore whether there are differences in the clinical presentation, risk factors and pathophysiology of the disease among adults or interventions aimed at preventing or treating pertussis encephalopathy.
Topics: AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Bordetella pertussis; Brain Diseases; Decerebrate State; HIV; Hospitalization; Humans; Male; Middle Aged; Polymerase Chain Reaction; Risk Factors; Treatment Outcome; Whooping Cough
PubMed: 32615931
DOI: 10.1186/s12879-020-05198-x -
American Journal of Physiology. Heart... Nov 2019Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the...
Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery ("ligated" rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats ( = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; < 0.01), whereas there was no effect in rats with "freely perfused" femoral arteries ( = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; = 0.87). In ligated rats ( = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors. We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.
Topics: Animals; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Femoral Artery; Ganglia, Spinal; Hindlimb; Indomethacin; Ligation; Male; Mechanoreceptors; Mechanotransduction, Cellular; Muscle Contraction; Muscle, Skeletal; Peripheral Arterial Disease; Prostaglandin-Endoperoxide Synthases; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Thromboxane A2, Prostaglandin H2; Reflex
PubMed: 31469294
DOI: 10.1152/ajpheart.00399.2019