Focal CO2/H+ alters phrenic motor output response to chemical stimulation of cat pre-Bötzinger complex in vivo

2003 ◽  
Vol 94 (6) ◽  
pp. 2151-2157 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Mechanically Ventilated ◽  
Bötzinger Complex ◽  
Tissue Acidosis ◽  
Tonic Excitation ◽  
Nerve Discharge

Microinjection ofdl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce tonic excitation of phrenic nerve discharge. Although this DLH-induced tonic excitation can be modified by systemic hypercapnia, the role of focal increases in pre-BötC CO2/H+ in this modulation of the DLH-induced response remains to be determined. Therefore, we examined the effects of unilateral microinjection of DLH (10 mM; 10–20 nl) into the pre-BötC before and during increased focal pre-BötC CO2/H+ (i.e., focal tissue acidosis) in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Focal tissue acidosis was produced by blockade of carbonic anhydrase with either focal acetazolamide (AZ) or methazolamide (MZ) microinjection. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC produced a nonphasic tonic excitation of phrenic nerve discharge ( n = 10). Microinjection of 10–20 nl AZ (50 μM) or MZ (50 μM) into these 10 sites in the pre-BötC increased the amplitude and/or frequency of eupneic phrenic bursts, as previously reported. Subsequent microinjection of DLH produced excitation in which phasic respiratory bursts were superimposed on tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency ( P < 0.05). These findings demonstrate that modulation of phrenic motor activity evoked by DLH-induced activation of the pre-BötC is influenced by focal CO2/H+chemosensitivity in this region. Furthermore, these findings suggest that focal increases in pre-BötC CO2/H+may have contributed to the modulation of the DLH-induced responses previously observed during systemic hypercapnia.

Glutamate Neurotransmission Is Not Required for, But May Modulate, Hypoxic Sensitivity of Pre-Bötzinger Complex In Vivo

2005 ◽  
Vol 93 (3) ◽  
pp. 1278-1284 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Motor Output ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Nerve Discharge

Focal hypoxia in the pre-Bötzinger complex (pre-BötC) in vivo elicits excitation of inspiratory motor output by modifying the patterning and timing of phrenic bursts. Hypoxia, however, has been reported to enhance glutamate release in some regions of the brain, including the medullary ventral respiratory column; thus the pre-BötC–mediated hypoxic respiratory excitation may result from, or be influenced by, hypoxia-induced activation of ionotropic glutamate [i.e., excitatory amino acid (EAA)] receptors. To test this possibility, the effects of focal pre-BötC hypoxia [induced by sodium cyanide (NaCN)] were examined before and after blockade of ionotropic EAA receptors [using kynurenic acid (KYN)] in this region in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Before blockade of ionotropic EAA receptors, unilateral microinjection of NaCN (1 mM; 10–20 nl) into the pre-BötC produced either phasic or tonic excitation of phrenic nerve discharge. Unilateral microinjection of KYN (50–100 mM; 40 nl) decreased the amplitude and frequency of basal phrenic nerve discharge; however, subsequent microinjection of NaCN, but not dl-homocysteic acid (DLH, a glutamate analog), still produced excitation of phrenic motor output. Under these conditions, the NaCN-induced excitation included frequency modulation (FM) of phasic phrenic bursts, and in many cases, augmented and/or fractionated phrenic bursts. These findings show that the hypoxia-sensing function of the in vivo pre-BötC, which produces excitation of phrenic nerve discharge, is not dependent on activation of ionotropic glutamate receptors, but ionotropic glutamate receptor activation may modify the expression of the focal hypoxia-induced response. Thus these findings provide additional support to the concept of intrinsic hypoxic sensitivity of the pre-BötC.

Pre-Bötzinger Complex Functions as a Central Hypoxia Chemosensor for Respiration In Vivo

2000 ◽  
Vol 83 (5) ◽  
pp. 2854-2868 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Judith A. Neubauer
Keyword(s):  
Short Duration ◽  
Phrenic Nerve ◽  
Excitatory Amino Acid ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Unique Region ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Nerve Discharge

Recently, we identified a region located in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) in which activation of ionotropic excitatory amino acid receptors usingdl-homocysteic acid (DLH) elicits a variety of excitatory responses in the phrenic neurogram, ranging from tonic firing to a rapid series of high-amplitude, rapid rate of rise, short-duration inspiratory bursts that are indistinguishable from gasps produced by severe systemic hypoxia. Therefore we hypothesized that this unique region is chemosensitive to hypoxia. To test this hypothesis, we examined the response to unilateral microinjection of sodium cyanide (NaCN) into the pre-BötC in chloralose- or chloralose/urethan-anesthetized vagotomized, paralyzed, mechanically ventilated cats. In all experiments, sites in the pre-BötC were functionally identified using DLH (10 mM, 21 nl) as we have previously described. All sites were histologically confirmed to be in the pre-BötC after completion of the experiment. Unilateral microinjection of NaCN (1 mM, 21 nl) into the pre-BötC produced excitation of phrenic nerve discharge in 49 of the 81 sites examined. This augmentation of inspiratory output exhibited one of the following changes in cycle timing and/or pattern: 1) a series of high-amplitude, short-duration bursts in the phrenic neurogram (a discharge similar to a gasp), 2) a tonic excitation of phrenic neurogram output, 3) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a gasplike burst), or 4) an increase in frequency of phrenic bursts accompanied by small increases or decreases in the amplitude of integrated phrenic nerve discharge. Our findings identify a locus in the brain stem in which focal hypoxia augments respiratory output. We propose that the respiratory rhythm generator in the pre-BötC has intrinsic hypoxic chemosensitivity that may play a role in hypoxia-induced gasping.

Influence of respiratory network drive on phrenic motor output evoked by activation of cat pre-Bötzinger complex

2003 ◽  
Vol 284 (2) ◽  
pp. R455-R466 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Chemical Stimulation ◽  
Motor Output ◽  
Peripheral Chemoreceptor ◽  
Homocysteic Acid ◽  
Respiratory Network ◽  
Bötzinger Complex ◽  
Tonic Excitation ◽  
Stimulation Of ◽  
Nerve Discharge

10.1152/ajpregu.00395.2002. We have previously demonstrated that microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce either phasic or tonic excitation of phrenic nerve discharge during hyperoxic normocapnia. Breathing, however, is influenced by input from both central and peripheral chemoreceptor activation. This influence of increased respiratory network drive on pre-BötC-induced modulation of phrenic motor output is unclear. Therefore, these experiments were designed to examine the effects of chemical stimulation of neurons (DLH; 10 mM; 10–20 nl) in the pre-BötC during hyperoxic modulation of CO2 (i.e., hypercapnia and hypocapnia) and during normocapnic hypoxia in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-BötC during baseline conditions of hyperoxic normocapnia [arterial Pco 2 (PaCO2 ) = 37–43 mmHg; n = 22] produced a tonic (nonphasic) excitation of phrenic nerve discharge. During hypercapnia (PaCO2 = 59.7 ± 2.8 mmHg; n= 17), similar microinjection produced excitation in which phasic respiratory bursts were superimposed on varying levels of tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency ( P < 0.01). In contrast, during hypocapnia (PaCO2 = 29.4 ± 1.5 mmHg; n= 11), microinjection of DLH produced nonphasic tonic excitation of phrenic nerve discharge that was less robust than the initial (normocapnic) response (i.e., decreased amplitude). During normocapnic hypoxia (PaCO2 = 38.5 ± 3.7; arterial Po 2 = 38.4 ± 4.4; n= 8) microinjection of DLH produced phrenic excitation similar to that seen during hypercapnia (i.e., increased frequency of phasic respiratory bursts superimposed on tonic discharge). These findings demonstrate that phrenic motor activity evoked by chemical stimulation of the pre-BötC is influenced by and integrates with modulation of respiratory network drive mediated by input from central and peripheral chemoreceptors.

Chemical activation of pre-Bötzinger complex in vivo reduces respiratory network complexity

2005 ◽  
Vol 288 (5) ◽  
pp. R1237-R1247 ◽  
Author(s):  
Xinnian Chen ◽  
Ki H. Chon ◽  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Chemical Stimulation ◽  
Multiscale Entropy ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Respiratory Dynamics ◽  
Adult Cat ◽  
Cat Model

In the in vivo anesthetized adult cat model, multiple patterns of inspiratory motor discharge have been recorded in response to chemical stimulation and focal hypoxia of the pre-Bötzinger complex (pre-BötC), suggesting that this region may participate in the generation of complex respiratory dynamics. The complexity of a signal can be quantified using approximate entropy (ApEn) and multiscale entropy (MSEn) methods, both of which measure the regularity (orderliness) in a time series, with the latter method taking into consideration temporal fluctuations in the underlying dynamics. The current investigation was undertaken to examine the effects of pre-BötC-induced excitation of phasic phrenic nerve discharge, which is characterized by high-amplitude, rapid-rate-of-rise, short-duration bursts, on the complexity of the central inspiratory neural controller in the vagotomized, chloralose-anesthetized adult cat model. To assess inspiratory neural network complexity, we calculated the ApEn and MSEn of phrenic nerve bursts during eupneic (basal) discharge and during pre-BötC-induced excitation of phasic inspiratory bursts. Chemical stimulation of the pre-BötC using DL-homocysteic acid (DLH; 10 mM; 10–20 nl; n = 10) significantly reduced the ApEn from 0.982 ± 0.066 (mean ± SE) to 0.664 ± 0.067 ( P < 0.001) followed by recovery (∼1–2 min after DLH) of the ApEn to 1.014 ± 0.067; a slightly enhanced magnitude reduction in MSEn was observed. Focal pre-BötC hypoxia (induced by sodium cyanide; NaCN; 1 mM; 20 nl; n = 2) also elicited a reduction in both ApEn and MSEn, similar to those observed for the DLH-induced response. These observations demonstrate that activation of the pre-BötC reduces inspiratory network complexity, suggesting a role for the pre-BötC in regulation of complex respiratory dynamics.

CO2/H+ chemoreception in the cat pre-Bötzinger complex in vivo

2000 ◽  
Vol 88 (6) ◽  
pp. 1996-2007 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Marvin H. O'Neal
Keyword(s):  
Phrenic Nerve ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
Tissue Acidosis ◽  
Respiratory Rhythm Generation ◽  
Additional Support ◽  
Nerve Discharge

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10–20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 μM) or methazolamide (MZ; 50 μM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5–15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO2/H+ brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO2/H+ and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.

Modulation of Gasp Frequency by Activation of Pre-Bötzinger Complex In Vivo

2002 ◽  
Vol 87 (3) ◽  
pp. 1664-1668 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Chemical Stimulation ◽  
Motor Output ◽  
Burst Frequency ◽  
Homocysteic Acid ◽  
Mechanically Ventilated ◽  
Bötzinger Complex ◽  
Inspiratory Motor ◽  
Additional Support ◽  
Stimulation Of

Under hyperoxic conditions, both chemical stimulation of neurons and focal hypoxia in the pre-Bötzinger complex (pre-BötC) in vivo modify the eupneic pattern of inspiratory motor output by eliciting changes in the patterning and timing of phrenic bursts, which includes both phasic and tonic excitation. The influence of this region on the gasping pattern of phrenic motor output produced during severe brain hypoxia is unknown. We therefore examined the effects of chemical stimulation of neurons (dl-homocysteic acid; DLH; 10 mM; ≤20 nl) and focal hypoxia (sodium cyanide; NaCN; 1 mM; ≤20 nl) in the pre-BötC on hypoxia-induced gasping in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Unilateral microinjection of DLH into the pre-BötC during hypoxia-induced gasping increased phrenic burst frequency by ∼630% ( P < 0.01) over baseline frequency due predominantly to a reduction in T E (from 28.9 ± 6.2 to 5.2 ± 1.8 s; mean ± SE; P < 0.01). No significant changes in T I or rate of rise between hypoxia-induced gasps and the DLH-induced bursts were observed; the effects on peak amplitude of integrated phrenic nerve discharge were variable. Similar responses were evoked by unilateral microinjection of NaCN into the pre-BötC. These findings demonstrate that both activation of pre-BötC neurons and focal hypoxia in the pre-BötC not only influence the eupneic pattern of phrenic motor output but also modify the expression of hypoxia-induced gasping in vivo. These findings also provide additional support to the concept of intrinsic hypoxic chemosensitivity of the pre-BötC.

scholarly journals Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Bötzinger Complex Region

2010 ◽  
Vol 103 (1) ◽  
pp. 409-418 ◽  
Author(s):  
Sanda Mustapic ◽  
Tomislav Radocaj ◽  
Antonio Sanchez ◽  
Zoran Dogas ◽  
Astrid G. Stucke ◽  
...  
Keyword(s):  
Opioid Analgesic ◽  
Plasma Concentrations ◽  
Respiratory Neurons ◽  
Opioid Antagonist ◽  
Direct Effects ◽  
Opioid Agonist ◽  
Homocysteic Acid ◽  
Respiratory Rhythmogenesis ◽  
Bötzinger Complex

Systemic administration of μ-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Bötzinger Complex (pre-BötC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BötC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent μ-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record pre-BötC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist d-homocysteic acid (DLH, 20 mM), or the MOR agonist [d-Ala2, N-Me-Phe4, gly-ol5]-enkephalin (DAMGO, 100 μM). Inspiratory and expiratory durations ( TI and TE) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BötC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (∼60% decrease in central breathing frequency, fB), bilateral injections of NAL in the pre-BötC did not change TI, TE, fB, and PPA. Also, NAL picoejected onto single pre-BötC neurons depressed by intravenous remi had no effect on their discharge. In contrast, ∼60 μg/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BötC increased fB by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that μ-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BötC region.

Ionotropic excitatory amino acid receptors in pre-Bötzinger complex play a modulatory role in hypoxia-induced gasping in vivo

2004 ◽  
Vol 96 (5) ◽  
pp. 1643-1650 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Respiratory Rhythm ◽  
Receptor Activation ◽  
Induced Response ◽  
Brain Hypoxia ◽  
Bötzinger Complex ◽  
Before And After ◽  
Additional Support

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-Bötzinger complex (pre-BötC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-BötC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-BötC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-BötC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased ( P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure ( P < 0.05), the duration of gasps was prolonged ( P < 0.05), and the duration between gasps was increased ( P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-BötC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-BötC as the primary locus of respiratory rhythm generation.

Patterns of Phrenic Motor Output Evoked by Chemical Stimulation of Neurons Located in the Pre-Bötzinger Complex In Vivo

1999 ◽  
Vol 81 (3) ◽  
pp. 1150-1161 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Judith A. Neubauer
Keyword(s):  
Short Duration ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Chemical Stimulation ◽  
Arterial Blood ◽  
Bötzinger Complex ◽  
Tonic Excitation ◽  
Stimulation Of

Patterns of phrenic motor output evoked by chemical stimulation of neurons located in the pre-Bötzinger complex in vivo. The pre-Bötzinger complex (pre-BötC) has been proposed to be essential for respiratory rhythm generation from work in vitro. Much less, however, is known about its role in the generation and modulation of respiratory rhythm in vivo. Therefore we examined whether chemical stimulation of the in vivo pre-BötC manifests respiratory modulation consistent with a respiratory rhythm generator. In chloralose- or chloralose/urethan-anesthetized, vagotomized cats, we recorded phrenic nerve discharge and arterial blood pressure in response to chemical stimulation of neurons located in the pre-BötC with dl-homocysteic acid (DLH; 10 mM; 21 nl). In 115 of the 122 sites examined in the pre-BötC, unilateral microinjection of DLH produced an increase in phrenic nerve discharge that was characterized by one of the following changes in cycle timing and pattern: 1) a rapid series of high-amplitude, rapid rate of rise, short-duration bursts, 2) tonic excitation (with or without respiratory oscillations), 3) an integration of the first two types of responses (i.e., tonic excitation with high-amplitude, short-duration bursts superimposed), or 4) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a high-amplitude, short-duration burst). In 107 of these sites, the phrenic neurogram response was accompanied by an increase or decrease (≥10 mmHg) in arterial blood pressure. Thus increases in respiratory burst frequency and production of tonic discharge of inspiratory output, both of which have been seen in vitro, as well as modulation of burst pattern can be produced by local perturbations of excitatory amino acid neurotransmission in the pre-BötC in vivo. These findings are consistent with the proposed role of this region as the locus for respiratory rhythm generation.

scholarly journals Hering-Breuer Reflex and pre-Botzinger Complex: A Literature Survey

1970 ◽  
Vol 2 ◽  
pp. 89-94
Author(s):  
M Ahmed
Keyword(s):  
Human Subjects ◽  
Respiratory Rhythm ◽  
Physiological Role ◽  
Personal Communication ◽  
In Vivo Studies ◽  
Respiratory Rhythmogenesis ◽  
Neuronal Regulation ◽  
Bötzinger Complex

The existence and physiological role of Hering-Breuer reflex and pre-Botzinger complex has long been depreciated by the Bangladesh society of physiologist (personal communication). The aim of this mini review is to highlight the recent findings on the aforementioned topics. Due to the difficulties in vivo studies in human subjects, many aspects of the neuronal regulation of the respiratory rhythm are still unclear. However, the recent localization of the pre-Botzinger complex in humans and advances in technologies necessitates further exploration of the neuronal circuits in the pre-BotC complex which will subsequently unwrap the magical box and pave the way to solve the puzzle of the mechanism of respiratory rhythmogenesis and its modulation in different pathophysiological conditions. Key Words: Physiology; Hering-Breuer reflex; pre-Botzinger complex; Rhythmic respiration  DOI:10.3329/jbsp.v2i0.988 J Bangladesh Soc Physiol. 2007 Dec;(2):89-94.  

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