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1 Department of Anatomy and Division of Pulmonary and Critical Care Medicine and 2 Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4941
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Posthypoxic frequency decline (PHFD) refers to the undershoot in respiratory frequency that follows brief hypoxic exposures. Lateral pontine neurons are required for PHFD. The neurotransmitters involved in the circuit that activate and/or are released by these pontine neurons regulating PHFD are unknown. We hypothesized that N-methyl-D-aspartate (NMDA) receptors are required for PHFD, because of the similarity in respiratory pattern after blocking lateral pontine activity or NMDA receptors. Furthermore, we hypothesized that the location of these NMDA receptors could be visualized by optimizing binding affinity with spermidine. In vagotomized, anesthetized rats (n = 16), cardiorespiratory responses to hypoxia (8% O2, 30-90 s) were recorded before and after dizocilpine (10 µg-1 mg/kg iv), and NMDA receptors were mapped with [3H]dizocilpine (n = 6). Dizocilpine elicited a dose-related effect on PHFD, blocking PHFD at high doses. Resting arterial blood pressure and breathing frequency decreased with high doses of dizocilpine, but the respiratory response to hypoxia remained intact. Our novel anatomical data indicate that NMDA receptors were widespread but distributed differentially in the brain stem. We conclude that NMDA receptors are located in pontine and medullary respiratory-related regions and that PHFD requires NMDA-receptor activation.
respiration; dizocilpine; hypoxia; pons; timing
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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POSTHYPOXIC FREQUENCY DECLINE (PHFD) refers to the undershoot in respiratory frequency after brief exposures to hypoxia (5). This decrease in frequency results primarily from a prolongation of expiration, which is blocked by inhibiting neuronal activity in the ventrolateral (VL) or dorsolateral (DL) pons (4). Furthermore, stimulating VL pontine neurons lengthens expiration (3, 6, 18). These data are consistent with our overall hypothesis that the decrease in respiratory frequency after hypoxia results from activation of neurons in the lateral pons (5). The neurotransmitter or neurotransmitters mediating this change in respiratory timing with reoxygenation are unknown.
The noncompetitive N-methyl-D-aspartate (NMDA)-receptor blocker, dizocilpine (MK-801), elicits apneusis, a prolonged inspiratory pattern of breathing, in vagotomized animals when given at sufficient doses (7, 11, 26). This alteration in breathing pattern mimics the effect of bilateral lesions in the VL (17) and DL pons (19, 34). Furthermore, dizocilpine may elicit apneusis by acting through lateral pontine neurons, because microinjections of dizocilpine into the pontine respiratory group prolong inspiration (21). Due to the similarity in breathing patterns after lateral pontine lesions and NMDA-receptor blockade, we hypothesized that PHFD requires NMDA-receptor activation. Thus PHFD would be blocked by systemic administration of dizocilpine. We tested this possibility by analyzing the respiratory pattern before, during, and after brief hypoxic challenges before and after intravenous injections of dizocilpine in vagotomized rats.
In addition to the regulation of respiratory timing and pattern, NMDA receptors play a role in the central processing of chemoreceptor afferent information. In particular, increases in respiratory frequency, a hallmark of the respiratory response to hypoxia, are mediated by NMDA and non-NMDA mechanisms within the nucleus of the solitary tract (NTS; 32). The involvement of alternate pathways provides a mechanism for hypoxia-mediated changes to persist, even though NMDA receptors have been blocked. Thus posthypoxic events dependent on NMDA neurotransmission may be affected independent of the respiratory response to hypoxia. We hypothesize that we can affect PHFD without eliminating the respiratory response to hypoxia.
The ability of NMDA antagonists to influence respiration implies that NMDA receptors exist in the brain stem, but autoradiographic mapping of NMDA receptors has yielded equivocal data. In an early study, [3H]glutamate binding to NMDA receptors was sparse, but detectable, in the inferior olive, NTS, facial nucleus, and parabrachial region (25). However, more recently, [3H]dizocilpine binding was reported to be nearly absent from the rat brain stem (30). Given the physiological evidence of NMDA receptors in respiratory-related areas, we hypothesized that NMDA receptors could be visualized by optimizing [3H]dizocilpine binding by use of spermidine. Spermidine, an endogenous polyamine, increases the affinity of NMDA receptors. We therefore tested our hypothesis by performing autoradiographic binding experiments in the presence of spermidine.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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General experimental procedures.
Breathing pattern was measured before, during, and after brief hypoxia
(8% O2-balance
N2) and before and after
systemic delivery of dizocilpine in male, Sprague-Dawley rats
(n = 16; 328-525 g). Rats were
anesthetized with chloral hydrate (1.33 mg/kg) and pentobarbital sodium
(0.3 mg/kg). Supplemental doses were administered if cardiorespiratory output increased in response to pinching a foot pad. Both cervical vagal nerves were dissected and looped for subsequent avulsion once the
animal was connected to the ventilator by a tracheal cannula. Animals
were ventilated with 100% O2, and
end-tidal CO2 and airflow were
monitored. A phrenic nerve was dissected, desheathed, and mounted on
bipolar silver wire electrodes to record central respiratory output. A
femoral vein was cannulated for infusion of paralytic agent (Pavulon,
pancuronium bromide, 0.1 mg · h
1 · 100 g1), dizocilpine, or a
bicarbonate-saline mixture to maintain blood pH. A femoral artery was
catheterized to monitor blood pressure. Body temperature was maintained
at 38.5 ± 0.5°C by a servo-controlled heating pad. The head of
the animal was fitted into the ear bars of a stereotaxic frame for the
duration of the experiment. Phrenic nerve activity (PNA) was amplified
and filtered (0.1 Hz-3 kHz, Grass P511) and then rectified and
integrated (Paynter filter; time constant, 50 ms) by use of a moving
averager (CWE, Ardmore, PA). Integrated PNA and airflow were acquired
by and stored on computer for subsequent analysis (Marlin Data
Acquisition and Analysis Program) and recorded on the chart recorder
(Astro-Med Dash 8) in addition to blood pressure, raw PNA, and event
markers.
Preparation of dizocilpine. Dizocilpine [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; MK-801 maleate; Research Biochemicals International, catalog no. M-107] was dissolved in 10% DMSO-90% 0.1 M PBS (pH 7.4). Doses used were divided into "low-dose" [0.01 (n = 3) and 0.03 (n = 4) mg/kg] and "high-dose" groups [0.30 (n = 5) and 1.0 (n = 4) mg/kg].
Experimental protocol. Baseline PNA was recorded during 100% O2 before the challenge with brief 8% O2 (30-90 s). After hypoxia, rats were returned to the hyperoxic breathing gas. Once the breathing pattern returned to baseline levels, either vehicle or dizocilpine was injected intravenously. Hypoxic exposure was repeated ~10 min after intravenous injections. At the end of the experiment, the animal was killed with an overdose of anesthetic.
Data analysis.
Integrated PNA was used as an index of the respiratory cycle. The area
under the integrated phrenic nerve signal
(
PNAareas) and inspiratory
(ti) and
expiratory (te)
times were measured and plotted sequentially. To quantify the
respiratory response,
PNAareas, ti,
te, and breathing
frequency were averaged for three consecutive cycles at the following
periods: A, baseline hyperoxia;
B, peak hypoxic breathing frequency;
C, last cycles in hypoxia;
D, maximal PHFD in hyperoxia; and
E, 30 s after
D. Normalized means of
te and
PNAareas
relative to hyperoxic baseline levels were plotted at these five points
in time. When PHFD was blocked by dizocilpine, the posthypoxic
variables were measured for the cycles that corresponded to PHFD before
treatment. Maximal ti
levels during hypoxia before treatment and after vehicle were chosen
after te
decreased in response to hypoxia. Maximal
ti levels during hypoxia
after dizocilpine were selected regardless of when they occurred during
the exposure. Normalized means of posthypoxic breathing frequencies and
PNAareas
were correlated against breathing frequencies and
PNAareas during the peak response to hypoxia (Figs. 4 and 7, respectively). The
Student's t-test for paired or
unpaired comparisons or the Wilcoxon sign-rank test was utilized to
determine differences (P 
0.05).
Differences in mean values at any two time points were evaluated using
one-way ANOVA for repeated measures followed by the Bonferroni post hoc
test (
= 0.05). All values are presented as means ± SE.
Receptor autoradiography.
Urethan-anesthetized (1 g/kg) Wistar rats
(n = 6; 300-800 g) were
exsanguinated. Their brains were removed quickly and flash frozen in
isopentane cooled on dry ice. Brain stems were mounted in medium
(Tissue-tek) and sectioned coronally (12-µm thickness at
18°C). Sections were thaw mounted directly onto glass slides coated twice with 1% gelatin and 0.1% chrome alum. Sequential sections were mounted on one of three slides. Reference slides were
placed in formaldehyde solution to fix the tissue for subsequent counterstaining. Slides for autoradiographic processing were kept at
4°C during sectioning, dried in a vacuum desiccator for 1 h, stored
at 20°C overnight to allow adhesion between the section and
the slide, and then stored at 70°C.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The cardiorespiratory response to hypoxia consisted of increases in arterial blood pressure, phrenic nerve amplitude, and breathing frequency, followed by a decrease in frequency relative to the peak hypoxic breathing frequency (Fig. 1, top). In the posthypoxic period, frequency decreased further, but the increase in amplitude of phrenic bursts was sustained. The posthypoxic decrease in frequency was present in all animals and was not affected by vehicle administration.
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Dizocilpine had a dose-related effect on the respiratory response to hypoxia. Low doses (0.01 or 0.03 mg/kg) of dizocilpine had little effect on baseline cardiorespiratory variables and on the respiratory response to hypoxia, and for that reason, the data from these animals were combined into the low-dose group. However, after the high dose [0.3 (Fig. 1, bottom) or 1.0 mg/kg] of dizocilpine, baseline inspiratory duration increased and increased further during the hypoxic exposure. After hypoxia, expiratory duration did not increase, and PHFD was blocked (Fig. 1, bottom). High doses of dizocilpine lowered resting blood pressure and dampened the pressor response to hypoxia (Fig. 1, bottom). Because PHFD was blocked in all animals that received the higher doses of dizocilpine, the data were combined into the high-dose group.
Dizocilpine elicited dose-related effects on breathing frequency. Baseline and posthypoxic breathing frequencies were altered in a dose-related manner by dizocilpine. Baseline breathing frequency increased slightly, but not significantly, after low doses of dizocilpine (Fig. 2A) and decreased significantly (P = 0.02) after high doses of dizocilpine (Fig. 2A). Despite decreased baseline frequency after high doses of dizocilpine, the posthypoxic breathing frequency was significantly greater than pretreatment posthypoxic frequency (P = 0.05; Fig. 2B). The difference in the posthypoxic breathing pattern due to high doses of dizocilpine was more apparent when posthypoxic breathing frequencies were plotted as percent changes from their respective baseline frequencies (Fig. 2C). PHFD was still significant (P = 0.02), although attenuated in the low-dose group (Fig. 2C). However, PHFD was blocked by high doses of dizocilpine, because normalized posthypoxic breathing frequency was not different from zero (P = 0.85; Fig. 2C).
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Dizocilpine elicited dose-related effects on respiratory response during hypoxia. Hypoxia elicited absolute increases in breathing frequency both before and after treatment, but peak breathing frequency was significantly decreased after high doses of dizocilpine compared with pretreatment (P = 0.002; Fig. 5A). In addition, there was a transient increase in inspiration during hypoxia in the high-dose group (P = 0.003; Fig. 5B).
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PNAareas
during the peak response to hypoxia and at the end of the hypoxic
exposure compared with baseline
PNAareas (in
high-dose dizocilpine group of animals;
P = 0.04 and 0.03, respectively; Fig.
6B). The
effect of low doses of dizocilpine and vehicle on PNAareas
were not different from baseline (Fig.
6A). However, the correlation
between posthypoxic and
pe
PNAareas that existed before dizocilpine and after vehicle
(r = 0.60 and 0.60 and
P = 0.01 and 0.12, respectively; Fig.
7, A and
B) was abolished after low
(r = 0.25;
P = 0.58; Fig.
7C) and high
(r = 0.24;
P = 0.53; Fig.
7D) doses of dizocilpine. Thus, with
pretreatment and vehicle, the increase in
PNAareas was
sustained; i.e., the greatest
PNAareas during hypoxia remained the greatest after hypoxia. This relationship was eliminated after treatment.
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Distribution of NMDA receptors in brain stem. Our in vivo results implied the presence of NMDA receptors in brain stem areas implicated in the control of respiratory timing. To test this, the distribution of NMDA receptors in rat brain stem was visualized. Specific binding of [3H]dizocilpine to NMDA receptors in pontine (Fig. 8A) and medullary (Fig. 8B) sections was widespread but distributed nonuniformly. Fiber tracts were not labeled and appeared dark in the sections (shaded areas in reconstructions). In contrast, light areas indicated presence of binding sites, which included regions known to affect the respiratory pattern. In the pons, [3H]dizocilpine labeling was present in the VL pontine reticular formation containing the A5 region immediately medial to the facial nerve and in the DL pontine parabrachial complex (Fig. 8A). In the medulla, labeling was observed in the parapyramidal nuclei (13) and throughout the solitary complex and reticular formation (Fig. 8B).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The present study addressed three hypotheses. First, we hypothesized that PHFD required activation of NMDA receptors. PHFD was attenuated after low doses and eliminated after high doses of dizocilpine, an NMDA-receptor channel antagonist. Second, we hypothesized that the response to hypoxia would remain after dizocilpine treatment. Expiratory duration decreased during the hypoxic exposure, but inspiratory duration increased transiently. Third, we confirmed that NMDA receptors exist in the brain stem and could be visualized using spermidine to enhance binding of radiolabeled dizocilpine. NMDA receptors were distributed widely, but differentially, throughout the brain stem and were present in regions containing respiratory-modulated activity.
Possible sites of action of dizocilpine for PHFD. The widespread distribution of NMDA receptors in the brain stem indicates the potential involvement of multiple target sites that could regulate respiratory rhythm during and after hypoxia. The effects of dizocilpine could be exerted at three potential sites: 1) the NTS which integrates carotid body input, 2) the VL medulla which generates the breathing pattern, and 3) the lateral pons which is necessary for PHFD (5). However, the exact neural pathway, which includes a pontine relay, is unknown, but evidence for the potential role of glutamate and NMDA receptors in hypoxia-related timing changes has been demonstrated at two of these sites. In the NTS, increased glutamate release coincides with hypoxia (24), and NTS-evoked excitatory input to DL pontine neurons has been blocked by NMDA-receptor antagonists (16). Our autoradiographic data show that NMDA receptors are located in both the VL and DL pons. This finding supports the physiological evidence that implicates both these pontine regions in the regulation of respiratory rhythm. Microinjections of dizocilpine into the parabrachial region perturbs the inspiratory off-switch in cats and rats (12, 21), and glutamatergic activation of VL pontine neurons prolongs expiration in rats (18). On the basis of the information from these previous reports (5, 12, 16, 18, 21, 24), we speculate that NTS relay neurons transmit chemosensory information to lateral pontine neurons which elicit PHFD through the VL medullary central pattern generator. If this relay exists, we would then anticipate a correlation between the level of activation of a chemosensitive index during hypoxia and PHFD. However, before dizocilpine treatment, peak hypoxic breathing frequency was not correlated to posthypoxic breathing frequency. Thus exposure to hypoxia results from noncorrelated increases in respiratory variables that may result from differences in the integration of chemoreceptor inputs.
Facilitatory aspects of hypoxia on cardiorespiration.
Activation of carotid chemoreceptor afferents elicits transient
increases in respiratory frequency and amplitude of phrenic nerve
activity (PNA). We hypothesized that these facilitatory responses to
hypoxia would be unaffected by dizocilpine, but dizocilpine altered
some aspects of the response to hypoxia. Increases in respiratory
frequency remained in response to hypoxia due to decreases in
expiratory duration, but the overall frequency response to hypoxia was
attenuated by high doses of dizocilpine. This attenuated frequency
response was due to the transient increase in
ti during hypoxia
after high-dose administration. The increases in
PNAareas reflect the combined relative increases in inspiration and amplitude of
PNA that also remained.
Relationship of peak breathing frequencies during hypoxia to breathing frequencies after hypoxia. We make the following assumptions regarding the respiratory variables that determine breathing frequencies under different conditions: 1) baseline breathing frequency is determined in the medulla by the RPG and a pontine influence; 2) peak breathing frequency is determined by an interaction between the RPG and chemoreceptor input; and 3) posthypoxic breathing frequency is determined by an interaction between the RPG and its dynamic pontine input. From these assumptions, we predict that baseline and peak hypoxic frequencies are related through properties of the RPG and that this correlation exists before and after NMDA-receptor blockade. We also predict that peak and posthypoxic breathing frequencies will not be or will be weakly correlated, because two independent variables are interacting on a common factor, the RPG.
Our results support these assumptions. Posthypoxic breathing frequency was not correlated to peak hypoxic breathing frequency in the groups of animals before treatment or after vehicle or in the low-dose dizocilpine group. Although a correlation between peak and posthypoxic breathing frequencies might have been expected, this was not the case. However, after the higher dizocilpine dose, posthypoxic breathing frequency was tightly correlated to peak frequency. In addition, peak frequency during hypoxia is correlated to baseline breathing frequency before treatment. We interpret these findings to indicate that a dynamic variable modulating the RPG after hypoxia was eliminated by dizocilpine, and the breathing pattern returns to the baseline breathing pattern which is determined primarily by properties of the RPG. In other words, the RPG receives an excitatory drive from the carotid sinus nerves during hypoxia and a modulating input from the VL pons after hypoxia. Once NMDA receptors are blocked, peak breathing frequency during hypoxia is correlated to posthypoxic breathing frequency, because, we speculate, the dynamic modulatory input from the pons has been blocked. Thus the RPG is unmodulated after hypoxia.NMDA-receptor activation is required for PHFD. The present study is the first to suggest that the pathway causing a prolongation of expiration after hypoxia might be dependent on glutamate activation through NMDA receptors. The undershoot in respiratory frequency, which occurs in the poststimulation period, has been described as "short-term depression" (STD) of respiratory frequency (15). However, we speculate that the undershoot in frequency represents an excitation of an inhibitory process, as the term STD implies, because blockade of excitatory neurotransmission prevented PHFD, even though the facilitatory response to hypoxia remained. Furthermore, an analogy can be drawn between this short-term potentiation of expiration and other time-dependent changes in respiration. For example, short-term potentiation of expiration follows the same time course as short-term potentiation (STP; Ref. 33), where the poststimulus effect lasts for seconds to minutes. We speculate that PHFD could be mediated by pontine activation of postinspiratory neurons (also termed E-Dec neurons), an element of the irreversible inspiratory off-switch (28) in the VL medulla. Recent evidence shows that E-Dec neurons in the caudal VL medulla are activated by stimulation of chemoreceptors and that their activation is NMDA dependent (8). This finding is consistent with our hypothesis that PHFD results from prolongations in expiration by exciting medullary expiratory neurons via a pontine glutamatergic mechanism.
Perspectives
Different respiratory responses are elicited by hypoxia at different stages of mammalian development. In the fetus, breathing movements cease during hypoxemia (2). In the newborn and adult, ventilation increases and then decreases during hypoxia (5, 15, 22). Specifically, in the newborn, tidal volume increases and then falls, whereas respiratory frequency decreases from the start of the exposure (22). In contrast, in the adult, respiratory frequency and amplitude of PNA increase during hypoxia. Although the amplitude increase is sustained, frequency decreases progressively toward the end of the hypoxic exposure (5, 15). Posthypoxia, respiratory frequency decreases even further in the adult (5, 15). We speculate that the decrease in respiratory frequency during hypoxia is neurally mediated and that the undershoot in frequency after hypoxia is a continuation of the slowing process initiated by hypoxia. Furthermore, we speculate that the decreases in frequency in the newborn and adult are related to the fetal response to hypoxia and that the primary goal of this system is to conserve energy during hypoxia. Lastly, we speculate that the mechanism decreasing respiratory frequency has an excitatory component rather than being strictly inhibitory or disfacilitatory. Specifically, excitation of brain stem expiratory neurons decreases frequency, and thus the decrease in frequency during and after acute hypoxia is short-term potentiation of expiration. We have presented evidence that VL pontine neurons are required for PHFD (5) and, in this study, that glutamatergic neurotransmission is involved in modulation of PHFD. We would expect both of these elements to be components of short-term potentiation of expiration.| |
ACKNOWLEDGEMENTS |
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We gratefully acknowledge Philip Martinak and Mohamad El-Khatib for help in some of the experiments and Philip Martinak for statistical analysis and graphs.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-25830, HL-42400, and HL-44514.
Address for reprint requests: S. K. Coles, Div. of Pulmonary and Critical Care Medicine, Dept. of Medicine, Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106-4941.
Received 2 October 1997; accepted in final form 5 February 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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vs. large 
; n = 9).
Nevertheless, mean absolute posthypoxic breathing frequency
significantly (B;
* P = 0.05) increased compared
with its respective pretreatment frequency
(B; n = 9). Due to this increase in posthypoxic breathing frequency, there
was no undershoot in respiratory frequency after hypoxia, and PHFD was
abolished (large 
, vehicle;
small 
