Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response

1992 ◽  
Vol 72 (4) ◽  
pp. 1480-1487 ◽  
Author(s):  
R. C. Ang ◽  
B. Hoop ◽  
H. Kazemi
Keyword(s):  
Excitatory Amino Acid ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Hypoxic Ventilatory Response ◽  
Mk 801 ◽  
Pulmonary Capillary ◽  
Before And After ◽  
Pulmonary Arterial ◽  
Spontaneously Breathing

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory responses to hypoxia in rats pretreated with nonpeptide NK1 receptor antagonist CP-96,345

1994 ◽  
Vol 76 (4) ◽  
pp. 1528-1532 ◽  
Author(s):  
G. T. De Sanctis ◽  
F. H. Green ◽  
X. Jiang ◽  
M. King ◽  
J. E. Remmers
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Acute Hypoxia ◽  
Frequency Component ◽  
Nk1 Receptor ◽  
Adult Rats ◽  
Nk1 Receptors ◽  
Before And After ◽  
Sites Of Action

This study reports experiments designed to evaluate the role of neurokinin-1 (NK1) receptors for substance P (SP) in the ventilatory response to acute hypoxia. Ventilation was measured by indirect plethysmography in eight unanesthetized unrestrained adult rats before and after bolus injection of 1, 5, or 10 mg/kg (ip) of CP-96,345 (Pfizer), a potent nonpeptide competitive antagonist of the SP NK1 receptor. Ventilation was measured while the rats breathed air or 8% O2–92% N2 with and without administration of SP antagonist. Pretreatment with CP-96,345 decreased the magnitude of the hypoxic response in a dose-dependent fashion. Minute ventilation in rats pretreated with CP-96,345 was reduced by 22.1% (P < 0.05) at the highest dose (10 mg/kg), largely because of an attenuation of the frequency component. Although both control and treated rats responded to hypoxia with a decrease in duration of inspiration and expiration rats pretreated with CP-96,345 displayed a smaller decrease in inspiration and expiration than control rats (P < 0.05). We have recently shown that neuropeptide-containing fibers are important for mediating the tachypnic response during acute isocapnic hypoxia in rats. The attenuation in minute ventilation at the highest dose (10 mg/kg) is comparable in magnitude to the attenuation observed with neonatal capsaicin treatment, which permanently ablates neuropeptide-containing unmyelinated fibers. Accordingly, this previously reported role of capsaicin-sensitive nerves in the hypoxic ventilatory response of rats is probably attributable to released SP acting at NK1 receptors. One of the likely sites of action of SP antagonists is the carotid body.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory response to moderate and severe hypoxia in adult dogs: role of endorphins

1988 ◽  
Vol 65 (3) ◽  
pp. 1383-1388 ◽  
Author(s):  
J. I. Schaeffer ◽  
G. G. Haddad
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Severe Hypoxia ◽  
Moderate Hypoxia ◽  
Arterial Blood Gas ◽  
Arterial Blood ◽  
Before And After ◽  
The Relationship ◽  
Arterial Po2

To determine the role of opioids in modulating the ventilatory response to moderate or severe hypoxia, we studied ventilation in six chronically instrumented awake adult dogs during hypoxia before and after naloxone administration. Parenteral naloxone (200 micrograms/kg) significantly increased instantaneous minute ventilation (VT/TT) during severe hypoxia, (inspired O2 fraction = 0.07, arterial PO2 = 28-35 Torr); however, consistent effects during moderate hypoxia (inspired O2 fraction = 0.12, arterial PO2 = 40-47 Torr) could not be demonstrated. Parenteral naloxone increased O2 consumption (VO2) in severe hypoxia as well. Despite significant increases in ventilation post-naloxone during severe hypoxia, arterial blood gas tensions remained the same. Control studies revealed that neither saline nor naloxone produced a respiratory effect during normoxia; also the preservative vehicle of naloxone induced no change in ventilation during severe hypoxia. These data suggest that, in adult dogs, endorphins are released and act to restrain ventilation during severe hypoxia; the relationship between endorphin release and moderate hypoxia is less consistent. The observed increase in ventilation post-naloxone during severe hypoxia is accompanied by an increase in metabolic rate, explaining the isocapnic response.

Acute mountain sickness, chemosensitivity, and cardiorespiratory responses in humans exposed to hypobaric and normobaric hypoxia

2014 ◽  
Vol 116 (7) ◽  
pp. 945-952 ◽  
Author(s):  
Normand A. Richard ◽  
Inderjeet S. Sahota ◽  
Nadia Widmer ◽  
Sherri Ferguson ◽  
A. William Sheel ◽  
...  
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Acute Mountain Sickness ◽  
Blood Oxygenation ◽  
Normobaric Hypoxia ◽  
Hypoxic Exposure ◽  
Hypoxic Ventilatory Response ◽  
Before And After ◽  
Mountain Sickness ◽  
Normobaric Normoxia

We examined the control of breathing, cardiorespiratory effects, and the incidence of acute mountain sickness (AMS) in humans exposed to hypobaric hypoxia (HH) and normobaric hypoxia (NH), and under two control conditions [hypobaric normoxia (HN) and normobaric normoxia (NN)]. Exposures were 6 h in duration, and separated by 2 wk between hypoxic exposures and 1 wk between normoxic exposures. Before and after exposures, subjects ( n = 11) underwent hyperoxic and hypoxic Duffin CO2 rebreathing tests and a hypoxic ventilatory response test (HVR). Inside the environmental chamber, minute ventilation (V̇e), tidal volume (Vt), frequency of breathing ( fB), blood oxygenation, heart rate, and blood pressure were measured at 5 and 30 min and hourly until exit. Symptoms of AMS were evaluated using the Lake Louise score (LLS). Both the hyperoxic and hypoxic CO2 thresholds were lower after HH and NH, whereas CO2 sensitivity was increased after HH and NH in the hypoxic test and after NH in the hyperoxic test. Values for HVR were similar across the four exposures. No major differences were observed for V̇e or any other cardiorespiratory variables between NH and HH. The LLS was greater in AMS-susceptible than in AMS-resistant subjects; however, LLS was alike between HH and NH. In AMS-susceptible subjects, fB correlated positively and Vt negatively with the LLS. We conclude that 6 h of hypoxic exposure is sufficient to lower the peripheral and central CO2 threshold but does not induce differences in cardiorespiratory variables or AMS incidence between HH and NH.

Role of endogenous adenosine in hypoxic ventilatory response in humans: a study with dipyridamole

1994 ◽  
Vol 76 (1) ◽  
pp. 196-203 ◽  
Author(s):  
M. Yamamoto ◽  
M. Nishimura ◽  
S. Kobayashi ◽  
Y. Akiyama ◽  
K. Miyamoto ◽  
...  
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Crossover Fashion ◽  
Hypoxic Ventilatory Response ◽  
Double Blind ◽  
Adenosine Receptor Antagonist ◽  
Endogenous Adenosine ◽  
Progressive Hypoxia ◽  
Sustained Hypoxia

To examine the role of endogenous adenosine in hypoxic ventilatory response, we measured, in nine normal young adults, ventilatory responses to isocapnic progressive hypoxia and subsequent sustained hypoxia [arterial O2 saturation (SaO2); 80%, 20 min] with and without pretreatment with dipyridamole in a double-blind crossover fashion. Dipyridamole, an adenosine uptake blocker, was expected to enhance the effect of endogenous adenosine. Pretreatment with dipyridamole (0.5 mg/kg) significantly augmented the slope of the ventilatory response to isocapnic progressive hypoxia from 0.35 +/- 0.13 (SE) to 0.70 +/- 0.25 l.min-1.%fall of SaO2(-1) (P < 0.01), although there were no significant changes in resting ventilation. On the other hand, minute ventilation, when expressed as a percentage of peak ventilation, declined to 68.4 +/- 4.3% with dipyridamole at the 9–11th min of sustained hypoxia, which was significantly lower than the 90.2 +/- 8.3% with a placebo (P < 0.05), and finally reached 56.1 +/- 7.2% with dipyridamole and 78.7 +/- 9.2% with the placebo (P < 0.1) at the 18–20th min of sustained hypoxia. In an attempt to more specifically examine the role of adenosine, aminophylline (5 mg/kg), an adenosine receptor antagonist, was injected before pretreatment with dipyridamole in four subjects. Aminophylline infusion abolished or at least attenuated the effect of dipyridamole in all four subjects. These data suggest that endogenous adenosine has a modulatory role in hypoxic ventilatory response in adult humans.

Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes

2002 ◽  
Vol 93 (4) ◽  
pp. 1498-1505 ◽  
Author(s):  
Nathan E. Townsend ◽  
Christopher J. Gore ◽  
Allan G. Hahn ◽  
Michael J. McKenna ◽  
Robert J. Aughey ◽  
...  
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Respiratory Control ◽  
Endurance Athletes ◽  
Hypoxic Exposure ◽  
Dependent Manner ◽  
Hypoxic Ventilatory Response ◽  
Ambient Conditions ◽  
Altitude Exposure ◽  
End Tidal

This study determined whether “living high-training low” (LHTL)-simulated altitude exposure increased the hypoxic ventilatory response (HVR) in well-trained endurance athletes. Thirty-three cyclists/triathletes were divided into three groups: 20 consecutive nights of hypoxic exposure (LHTLc, n = 12), 20 nights of intermittent hypoxic exposure (four 5-night blocks of hypoxia, each interspersed with 2 nights of normoxia, LHTLi, n = 10), or control (Con, n = 11). LHTLc and LHTLi slept 8–10 h/day overnight in normobaric hypoxia (∼2,650 m); Con slept under ambient conditions (600 m). Resting, isocapnic HVR (ΔV˙e/ΔSpO2 , whereV˙e is minute ventilation and SpO2 is blood O2 saturation) was measured in normoxia before hypoxia (Pre), after 1, 3, 10, and 15 nights of exposure (N1, N3, N10, and N15, respectively), and 2 nights after the exposure night 20 (Post). Before each HVR test, end-tidal Pco 2(Pet CO2 ) and V˙e were measured during room air breathing at rest. HVR (l · min−1 · %−1) was higher ( P < 0.05) in LHTLc than in Con at N1 (0.56 ± 0.32 vs. 0.28 ± 0.16), N3 (0.69 ± 0.30 vs. 0.36 ± 0.24), N10 (0.79 ± 0.36 vs. 0.34 ± 0.14), N15 (1.00 ± 0.38 vs. 0.36 ± 0.23), and Post (0.79 ± 0.37 vs. 0.36 ± 0.26). HVR at N15 was higher ( P < 0.05) in LHTLi (0.67 ± 0.33) than in Con and in LHTLc than in LHTLi. Pet CO2 was depressed in LHTLc and LHTLi compared with Con at all points after hypoxia ( P < 0.05). No significant differences were observed for V˙e at any point. We conclude that LHTL increases HVR in endurance athletes in a time-dependent manner and decreases Pet CO2 in normoxia, without change inV˙e. Thus endurance athletes sleeping in mild hypoxia may experience changes to the respiratory control system.

Endothelin effects in isolated, perfused lamb lungs: role of cyclooxygenase inhibition and vasomotor tone

1991 ◽  
Vol 261 (2) ◽  
pp. H443-H450 ◽  
Author(s):  
H. Toga ◽  
J. Usha Raj ◽  
R. Hillyard ◽  
B. Ku ◽  
J. Anderson
Keyword(s):  
Vasomotor Tone ◽  
Cyclooxygenase Inhibition ◽  
Group Iii ◽  
Group I ◽  
Before And After ◽  
Pulmonary Arterial ◽  
Group Ii ◽  
Sites Of Action ◽  
Arteries And Veins

We have determined the sites of action of endothelin-1 (ET) in the lamb pulmonary circulation. The influence of cyclooxygenase inhibition and baseline vasomotor tone on ET effects was also studied. Lungs of 14 lambs (6-9 wk of age, 12.1 +/- 0.6 kg body wt) were isolated and perfused with blood. Group I lungs (n = 5) were untreated, group II lungs (n = 5) were treated with indomethacin to inhibit cyclooxygenase, and group III lungs (n = 4) were treated with indomethacin and a thromboxane A2 analogue, U-46619, to elevate vasomotor tone. All lungs were perfused with constant flow in zone 3, with left atrial and airway pressures being 8 and 6 cmH2O, respectively. We measured pulmonary arterial pressure and, by the micropuncture servo-null method, pressures in 20- to 50-microns diameter subpleural venules, both before and after each dose of ET was infused (50, 100, 250, and 500 ng/kg). Group I lungs, with high baseline vasomotor tone, exhibited a biphasic response to ET; 50-100 ng/kg of ET dilated both arteries and veins, whereas 500 ng/kg of ET constricted both arteries and veins. In group II lungs with low vasomotor tone, all doses of ET caused constriction of arteries only. In group III lungs (indomethacin treated with elevated vasomotor tone), 50-100 ng/kg of ET caused dilation of arteries and veins, whereas 500 ng/kg of ET induced constriction, this time only in arteries. We conclude that ET has both dilator and constrictor effects in arteries and veins of isolated, perfused lamb lungs. ET-induced arterial and venous dilation is dependent on initial vasomotor tone but not on cyclooxygenase metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women

2004 ◽  
Vol 97 (5) ◽  
pp. 1673-1680 ◽  
Author(s):  
Chris Morelli ◽  
M. Safwan Badr ◽  
Jason H. Mateika
Keyword(s):  
Carbon Dioxide ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
High Oxygen ◽  
Set Point ◽  
Ventilatory Responses ◽  
Episodic Hypoxia ◽  
Before And After ◽  
Oxygen Gas ◽  
End Tidal

We hypothesized that the acute ventilatory response to carbon dioxide in the presence of low and high levels of oxygen would increase to a greater extent in men compared with women after exposure to episodic hypoxia. Eleven healthy men and women of similar race, age, and body mass index completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the end-tidal partial pressure of carbon dioxide (PetCO2) below 25 Torr. Subjects then rebreathed from a bag containing a normocapnic (42 Torr), low (50 Torr), or high oxygen gas mixture (150 Torr). During the trials, PetCO2 increased while the selected level of oxygen was maintained. The point at which minute ventilation began to rise in a linear fashion as PetCO2 increased was considered to be the carbon dioxide set point. The ventilatory response below and above this point was determined. The results showed that the ventilatory response to carbon dioxide above the set point was increased in men compared with women before exposure to episodic hypoxia, independent of the oxygen level that was maintained during the rebreathing trials (50 Torr: men, 5.19 ± 0.82 vs. women, 4.70 ± 0.77 l·min−1·Torr−1; 150 Torr: men, 4.33 ± 1.15 vs. women, 3.21 ± 0.58 l·min−1·Torr−1). Moreover, relative to baseline measures, the ventilatory response to carbon dioxide in the presence of low and high oxygen levels increased to a greater extent in men compared with women after exposure to episodic hypoxia (50 Torr: men, 9.52 ± 1.40 vs. women, 5.97 ± 0.71 l·min−1·Torr−1; 150 Torr: men, 5.73 ± 0.81 vs. women, 3.83 ± 0.56 l·min−1·Torr−1). Thus we conclude that enhancement of the acute ventilatory response to carbon dioxide after episodic hypoxia is sex dependent.

Mechanical role of expiratory muscles during breathing in upright dogs

1988 ◽  
Vol 64 (3) ◽  
pp. 1060-1067 ◽  
Author(s):  
G. A. Farkas ◽  
R. E. Baer ◽  
M. Estenne ◽  
A. De Troyer
Keyword(s):  
Tidal Volume ◽  
Progressive Increase ◽  
Substantial Contribution ◽  
Postural Changes ◽  
Before And After ◽  
Cervical Vagotomy ◽  
Anesthetized Dogs ◽  
Expiratory Muscles ◽  
Spontaneously Breathing

To examine the mechanical effects of the abdominal and triangularis sterni expiratory recruitment that occurs when anesthetized dogs are tilted head up, we measured both before and after cervical vagotomy the end-expiratory length of the costal and crural diaphragmatic segments and the end-expiratory lung volume (FRC) in eight spontaneously breathing animals during postural changes from supine (0 degree) to 80 degrees head up. Tilting the animals from 0 degree to 80 degrees head up in both conditions was associated with a gradual decrease in end-expiratory costal and crural diaphragmatic length and with a progressive increase in FRC. All these changes, however, were considerably larger (P less than 0.005 or less) postvagotomy when the expiratory muscles were no longer recruited with tilting. Alterations in the elastic properties of the lung could not account for the effects of vagotomy on the postural changes. We conclude therefore that 1) by contracting during expiration, the canine expiratory muscles minimize the shortening of the diaphragm and the increase in FRC that the action of gravity would otherwise introduce, and 2) the end-expiratory diaphragmatic length and FRC in upright dogs are thus actively determined. The present data also indicate that by relaxing at end expiration, the expiratory muscles make a substantial contribution to tidal volume in upright dogs; in the 80 degrees head-up posture, this contribution would amount to approximately 60% of tidal volume.

Phrenic afferents and ventilatory control at increased end-expiratory lung volumes in cats

1989 ◽  
Vol 66 (3) ◽  
pp. 1297-1303 ◽  
Author(s):  
S. Iscoe
Keyword(s):  
Steady State ◽  
Independent Effect ◽  
Respiratory Drive ◽  
Phrenic Motoneurons ◽  
Partial Pressure Of Co2 ◽  
Before And After ◽  
Steady State Responses ◽  
Spontaneously Breathing ◽  
State Responses

The role of phrenic afferents in controlling inspiratory duration (TI) at elevated end-expiratory lung volume (EEV) has been studied in pentobarbital-anesthetized, spontaneously breathing cats with intact vagi. Responses to increases in EEV, induced by imposition of an expiratory threshold load (ETL) of 10 cmH2O, were monitored before and after section of cervical dorsal roots C3-C7. The immediate (first-breath) effect of application of ETL was a prolongation of both TI and expiratory duration (TE). After 10 min of breathing against the ETL, average TI returned to control values but TE remained prolonged. Abolishing feedback from the diaphragm did not affect these responses. When steady-state responses to ETL were compared with those elicited by inhalation of 5–6% CO2 in O2, changes in EEV had, on average, no independent effect on respiratory drive (rate of rise of integrated phrenic activity), although phrenic activity increased greatly in some cats despite little or no change in arterial partial pressure of CO2. These data indicate that diaphragmatic receptors do not contribute to either the immediate (first-breath) or steady-state responses of phrenic motoneurons to increases in EEV in intact cats.

N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs

1991 ◽  
Vol 260 (4) ◽  
pp. H1299-H1306 ◽  
Author(s):  
J. R. Fineman ◽  
M. A. Heymann ◽  
S. J. Soifer
Keyword(s):  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Vascular Tone ◽  
Pulmonary Arterial Pressure ◽  
Competitive Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Spontaneously Breathing ◽  
Dose Dependent Increase

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production. During U-46619 infusions, acetylcholine, ATP-MgCl2, isoproterenol, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) decreased pulmonary arterial pressure. During N omega-nitro-L-arginine infusions, the decrease in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) was significantly attenuated, but the decrease caused by isoproterenol, sodium nitroprusside, and 8-bromo-cGMP (endothelium-independent vasodilators) was unchanged. This study supports the hypothesis that EDRF in part mediates resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation. N omega-nitro-L-arginine is useful for studying EDRF inhibition in intact animals.

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