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)

Calcium/calmodulin-dependent kinase II mediates critical components of the hypoxic ventilatory response within the nucleus of the solitary tract in adult rats

2005 ◽  
Vol 289 (3) ◽  
pp. R871-R876 ◽  
Author(s):  
Stephen R. Reeves ◽  
Edwin S. Carter ◽  
Shang Z. Guo ◽  
David Gozal
Keyword(s):  
Ventilatory Response ◽  
Minute Ventilation ◽  
Acute Hypoxia ◽  
Respiratory Frequency ◽  
Whole Body ◽  
Solitary Tract ◽  
Hypoxic Ventilatory Response ◽  
Adult Rats ◽  
Osmotic Pumps ◽  
Calcium Calmodulin Dependent

Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-d-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O2-balance N2 for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.

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.

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)

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.

Control of ventilation in adult rats hypoxic in the neonatal period

1990 ◽  
Vol 259 (4) ◽  
pp. R836-R841 ◽  
Author(s):  
S. Okubo ◽  
J. P. Mortola
Keyword(s):  
Neonatal Period ◽  
Ventilatory Response ◽  
Acute Hypoxia ◽  
Lower Sensitivity ◽  
Adult Rats ◽  
Genetic Characteristics ◽  
Ventilatory Responses ◽  
Central Inhibition ◽  
Inspiratory Activity ◽  
High Altitude Natives

Three groups of 50-day-old (i.e., postpuberty) rats have been studied: controls, rats exposed to 6 days of hypoxia [inspired fraction of O2 (FIo2) = 10% O2] when newborn (Nb-Hypox), and rats exposed to the same level and duration of hypoxia after weaning (Ad-Hypox). Ventilation during normoxic breathing was higher in Nb-Hypox than in controls or Ad-Hypox. The ventilatory response to acute hypoxia (10 min of 10% O2) was about one-half in Nb-Hypox than in the other two groups. Additional measurements performed on Nb-Hypox and controls showed minimal or no differences between the two groups in the ventilatory responses to hyperoxia and hypercapnia, heart rate and blood pressure at various FIO2, and blood biochemistry. Analysis of the Hering-Breuer reflexes, during barbiturate anesthesia, suggested a decreased central inhibition on inspiratory activity in Nb-Hypox, which with a lower sensitivity to inputs from the peripheral chemoreceptors may contribute to the normoxic hyperventilation and the blunted response to acute hypoxia. The ventilatory patterns of Nb-Hypox rats bear numerous similarities with those of high-altitude natives and could suggest that the highlander's ventilatory responses are not genetic characteristics but relate to chronic hypoxia early in life.

Effect of acute hypoxia on respiration and brain stem blood flow in the piglet

1991 ◽  
Vol 70 (1) ◽  
pp. 251-259 ◽  
Author(s):  
R. A. Darnall ◽  
G. Green ◽  
L. Pinto ◽  
N. Hart
Keyword(s):  
Blood Flow ◽  
Brain Stem ◽  
Minute Ventilation ◽  
Acute Hypoxia ◽  
Extracellular Fluid ◽  
Respiratory Drive ◽  
Peripheral Chemoreceptor ◽  
Before And After ◽  
Spontaneously Breathing ◽  
Local Brain

Changes in local brain stem perfusion that alter extracellular fluid Pco2 and/or [H+] near central chemoreceptors may contribute to the decrease in respiration observed during hypoxia after peripheral chemoreceptor denervation and to the delayed decrease observed during hypoxia in the newborn. In this study, we measured the changes in respiration and brain stem blood flow (BBF) during 2–4 min of hypoxic hypoxia in both intact and denervated piglets and calculated the changes in brain stem Pco2 and [H+] that would be expected to occur as a result of the changes in BBF. All animals were anesthetized, spontaneously breathing, and between 2 and 7 days of age. Respiratory and other variables were measured before and during hypoxia in all animals, and BBF (microspheres) was measured in a subgroup of intact and denervated animals at 0, 30, and 260 s and at 0 and 80 s, respectively. During hypoxia, minute ventilation increased and then decreased (biphasic response) in the intact animals but decreased only in the denervated animals. BBF increased in a near linear fashion, and calculated brain stem extracellular fluid Pco2 and [H+] decreased over the first 80 s both before and after denervation. We speculate that a rapid increase in BBF during acute hypoxia decreases brain stem extracellular fluid Pco2 and [H+], which, in turn, negatively modulate the increase in respiratory drive produced by peripheral chemoreceptor input to the central respiratory generator.

Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats

1997 ◽  
Vol 83 (2) ◽  
pp. 537-542 ◽  
Author(s):  
Chikako Saiki ◽  
Jacopo P. Mortola
Keyword(s):  
Body Temperature ◽  
Oxidative Phosphorylation ◽  
Acute Hypoxia ◽  
Mammalian Species ◽  
Metabolic Effect ◽  
Adult Rats ◽  
Open Flow ◽  
Pharmacological Stimulation ◽  
Before And After ◽  
Mitochondrial Uncoupler

Saiki, Chikako, and Jacopo P. Mortola. Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats. J. Appl. Physiol. 83(2): 537–542, 1997.—During acute hypoxia, a hypometabolic response is commonly observed in many newborn and adult mammalian species. We hypothesized that, if hypoxic hypometabolism were entirely a regulated response with no limitation in O2availability, pharmacological uncoupling of the oxidative phosphorylation should raise O2consumption (V˙o 2) by similar amounts in hypoxia and normoxia. Metabolic, ventilatory, and cardiovascular measurements were collected from conscious rats in air and in hypoxia, both before and after intravenous injection of the mitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10% O2 breathing, 60% arterial O2 saturation),V˙o 2, as measured by an open-flow technique, was less than in normoxia (∼80%). Successive DNP injections (6 mg/kg, 4 times) progressively increasedV˙o 2 in both normoxia and hypoxia by similar amounts. Body temperature slightly increased in normoxia, whereas it did not change in hypoxia. The DNP-stimulatedV˙o 2 during hypoxia could even exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted in hypotension and a drop in systemic vascular resistance. We conclude that pharmacological stimulation ofV˙o 2 counteracts theV˙o 2 drop determined by hypoxia and stimulates V˙o 2not dissimilarly from normoxia. Hypoxic hypometabolism is likely to reflect a regulated process of depression of thermogenesis, with no limitation in cellular O2availability.

scholarly journals Potentiation of hypoxic ventilatory response by hyperoxia in the conscious rat: putative role of nitric oxide

1998 ◽  
Vol 85 (1) ◽  
pp. 129-132 ◽  
Author(s):  
David Gozal
Keyword(s):  
Nitric Oxide ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Hypoxic Ventilatory Response ◽  
Sprague Dawley ◽  
Conscious Rat ◽  
Adult Rats ◽  
Hyperoxic Exposure ◽  
Essential Components ◽  
Oxide Synthase

In humans, the hypoxic ventilatory response (HVR) is augmented when preceded by a short hyperoxic exposure (Y. Honda, H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. J. Appl. Physiol. 81: 1627–1632, 1996). To examine whether neuronal nitric oxide synthase (nNOS) is involved in such hyperoxia-induced HVR potentiation, 17 male Sprague-Dawley adult rats underwent hypoxic challenges (10% O2-5% CO2-balance N2) preceded either by 10 min of room air (−O2) or of 100% O2(+O2). At least 48 h later, similar challenges were performed after the animals received the selective nNOS inhibitor 7-nitroindazole (25 mg/kg ip). In −O2 runs, minute ventilation (V˙e) increased from 121.3 ± 20.5 (SD) ml/min in room air to 191.7 ± 23.8 ml/min in hypoxia ( P< 0.01). After +O2,V˙e increased from 114.1 ± 19.8 ml/min in room air to 218.4 ± 47.0 ml/min in hypoxia (+O2 vs. −O2: P < 0.005, ANOVA). After 7-nitroindazole administration, HVR was not affected in the −O2 treatment group withV˙e increasing from 113.7 ± 17.8 ml/min in room air to 185.8 ± 35.0 ml/min in hypoxia ( P < 0.01). However, HVR potentiation in +O2-exposed animals was abolished (111.8 ± 18.0 ml/min in room air to 184.1 ± 35.6 ml/min in hypoxia; +O2 vs. −O2: P not significant). We conclude that in the conscious rat nNOS activation mediates essential components of the HVR potentiation elicited by a previous short hyperoxic exposure.

scholarly journals Ventilatory responses to ozone are reduced in immature rats

2000 ◽  
Vol 88 (6) ◽  
pp. 2023-2030 ◽  
Author(s):  
S. A. Shore ◽  
J. H. Abraham ◽  
I. N. Schwartzman ◽  
G. G. Krishna Murthy ◽  
J. D. Laporte
Keyword(s):  
Bronchoalveolar Lavage ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Ventilatory Responses ◽  
Sprague Dawley Rats ◽  
Immature Rats ◽  
Old Rats ◽  
Induced Changes

During ozone (O3) exposure, adult rats decrease their minute ventilation (V˙e). To determine whether such changes are also observed in immature animals, Sprague-Dawley rats, aged 2, 4, 6, 8, or 12 wk, were exposed to O3(2 ppm) in nose-only-exposure plethysmographs. BaselineV˙e normalized for body weight decreased with age from 2.1 ± 0.1 ml ⋅ min−1⋅ g−1in 2-wk-old rats to 0.72 ± 0.03 ml ⋅ min−1⋅ g−1in 12-wk-old rats, consistent with the higher metabolic rates of younger animals. In adult (8- and 12-wk-old) rats, O3caused 40–50% decreases in V˙e that occurred primarily as the result of a decrease in tidal volume. In 6-wk-old rats, O3-induced changes inV˙e were significantly less, and in 2- and 4-wk-old rats, no significant changes inV˙e were observed during O3exposure. The increased baseline V˙e and the smaller decrements in V˙e induced by O3in the immature rats imply that their delivered dose of O3is much higher than in adult rats. To determine whether these differences in O3dose influence the extent of injury, we measured bronchoalveolar lavage protein concentrations. The magnitude of the changes in bronchoalveolar lavage induced by O3was significantly greater in 2- than in 8-wk-old rats (267 ± 47 vs. 165 ± 22%, respectively, P < 0.05). O3exposure also caused a significant increase in PGE2in 2-wk-old but not in adult rats. The results indicate that the ventilatory response to O3is absent in 2-wk-old rats and that lack of this response, in conjunction with a greater specific ventilation, leads to greater lung injury.

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