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Modulation of hypoxic depressions of ventilatory activity in the newborn piglet by mesencephalic mechanisms
Brain Research 819 Ž1999. 147–149
Short communication
Modulation of hypoxic depressions of ventilatory activity in the newborn piglet by mesencephalic mechanisms Walter M. St.-John ) , Rene´ St. Jacques, Aihua Li, Robert A. Darnall Departments of Physiology and Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756 USA Accepted 1 December 1998
Abstract In neonates, ventilatory responses to hypoxia are ‘biphasic,’ with an augmentation followed by a decline. The hypoxia-induced augmentations in ventilation are attenuated and the depressions are accentuated following denervation of the peripheral chemoreceptors. Piglets that were decerebrated at a rostral mesencephalic level exhibited these hypoxia-induced depressions. These depressions were lessened following transection through the caudal mesencephalon. Mesencephalic mechanisms play a fundamental role in the brainstem regulation of ventilatory responses to hypoxia. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Control of breathing; Hypoxia; Neonate; Piglets
The ventilatory response to hypoxia represents the net result of two counteracting stimuli. These stimuli are an augmentation of brainstem neuronal activities via afferent influences from the peripheral chemoreceptors and a reduction of these activities via influences of hypoxia upon the central nervous system. The relative balance changes with development. Thus, hypoxia abolishes fetal ‘breathing movements’ whereas, in the newborn, ventilatory responses to hypoxia are ‘biphasic’ with stimulation followed by depression. With development, the stimulation of ventilation becomes more sustained. However, at all ages, removal of the peripheral chemoreceptors reveals the depressive component in that augmentations in ventilation are greatly reduced or totally eliminated with acute hypoxia in decerebrate or anesthetized preparations w6,11,12x. Hypoxia-induced ventilatory depression does not reflect a depletion of energy substrates within the neurons but, rather, changes in the release of neurotransmitters in the region of brainstem respiratory neurons w12x. Supporting such a process is the finding that these depressions in the fetus and neonate are attenuated following transections or lesions of the mesencephalon or rostral pons w1,2,5,7,10,12,13x. An attenuation follows similar transections in adult animals having denervation of the carotid
)
Corresponding author. [email protected]
Fax:
q 1-603-650-6130;
E-mail:
chemoreceptors w9x. The present experiments were undertaken to evaluate the hypothesis that the same mesencephalic region would regulate both the depressive component of the biphasic response to hypoxia in the newborn and that following denervation of the carotid chemoreceptors. Eight piglets, of ages from day of birth to four days thereafter, were studied. Under halothane anesthesia, the internal carotid arteries were ligated, the vagi were bilaterally sectioned in seven animals and, in three, the carotid sinus nerves were also sectioned. The brainstem was transected through the rostral portion of the superior colliculi w8x. Halothane anesthesia was discontinued, the animals were paralyzed and artificially ventilated. End-tidal fractional concentrations of carbon dioxide ŽFETCO2 . and oxygen ŽFETO2 ., arterial blood pressure and body temperature were monitored continuously; the latter was maintained at 38–398C. Efferent activity of the phrenic nerve and its integral were recorded. The peak height of the integrated activity ŽPeak. multiplied by the frequency of phrenic bursts Ž f . was taken as the index of ventilatory activity ŽPeak P f .. Control recordings were obtained at FETCO 2 levels of 0.05–0.06 in oxygen Žhyperoxia.. Animals were then exposed to normoxia andror hypoxia ŽFETO2 s 0.10–0.07.. FETCO 2 was maintained constant at control levels. Recordings in hypoxia were continued for a maximum of 15 min. This experimental sequence was repeated following addi-
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 8 . 0 1 3 1 0 - 9
148
W.M. St.-John et al.r Brain Research 819 (1999) 147–149
tional sections of the brainstem through the rostral andror caudal portions of the inferior colliculi. Following brainstem sections at each level, values of ‘minute ventilatory activity’ ŽPeak P f . in hyperoxia were designated as 100%. Values of Fig. 1 at time of 0 s are those recorded in hyperoxia. Other values are at designated times after exposure to hypoxia. Following the decerebration through the rostral portion of the superior colliculi, hypoxia-induced augmentations of ventilatory activity were variable. However, depressions were consistent and profound. Phrenic activity entirely ceased for two of five animals having intact carotid chemoreceptors and two of three having carotid sinus nerve section ŽFigs. 1 and 2.. Following a transection through the rostral inferior colliculi, depressions of ventilatory activity in hypoxia were still observed but were not as severe. Thus, two animals in which phrenic activity had ceased in hypoxia now had sustained rhythmic activity. Following a transection through the caudal inferior colliculi, hypoxia-induced depressions of ventilatory activity were abated in seven of eight animals. In the one other animal, ventilatory activity declined little following the rostral or caudal transections ŽFig. 2.. Responses of the animal having intact vagi were similar to those of the vagotomized animals.
Results herein are consistent with the hypothesis that a mesencephalic ‘central oxygen detector’ can modify the release of neurotransmitters onto brainstem respiratory neurons. Hence, in animals having an intact mesencephalon, phrenic activity frequently ceased after exposure to hypoxia. Following removal of the mesencephalon, no cessation of phrenic activity was observed in hypoxia. Since the piglets were artificially ventilated, the brainstem ventilatory control system would be exposed to similar levels of hypoxia following more caudal mesencephalic transections. Physical lesions of the mesencephalic red nucleus have been reported to attenuate the depressive component of the biphasic response to hypoxia in newborn rabbits w13x. Our results are consistent with this finding. However, as the rostral portion of the red nucleus would be destroyed by the midcollicular transection, it would appear that the caudal portion of this nucleus must be considered as a candidate for the mesencephalic ‘central oxygen detector’. In addition to mesencephalic mechanisms, others must also regulate hypoxia-induced ventilatory depression. Following removal of the mesencephalon, some hypoxia-induced depression remained. This remaining depression may reflect generalized changes in regional blood flow and alterations in the environment of the ponto-medullary respiratory control system Žsee Refs. w3,4x..
Fig. 1. Examples in two piglets of alterations of ventilatory activity in hypoxia. Values are means Ž" standard errors. taken over successive intervals of 30 s. Peak P f s peak integrated phrenic activity multiplied by frequency. Values are normalized as percent of value in hyperoxia at identical level of FETCO 2 . Time s 0 is hyperoxic value of 100%. Open circles are values following rostral mesencephalic transection. Solid circles are values following caudal mesencephalic transection. CSNq designates animal having intact carotid sinus nerves. CSNy is animal having bilateral sections of carotid sinus nerves.
W.M. St.-John et al.r Brain Research 819 (1999) 147–149
149
Committee of Dartmouth College and Dartmouth-Hitchcock Medical Center.
References
Fig. 2. Minimal values of ventilatory activity in hypoxia. Values are minima which were achieved at any time after exposure to air or hypoxia. PeakP f s peak integrated phrenic activity multiplied by frequency. Values following each transection are normalized as percent of value in hyperoxia at identical level of FETCO 2 . ROSTRAL and CAUDAL are transections of the rostral and caudal mesencephalon. Solid triangles are animals having intact carotid sinus nerves; open triangles are following bilateral carotid sinus nerve sections.
These studies were supported by Program Project Grant F139254 from the National Institute of Child Health and Human Development, National Institutes of Health, USA and approved by the Institutional Animal Care and Use
w1x C.E. Blanco, G.S. Dawes, M.A. Hanson, H.B. McCooke, The response to hypoxia of arterial chemoreceptors in fetal sheep and newborn lambs, J. Physiol. ŽLondon. 351 Ž1984. 25–37. w2x C.E. Blanco, M.A. Hanson, P. Johnson, H. Rigatto, Breathing pattern of kittens during hypoxia, J. Appl. Physiol. 56 Ž1984. 12–17. w3x R.A. Darnall, R.D. Bruce, Effects of adenosine and xanthine derivatives on breathing during acute hypoxia in the anesthetized newborn piglet, Pediatric Pulmonology 3 Ž1987. 110–116. w4x R.A. Darnall, G. Green, L. Pinto, N. Hart, The effect of hypoxic hypoxia on respiratory and brainstem blood flow in the newborn piglet, J. Appl. Physiol. 70 Ž1991. 251–259. w5x G.S. Dawes, W.N. Gardner, B.M. Johnson, B.W. Walker, Breathing in fetal lambs: the effect of brain stem section, J. Physiol. ŽLondon. 335 Ž1983. 535–553. w6x A.H. Jansen, V. Chernick, Fetal breathing and development of control of breathing, J. Appl. Physiol. 70 Ž1991. 1431–1446. w7x B.D. Johnson, P.D. Gluckman, Lateral pontine lesions affect central chemosensitivity in fetal lambs, J. Appl. Physiol. 67 Ž1989. 1113– 1118. w8x E.B. Kirsten, W.M. St. John, A feline decerebration technique with low mortality and long term homeostasis, J. Pharmacol. Methods 1 Ž1978. 263–268. w9x R.L. Martin-Body, Brain transections demonstrate the central origin of hypoxic ventilatory depression in carotid body-denervated rats, J. Physiol. ŽLondon. 407 Ž1988. 41–52. w10x R.L. Martin-Body, B.M. Johnson, Central origin of the hypoxic depression of breathing in the newborn, Respir. Physiol. 71 Ž1988. 25–32. w11x J.P. Mortola, Breathing pattern in newborns, J. Appl. Physiol. 56 Ž1984. 1533–1540. w12x J.A. Neubauer, J.E. Melton, N.H. Edelman, Modulation of respiration during brain hypoxia, J. Appl. Physiol. 68 Ž1990. 441–451. w13x B.A. Waites, G.L. Ackland, R. Noble, M.P. Hanson, Red nucleus lesions abolish the biphasic respiratory response to isocapnic hypoxia in decerebrate young rabbits, J. Physiol. ŽLondon. 495 Ž1996. 217–225.
Short communication
Modulation of hypoxic depressions of ventilatory activity in the newborn piglet by mesencephalic mechanisms Walter M. St.-John ) , Rene´ St. Jacques, Aihua Li, Robert A. Darnall Departments of Physiology and Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756 USA Accepted 1 December 1998
Abstract In neonates, ventilatory responses to hypoxia are ‘biphasic,’ with an augmentation followed by a decline. The hypoxia-induced augmentations in ventilation are attenuated and the depressions are accentuated following denervation of the peripheral chemoreceptors. Piglets that were decerebrated at a rostral mesencephalic level exhibited these hypoxia-induced depressions. These depressions were lessened following transection through the caudal mesencephalon. Mesencephalic mechanisms play a fundamental role in the brainstem regulation of ventilatory responses to hypoxia. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Control of breathing; Hypoxia; Neonate; Piglets
The ventilatory response to hypoxia represents the net result of two counteracting stimuli. These stimuli are an augmentation of brainstem neuronal activities via afferent influences from the peripheral chemoreceptors and a reduction of these activities via influences of hypoxia upon the central nervous system. The relative balance changes with development. Thus, hypoxia abolishes fetal ‘breathing movements’ whereas, in the newborn, ventilatory responses to hypoxia are ‘biphasic’ with stimulation followed by depression. With development, the stimulation of ventilation becomes more sustained. However, at all ages, removal of the peripheral chemoreceptors reveals the depressive component in that augmentations in ventilation are greatly reduced or totally eliminated with acute hypoxia in decerebrate or anesthetized preparations w6,11,12x. Hypoxia-induced ventilatory depression does not reflect a depletion of energy substrates within the neurons but, rather, changes in the release of neurotransmitters in the region of brainstem respiratory neurons w12x. Supporting such a process is the finding that these depressions in the fetus and neonate are attenuated following transections or lesions of the mesencephalon or rostral pons w1,2,5,7,10,12,13x. An attenuation follows similar transections in adult animals having denervation of the carotid
)
Corresponding author. [email protected]
Fax:
q 1-603-650-6130;
E-mail:
chemoreceptors w9x. The present experiments were undertaken to evaluate the hypothesis that the same mesencephalic region would regulate both the depressive component of the biphasic response to hypoxia in the newborn and that following denervation of the carotid chemoreceptors. Eight piglets, of ages from day of birth to four days thereafter, were studied. Under halothane anesthesia, the internal carotid arteries were ligated, the vagi were bilaterally sectioned in seven animals and, in three, the carotid sinus nerves were also sectioned. The brainstem was transected through the rostral portion of the superior colliculi w8x. Halothane anesthesia was discontinued, the animals were paralyzed and artificially ventilated. End-tidal fractional concentrations of carbon dioxide ŽFETCO2 . and oxygen ŽFETO2 ., arterial blood pressure and body temperature were monitored continuously; the latter was maintained at 38–398C. Efferent activity of the phrenic nerve and its integral were recorded. The peak height of the integrated activity ŽPeak. multiplied by the frequency of phrenic bursts Ž f . was taken as the index of ventilatory activity ŽPeak P f .. Control recordings were obtained at FETCO 2 levels of 0.05–0.06 in oxygen Žhyperoxia.. Animals were then exposed to normoxia andror hypoxia ŽFETO2 s 0.10–0.07.. FETCO 2 was maintained constant at control levels. Recordings in hypoxia were continued for a maximum of 15 min. This experimental sequence was repeated following addi-
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 8 . 0 1 3 1 0 - 9
148
W.M. St.-John et al.r Brain Research 819 (1999) 147–149
tional sections of the brainstem through the rostral andror caudal portions of the inferior colliculi. Following brainstem sections at each level, values of ‘minute ventilatory activity’ ŽPeak P f . in hyperoxia were designated as 100%. Values of Fig. 1 at time of 0 s are those recorded in hyperoxia. Other values are at designated times after exposure to hypoxia. Following the decerebration through the rostral portion of the superior colliculi, hypoxia-induced augmentations of ventilatory activity were variable. However, depressions were consistent and profound. Phrenic activity entirely ceased for two of five animals having intact carotid chemoreceptors and two of three having carotid sinus nerve section ŽFigs. 1 and 2.. Following a transection through the rostral inferior colliculi, depressions of ventilatory activity in hypoxia were still observed but were not as severe. Thus, two animals in which phrenic activity had ceased in hypoxia now had sustained rhythmic activity. Following a transection through the caudal inferior colliculi, hypoxia-induced depressions of ventilatory activity were abated in seven of eight animals. In the one other animal, ventilatory activity declined little following the rostral or caudal transections ŽFig. 2.. Responses of the animal having intact vagi were similar to those of the vagotomized animals.
Results herein are consistent with the hypothesis that a mesencephalic ‘central oxygen detector’ can modify the release of neurotransmitters onto brainstem respiratory neurons. Hence, in animals having an intact mesencephalon, phrenic activity frequently ceased after exposure to hypoxia. Following removal of the mesencephalon, no cessation of phrenic activity was observed in hypoxia. Since the piglets were artificially ventilated, the brainstem ventilatory control system would be exposed to similar levels of hypoxia following more caudal mesencephalic transections. Physical lesions of the mesencephalic red nucleus have been reported to attenuate the depressive component of the biphasic response to hypoxia in newborn rabbits w13x. Our results are consistent with this finding. However, as the rostral portion of the red nucleus would be destroyed by the midcollicular transection, it would appear that the caudal portion of this nucleus must be considered as a candidate for the mesencephalic ‘central oxygen detector’. In addition to mesencephalic mechanisms, others must also regulate hypoxia-induced ventilatory depression. Following removal of the mesencephalon, some hypoxia-induced depression remained. This remaining depression may reflect generalized changes in regional blood flow and alterations in the environment of the ponto-medullary respiratory control system Žsee Refs. w3,4x..
Fig. 1. Examples in two piglets of alterations of ventilatory activity in hypoxia. Values are means Ž" standard errors. taken over successive intervals of 30 s. Peak P f s peak integrated phrenic activity multiplied by frequency. Values are normalized as percent of value in hyperoxia at identical level of FETCO 2 . Time s 0 is hyperoxic value of 100%. Open circles are values following rostral mesencephalic transection. Solid circles are values following caudal mesencephalic transection. CSNq designates animal having intact carotid sinus nerves. CSNy is animal having bilateral sections of carotid sinus nerves.
W.M. St.-John et al.r Brain Research 819 (1999) 147–149
149
Committee of Dartmouth College and Dartmouth-Hitchcock Medical Center.
References
Fig. 2. Minimal values of ventilatory activity in hypoxia. Values are minima which were achieved at any time after exposure to air or hypoxia. PeakP f s peak integrated phrenic activity multiplied by frequency. Values following each transection are normalized as percent of value in hyperoxia at identical level of FETCO 2 . ROSTRAL and CAUDAL are transections of the rostral and caudal mesencephalon. Solid triangles are animals having intact carotid sinus nerves; open triangles are following bilateral carotid sinus nerve sections.
These studies were supported by Program Project Grant F139254 from the National Institute of Child Health and Human Development, National Institutes of Health, USA and approved by the Institutional Animal Care and Use
w1x C.E. Blanco, G.S. Dawes, M.A. Hanson, H.B. McCooke, The response to hypoxia of arterial chemoreceptors in fetal sheep and newborn lambs, J. Physiol. ŽLondon. 351 Ž1984. 25–37. w2x C.E. Blanco, M.A. Hanson, P. Johnson, H. Rigatto, Breathing pattern of kittens during hypoxia, J. Appl. Physiol. 56 Ž1984. 12–17. w3x R.A. Darnall, R.D. Bruce, Effects of adenosine and xanthine derivatives on breathing during acute hypoxia in the anesthetized newborn piglet, Pediatric Pulmonology 3 Ž1987. 110–116. w4x R.A. Darnall, G. Green, L. Pinto, N. Hart, The effect of hypoxic hypoxia on respiratory and brainstem blood flow in the newborn piglet, J. Appl. Physiol. 70 Ž1991. 251–259. w5x G.S. Dawes, W.N. Gardner, B.M. Johnson, B.W. Walker, Breathing in fetal lambs: the effect of brain stem section, J. Physiol. ŽLondon. 335 Ž1983. 535–553. w6x A.H. Jansen, V. Chernick, Fetal breathing and development of control of breathing, J. Appl. Physiol. 70 Ž1991. 1431–1446. w7x B.D. Johnson, P.D. Gluckman, Lateral pontine lesions affect central chemosensitivity in fetal lambs, J. Appl. Physiol. 67 Ž1989. 1113– 1118. w8x E.B. Kirsten, W.M. St. John, A feline decerebration technique with low mortality and long term homeostasis, J. Pharmacol. Methods 1 Ž1978. 263–268. w9x R.L. Martin-Body, Brain transections demonstrate the central origin of hypoxic ventilatory depression in carotid body-denervated rats, J. Physiol. ŽLondon. 407 Ž1988. 41–52. w10x R.L. Martin-Body, B.M. Johnson, Central origin of the hypoxic depression of breathing in the newborn, Respir. Physiol. 71 Ž1988. 25–32. w11x J.P. Mortola, Breathing pattern in newborns, J. Appl. Physiol. 56 Ž1984. 1533–1540. w12x J.A. Neubauer, J.E. Melton, N.H. Edelman, Modulation of respiration during brain hypoxia, J. Appl. Physiol. 68 Ž1990. 441–451. w13x B.A. Waites, G.L. Ackland, R. Noble, M.P. Hanson, Red nucleus lesions abolish the biphasic respiratory response to isocapnic hypoxia in decerebrate young rabbits, J. Physiol. ŽLondon. 495 Ž1996. 217–225.