The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

Purves, M. J.

doi:10.1113/jphysiol.1966.sp007972

Cited by 40 publications

(22 citation statements)

References 34 publications

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“…Hornbein, Roos and Griffo [1961] showed that the adult cat sensed a fall in Pa,O2 of 7 mm. Hg, and Purves [1966] has shown that the newborn lamb can sense a change of + 6-10 mm. Hg Pa,O2 in the normoxic range (70-80 mm.…”

Section: Discussionmentioning

confidence: 99%

Some Effects of Maternal Hyperoxia and Hypoxia on the Blood Gas Tensions and Vascular Pressures in the Foetal Sheep

Parker¹,

Purves²

1967

Exp Physiol

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Blood gas tensions, pH and intravascular pressures have been measured at various sites in 22 foetal sheep of gestational age 110-147 days. Umbilical venous oxygen tension did not change significantly with age. The mean pulmonary artery pressure always exceeded that in the aorta and this pressure gradient did not change with age. By contrast the umbilical arterio-venous pressure gradient increased with age. When the ewe breathed room air, the oxygen difference between uterine artery and umbilical vein was 43-62 mm. Hg. When the ewe breathed 100 per cent 02 umbilical venous Po2 rose by 4-15 mm. Hg and umbilical venous pH fell by 0 04-0 07 pH units.There were no consistent changes in foetal heart rate or blood pressures.When the ewe breathed 10 per cent 02 in N2, umbilical venous Po. fell by [7][8][9][10][11][12][13][14] mm. Hg, mean pressures in pulmonary artery and aorta and the pulmonary artery/ aortic pressure gradient increased as did the size of the right to left shunt across the ductus arteriosus. Heart rate invariably increased. The oxygen saturation difference between ascending and descending aorta was maintained or increased.These results suggest (1) that factors other than a diffusion barrier to oxygen are responsible for the maternal/foetal oxygen gradient and (2) that, with maternal hypoxia, there is a redistribution of blood flow in the foetus so that as high a tissue Po, as possible is maintained in coronary and cerebral circulations.

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Section: Discussionmentioning

confidence: 99%

Some Effects of Maternal Hyperoxia and Hypoxia on the Blood Gas Tensions and Vascular Pressures in the Foetal Sheep

Parker¹,

Purves²

1967

Exp Physiol

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“…Type I cells act as the primary O 2 sensors in mammals and are responsible for matching changes in arterial pO 2 with appropriate changes in respiration (14). Our laboratory has used PC12 cells as a model system to study the biophysical and molecular properties of oxygen-sensing cells (15).…”

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confidence: 99%

EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK

Conrad

Freeman

Beitner‐Johnson

et al. 1999

Journal of Biological Chemistry

158

116

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Hypoxia is a common environmental stress that regulates gene expression and cell function. A number of hypoxia-regulated transcription factors have been identified and have been shown to play critical roles in mediating cellular responses to hypoxia. One of these is the endothelial PAS-domain protein 1 (EPAS1/HIF2-␣/HLF/ HRF). This protein is 48% homologous to hypoxia-inducible factor 1-␣ (HIF1-␣). To date, virtually nothing is known about the signaling pathways that lead to either EPAS1 or HIF1-␣ activation. Here we show that EPAS1 is phosphorylated when PC12 cells are exposed to hypoxia and that p42/p44 MAPK is a critical mediator of EPAS1 activation. Pretreatment of PC12 cells with the MEK inhibitor, PD98059, completely blocked hypoxiainduced trans-activation of a hypoxia response element (HRE) reporter gene by transfected EPAS1. Likewise, expression of a constitutively active MEK1 mimicked the effects of hypoxia on HRE reporter gene expression. However, pretreatment with PD98059 had no effect on EPAS1 phosphorylation during hypoxia, suggesting that MAPK targets other proteins that are critical for the trans-activation of EPAS1. We further show that hypoxia-induced trans-activation of EPAS1 is independent of Ras. Finally, pretreatment with calmodulin antagonists nearly completely blocked both the hypoxia-induced phosphorylation of MAPK and the EPAS1 trans-activation of HRE-Luc. These results demonstrate that the MAPK pathway is a critical mediator of EPAS1 activation and that activation of MAPK and EPAS1 occurs through a calmodulin-sensitive pathway and not through the GTPase, Ras. These results are the first to identify a specific signaling pathway involved in EPAS1 activation.Regulation of gene expression is a primary response by which cells adapt to changes in the environment. The mechanisms involved in regulation of gene expression in response to hypoxia are beginning to be understood. Transcription factors that are activated by hypoxia include the hypoxia-inducible factor (HIF1-␣), 1 c-fos, and CREB (1-4). HIF1-␣ has been shown to be critical for hypoxia-induced regulation of a number of genes, including glycolytic enzymes, vascular endothelial growth factor, and erythropoieitin (5-7). Recently, endothelial PAS-domain protein 1 (EPAS1, also known as HIF2-␣, HLF, and HRF) was identified as a hypoxia-inducible transcription factor (8 -10). EPAS1 is a basic helix-loop-helix transcription factor, which shares 48% sequence identity with HIF1-␣ (8). EPAS1 protein levels, like HIF1-␣ levels, are relatively low under basal conditions and accumulate upon exposure of cells to hypoxia (11). These factors then translocate to the nucleus and trans-activate target genes containing the sequence 5Ј-GCCCTACGTGCTGTCTCA-3Ј, which is commonly referred to as the hypoxia response element (HRE) (8, 12). EPAS1 is expressed in many tissues and is particularly abundant in the type I oxygen-sensing cells of the carotid body (13). Type I cells act as the primary O 2 sensors in mammals and are responsible for matching changes in art...

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“…Peripheral chemoreceptors other than the carotid glomi have not been shown to be of importance in the young lamb [6,11,12]. Recovery of ventilation after division of the first carotid sinus nerve, therefore, must be attributed to increased activity of the contralateral carotid body and of central chemosensing mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Respiratory Effects of Division of the Carotid Sinus Nerve in the Lamb Soon After the Initiation of Breathing

et al. 1968

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ExtractIncreased activity of the carotid chemorecep tors from hypoxia and hypercarbia, induced by occlusion of the umbilical cord, has importance in initiating effective respiration of the term lamb. The state of hypoxia and hypercarbia continuing after birth should also evoke strong stimulation from the carotid glomi. The present experiments measure the effects on ventilation resulting from interruption of carotid chemoreceptor stimulation to the respiratory center by division of each carotid sinus nerve of the lamb during the newborn period.Ewes were given spinal anesthesia and each lamb was partly removed from the uterus to permit an operative approach through the neck. The carotid sinus nerves were exposed and tagged with loose threads to facilitate division of the nerve at a later stage. The lamb was then delivered, its umbilical cord clamped, and its inspiratory volume measured by pneumotachometric techniques.Each of the seven lambs studied was permitted to establish respiration before its first carotid sinus nerve was divided. The time intervals between birth and division of the first nerves varied from 5.5 to 38.5 minutes after birth. The second nerves were divided several minutes later when respiration had recovered from the effects of division of the first nerve. A significant fall in ventilation was observed within 50 seconds after division of each carotid sinus nerve. Improved ventilation began to occur in some animals 150 seconds later, and occurred in all animals within several minutes after division of each nerve. Levels of Pc>2> pH and PCO2 i n carotid artery blood before nerve division revealed hypoxia, hypercarbia and acidosis; this aberrant state became worse during the period of diminished ventilation. The minimal changes in heart rate and blood pressure resulting from interruption of baroreceptor fibers were insufficient to influence respiration. Speculation

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The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

Cited by 40 publications

References 34 publications

Some Effects of Maternal Hyperoxia and Hypoxia on the Blood Gas Tensions and Vascular Pressures in the Foetal Sheep

Some Effects of Maternal Hyperoxia and Hypoxia on the Blood Gas Tensions and Vascular Pressures in the Foetal Sheep

EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK

Respiratory Effects of Division of the Carotid Sinus Nerve in the Lamb Soon After the Initiation of Breathing

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