Neonatal Intermittent Hypoxia Leads to Long-Lasting Facilitation of Acute Hypoxia-Evoked Catecholamine Secretion From Rat Chromaffin Cells

Souvannakitti, Dangjai; Kumar, Ganesh K.; Fox, Aaron P.; Prabhakar, Nanduri R.

doi:10.1152/jn.00036.2009

Cited by 49 publications

(76 citation statements)

References 35 publications

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“…Previous studies have documented that oxidative stress mediates the effects of neonatal IH on the carotid body and adrenal medulla (12,14). To determine whether adult rats that were subjected to neonatal IH exhibit oxidative stress, we measured malondialdehyde levels (in the carotid body) and aconitase activity (in the adrenal medulla), which are two established markers of oxidative stress (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…Rat pups and their dams were exposed to IH from ages P1 to P10 between 9:00 AM and 5:00 PM, as described previously (8,12,38). Control experiments were performed on age-matched rats exposed to alternating cycles of room air instead of hypoxia.…”

Section: Methodsmentioning

confidence: 99%

“…In neonates, hypoxia facilitates catecholamine secretion by directly affecting the excitability of adrenal chromaffin cells (11), a response that is markedly augmented in neonatal rats subjected to IH (12,13). Exaggerated hypoxic sensing of carotid body and adrenal chromaffin cells in neonates by IH is attributed to increased oxidative stress (12,14). IH also augments hypoxic responses of the carotid body and adrenal medulla in adult rats (15, 16), which is completely reversed following reoxygenation (15).…”

mentioning

confidence: 99%

“…Catecholamine secretion from the adrenal medulla is another important homeostatic mechanism that preserves cardiovascular function under hypoxia (9,10). In neonates, hypoxia facilitates catecholamine secretion by directly affecting the excitability of adrenal chromaffin cells (11), a response that is markedly augmented in neonatal rats subjected to IH (12,13). Exaggerated hypoxic sensing of carotid body and adrenal chromaffin cells in neonates by IH is attributed to increased oxidative stress (12,14).…”

mentioning

confidence: 99%

“…IH also augments hypoxic responses of the carotid body and adrenal medulla in adult rats (15,16), which is completely reversed following reoxygenation (15). In striking contrast, in neonates the augmented hypoxic sensitivity that is induced by IH persists into adulthood (8,12,14). The molecular mechanisms underlying the long-lasting effects of neonatal IH on hypoxic sensing and its physiological consequences in adult life are not known.…”

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confidence: 99%

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Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis

Nanduri

Makarenko

Reddy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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120

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Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.blood pressure | developmental programming | norepinephrine I n preterm infants, respiratory disorders with recurrent apnea and the associated intermittent hypoxemia (IH) are major clinical problems (1). Infants with recurrent apnea exhibit an enhanced hypoxic ventilatory response (2), an effect that was attributed to a heightened chemo-reflex arising from the carotid body, which is a sensory organ that detects changes in arterial blood O 2 levels (3). Carotid body sensitivity to hypoxia is reset after birth and this effect is modulated by chronic hypoxia (4-6). Neonatal rats exposed to IH showed exaggerated carotid body and ventilatory responses to hypoxia (7,8). Catecholamine secretion from the adrenal medulla is another important homeostatic mechanism that preserves cardiovascular function under hypoxia (9, 10). In neonates, hypoxia facilitates catecholamine secretion by directly affecting the excitability of adrenal chromaffin cells (11), a response that is markedly augmented in neonatal rats subjected to IH (12,13). Exaggerated hypoxic sensing of carotid body and adrenal chromaffin cells in neonates by IH is attributed to increased oxidative stress (12,14). IH also augments hypoxic responses of the carotid body and adrenal medulla in adult rats (15, 16), which is completely reversed following reoxygenation (15). In striking contrast, in neonates the augmented hypoxic sensitivity that is induced by IH persists into adulthood (8,12,14). The molecular mechanisms underlying the long-lasting effects of neonatal IH on hypoxic sensing and its physiological consequences in adult life are not known.It is being increasingly recognized that environm...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis

Nanduri

Makarenko

Reddy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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120

161

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Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia

Prabhakar

Peng

Kumar

et al. 2015

Comprehensive Physiology

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Carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen levels, and the resulting chemoreflex is a potent regulator of blood pressure. Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in adult humans and infants born preterm. Adult patients with recurrent apnea exhibit heightened sympathetic nerve activity and hypertension. Adults born preterm are predisposed to early onset of hypertension. Available evidence suggests that carotid body chemoreflex contributes to hypertension caused by IH in both adults and neonates. Experimental models of IH provided important insights into cellular and molecular mechanisms underlying carotid body chemoreflex-mediated hypertension. This article provides a comprehensive appraisal of how IH affects carotid body function, underlying cellular, molecular, and epigenetic mechanisms, and the contribution of chemoreflex to the hypertension.

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