Regulation of Catecholamines by Sustained and Intermittent Hypoxia in Neuroendocrine Cells and Sympathetic Neurons

Abstract

Abstract-Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemoreceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O 2 ) or to sustained hypoxia (10% O 2 ) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine ␤-hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small. Key Words: blood pressure Ⅲ catecholamines Ⅲ chemoreceptors Ⅲ sympathetic nervous system Ⅲ sleep apnea syndromes Ⅲ oxygen Ⅲ adrenal gland S leep-disordered breathing (SDB) is a frequent condition that affects Ϸ5% of the population and is characterized by repetitive episodes of hypoxemia and hypercapnia, followed by arousal, respiratory recovery, and reoxygenation. Persistent SDB is causally associated with substantial cardiovascular morbidity, the most important being systemic arterial hypertension (for recent comprehensive review, see Fletcher, 2003 1 ). The mechanisms involved in the genesis of this hypertension appear to involve several different components including augmented sympathetic nerve activity, 1-4 altered function of arterial chemoreceptors, 1,5-7 elevated levels of circulating norepinephrine (NE), 8 -10 decreased vascular responses to nitric oxide, 11 increased plasma concentrations of endothelin, 12,13 and altered regulation of the renal kallikrein-kallistatin pathway. 14 The use of animal model systems in which different components of SDB can be studied individually have revealed that intermittent hy...

Muscle Sympathetic Nerve Activity During Wakefulness in Heart Failure Patients With and Without Sleep Apnea

“…creases in sympathetic discharge and BP than those changes induced by sustained hypoxia. 29 These observations suggest that the recurrent nocturnal apneas of OSA and CSA have the capacity to elicit sustained aftereffects on sympathetic vasoconstrictor outflow during wakefulness. Indeed, in subjects without HF, OSA itself has been associated with an Ϸ50% increase in daytime MSNA.…”

“…On the other hand, the magnitude of intermittent hypoxemia is, in general, more pronounced in OSA than in CSA. 8 Thus, in OSA, the aftereffects of intermittent nocturnal hypoxia could augment daytime MSNA in OSA, [27][28][29] whereas in CSA, the summation of this carryover effect of nocturnal oxygen desaturation, plus enhanced peripheral and central chemosensitivity, 39,40 would be anticipated to elevate daytime MSNA. Because many factors interact to elicit surges in sympathetic outflow at night, the absence of a specific individual correlation between 1 of these indices, such as AHI or arousal frequency, and daytime MSNA is not surprising.…”

Ca2+/Calmodulin Kinase-dependent Activation of Hypoxia Inducible Factor 1 Transcriptional Activity in Cells Subjected to Intermittent Hypoxia

“…TH is the rate-limiting enzyme in catecholamine synthesis, and circulating catecholamines are increased in humans with chronic IH caused by recurrent apneas as well as animals exposed to chronic IH (40,41,49). A recent study has shown that IH increases TH enzymatic activity through posttranslational modification in PC12 cells (50).…”

Obstructive sleep apnea and cardiovascular risk in children

“…Полученные данные позволяют говорить о том, что обструктивное апноэ сна, возникшее в критическом периоде развития организма, может иметь необратимые отдаленные последствия. Интермиттирующая гипоксия способ-ствует повышению содержания катехоламинов в ка-ротидных тельцах [29] -структуре, которая играет важную роль в индукции гипертензии на фоне об-структивного апноэ сна [30]. Интермиттирующая ги-поксия во время сна приводит к нарушению функции системы ренин-ангиотензин [31], а также нарушает экспрессию в таламической области ЦНС гена c-fos, который играет роль в обеспечении центральной ре-гуляции артериального давления [32].…”