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151 Vascular sequelae of intermittent hypoxia
Abstracts / Sleep Medicine 7 (2006) S1–S127
151 Vascular sequelae of intermittent hypoxia Christopher P. O’Donnell * University of Pittsburgh , Division of Pulmonary and Critical Care Medicine, School of Medicine, Pittsburgh, CA 15213, USA Obstructive sleep apnea, which is characterized by brief, repeated episodes of hypoxia, causes acute periods of hypertension at night in response to airway obstruction and leads to sustained systemic hypertension during the daytime when breathing is normal. The mechanisms that cause the acute nighttime hypertensive episodes and the sustained daytime hypertension have been largely determined in animal models of experimentally-induced airway obstruction or in response to intermittent hypoxia (IH) exposure during the light, or sleeping phase, in rodents. Brief periods of airway obstruction lead to acute hypertensive periods, the magnitude of which is largely determined by two opposing actions of hypoxia. Hypoxia stimulates the carotid body and leads to a marked reflex activation of the sympathetic nervous system (SNS) causing systemic vasoconstriction. Simultaneously, hypoxia exerts a direct vasodilatation at the level of the vascular smooth muscle. This overall balance between the reflex vasoconstriction and smooth muscle hypoxic dilatation determines the magnitude of the acute hypertensive response, and is in part dependent on genetic background. The carotid body and SNS are also key mediators of the sustained systemic hypertension that develops after prolonged exposure to nighttime periods of repetitive airway obstruction or to IH exposure during the light phase. Denervation of the carotid bodies, blockade of the SNS, renal sympathectomy, adrenal medullectomy, angiotensin II blockade, endothelin 1 blockade, and transgenic overexpression of human kallikrein abrogate the systemic hypertension that normally develops in rats exposed to long-term IH. Exposure to IH has also been shown to impact on systemic vasoreactivity by reducing vadilatory responsiveness to nitric oxide and increasing vasoconstrictor responsiveness to catecholamines. Airway obstruction and IH can also cause hypertension in the pulmonary circulation. In contrast to the systemic circulation, hypoxia causes constriction of pulmonary vascular smooth muscle and the SNS is largely ineffective at altering pulmonary vascular tone. Acute pulmonary hypertensive episodes occur in response to airway obstruction and IH, and some studies show that sustained pulmonary hypertension may also occur and is associated with neomuscularization of the pulmonary vascular smooth muscle. In summary, IH leads to acute periods of systemic and pulmonary hypertension, causes sustained systemic hypertension through activation of reflex carotid body-SNS-renal pathways and impairing the vasoreactive properties of vascular smooth muscle, and can produce sustained pulmonary hypertension
S21
through altered vascular structure in pulmonary smooth muscle cells. doi:10.1016/j.sleep.2006.07.055
152 The effect of intermittent hypoxia on maintenance of upper airway tone Kenneth D. O’Halloran * UCD School of Medicine and Medical Science, University College Dublin, Ireland Sleep-disordered breathing has emerged as a major public health problem with the cumulative effect over many months and years significantly increasing morbidity and mortality. Obstructive sleep apnoea (OSA) is a common, often debilitating disorder characterised by repetitive occlusions of the upper airway during sleep. The causes of upper airway obstruction during sleep are likely multi-factorial but there is evidence implicating upper airway muscle dysfunction and impaired motor control of the pharyngeal airway in the pathophysiology of OSA. We have developed a rodent model of OSA that mimics the hypoxia/reoxygenation cycles that are a feature of the disorder due to recurrent apnoea. Using our model we have shown that chronic intermittent hypoxia alters upper airway muscle structure and function and CNS control of the pharyngeal dilator muscles. Specifically, work from our laboratory has shown that episodic hypoxia/asphyxia reduces upper airway muscle endurance and selectively impairs pharyngeal dilator EMG responses to physiological stimulation. This has led us to speculate that episodic hypoxia may be responsible for progression of OSA through impairment of the neural control systems that regulate upper airway patency and through altered respiratory muscle contractile function, leading to the establishment of a vicious cycle of further airway obstruction and hypoxic insult that chronically exacerbates and perpetuates the condition. More recently, we have begun to explore the role of oxidative stress as an underlying trigger of the maladaptive changes that are secondary to episodic hypoxic insult in our model. There is increasing evidence that OSA is, at least in part, an oxidative stress disorder. Our recent findings show that a pro-oxidant challenge exacerbates – whereas anti-oxidant treatment ameliorates – the effects of chronic intermittent hypoxia on pharyngeal dilator muscle endurance. Our results may have particular relevance to respiratory conditions that are characterised by episodic hypoxia and may have implications for the treatment of such disorders in humans. As such, anti-oxidant treatment may yet prove a useful and necessary adjunct to therapies designed to treat sleep-disordered breathing. doi:10.1016/j.sleep.2006.07.056
151 Vascular sequelae of intermittent hypoxia Christopher P. O’Donnell * University of Pittsburgh , Division of Pulmonary and Critical Care Medicine, School of Medicine, Pittsburgh, CA 15213, USA Obstructive sleep apnea, which is characterized by brief, repeated episodes of hypoxia, causes acute periods of hypertension at night in response to airway obstruction and leads to sustained systemic hypertension during the daytime when breathing is normal. The mechanisms that cause the acute nighttime hypertensive episodes and the sustained daytime hypertension have been largely determined in animal models of experimentally-induced airway obstruction or in response to intermittent hypoxia (IH) exposure during the light, or sleeping phase, in rodents. Brief periods of airway obstruction lead to acute hypertensive periods, the magnitude of which is largely determined by two opposing actions of hypoxia. Hypoxia stimulates the carotid body and leads to a marked reflex activation of the sympathetic nervous system (SNS) causing systemic vasoconstriction. Simultaneously, hypoxia exerts a direct vasodilatation at the level of the vascular smooth muscle. This overall balance between the reflex vasoconstriction and smooth muscle hypoxic dilatation determines the magnitude of the acute hypertensive response, and is in part dependent on genetic background. The carotid body and SNS are also key mediators of the sustained systemic hypertension that develops after prolonged exposure to nighttime periods of repetitive airway obstruction or to IH exposure during the light phase. Denervation of the carotid bodies, blockade of the SNS, renal sympathectomy, adrenal medullectomy, angiotensin II blockade, endothelin 1 blockade, and transgenic overexpression of human kallikrein abrogate the systemic hypertension that normally develops in rats exposed to long-term IH. Exposure to IH has also been shown to impact on systemic vasoreactivity by reducing vadilatory responsiveness to nitric oxide and increasing vasoconstrictor responsiveness to catecholamines. Airway obstruction and IH can also cause hypertension in the pulmonary circulation. In contrast to the systemic circulation, hypoxia causes constriction of pulmonary vascular smooth muscle and the SNS is largely ineffective at altering pulmonary vascular tone. Acute pulmonary hypertensive episodes occur in response to airway obstruction and IH, and some studies show that sustained pulmonary hypertension may also occur and is associated with neomuscularization of the pulmonary vascular smooth muscle. In summary, IH leads to acute periods of systemic and pulmonary hypertension, causes sustained systemic hypertension through activation of reflex carotid body-SNS-renal pathways and impairing the vasoreactive properties of vascular smooth muscle, and can produce sustained pulmonary hypertension
S21
through altered vascular structure in pulmonary smooth muscle cells. doi:10.1016/j.sleep.2006.07.055
152 The effect of intermittent hypoxia on maintenance of upper airway tone Kenneth D. O’Halloran * UCD School of Medicine and Medical Science, University College Dublin, Ireland Sleep-disordered breathing has emerged as a major public health problem with the cumulative effect over many months and years significantly increasing morbidity and mortality. Obstructive sleep apnoea (OSA) is a common, often debilitating disorder characterised by repetitive occlusions of the upper airway during sleep. The causes of upper airway obstruction during sleep are likely multi-factorial but there is evidence implicating upper airway muscle dysfunction and impaired motor control of the pharyngeal airway in the pathophysiology of OSA. We have developed a rodent model of OSA that mimics the hypoxia/reoxygenation cycles that are a feature of the disorder due to recurrent apnoea. Using our model we have shown that chronic intermittent hypoxia alters upper airway muscle structure and function and CNS control of the pharyngeal dilator muscles. Specifically, work from our laboratory has shown that episodic hypoxia/asphyxia reduces upper airway muscle endurance and selectively impairs pharyngeal dilator EMG responses to physiological stimulation. This has led us to speculate that episodic hypoxia may be responsible for progression of OSA through impairment of the neural control systems that regulate upper airway patency and through altered respiratory muscle contractile function, leading to the establishment of a vicious cycle of further airway obstruction and hypoxic insult that chronically exacerbates and perpetuates the condition. More recently, we have begun to explore the role of oxidative stress as an underlying trigger of the maladaptive changes that are secondary to episodic hypoxic insult in our model. There is increasing evidence that OSA is, at least in part, an oxidative stress disorder. Our recent findings show that a pro-oxidant challenge exacerbates – whereas anti-oxidant treatment ameliorates – the effects of chronic intermittent hypoxia on pharyngeal dilator muscle endurance. Our results may have particular relevance to respiratory conditions that are characterised by episodic hypoxia and may have implications for the treatment of such disorders in humans. As such, anti-oxidant treatment may yet prove a useful and necessary adjunct to therapies designed to treat sleep-disordered breathing. doi:10.1016/j.sleep.2006.07.056