Obstructive Sleep Apnea (OSA) is a significant health risk occurring in as many as 24% of adult males and 9% of adult females within the United States population. Adults with OSA experience chronic nocturnal recurrent apneas and intermittent hypoxia, and have an increased risk of hypertension, arrhythmias, myocardial ischemia and stroke. Severe OSA increases cardiovascular mortality 4 fold, and even when corrected for other risk factors severe OSA increases cardiovascular mortality 3 fold. Unfortunately, however, there are few effective treatment options for OSA, and little is currently known about the mechanisms responsible for the increased risk of cardiovascular diseases and mortality. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive episodes of apneas and hypoxia that occurs in humans with OSA. CIH impairs the baroreflex control of heart rate and diminishes cardioprotective parasympathetic activity to the heart and current research indicates these changes are due to changes in the activity of premotor cardiac vagal neurons (CVNs) in the brainstem. Acute exposure to hypoxia evokes an initial tachycardia followed by a bradycardia. Previous work from this lab, and others, have shown brief (5-15 minute) periods of hypoxia and/or hypercapnia evoke a biphasic increase, then decrease in inhibitory glycinergic and GABAergic neurotransmission to parasympathetic premotor CVNs in the brainstem with a time course that closely parallels the biphasic changes in heart rate in-vivo. In addition, increased activity of serotonergic pathways by hypoxia activates excitatory post-synaptic 5HT3 receptors in CVNs. Following hypoxia excitation of CVNs continues as a purinergic pathway, activating P2x receptors, and a glutamatergic neurotransmission to CVNs are recruited. The focus and overarching hypothesis of the current application is that CIH alters the endogenous spontaneously active synaptic pathways to CVNs as well as those that are initiated in response to acute hypoxia challenges, and in addition impairs essential reflex activation and excitation of premotor CVNs. Stated concisely, we will test if CIH prolongs and exaggerates spontaneous and hypoxia evoked increases in inhibitory GABA and glycine pathways to CVNs;inhibits both spontaneously active excitatory pathways, as well as the excitation and activation of CVNs that occurs during and post acute hypoxia challenges by recruited glutamatergic, purinergic and serotonergic neurotransmission;and impairs the critical and persistent activation of CVNs from a synaptic pathway originating from neurons in the nucleus tractus solitarius (NTS), which is likely the essential baroreflex link between baroreceptor activity and parasympathetic cardiac vagal activity. The successful completion of this proposal will lead to a significantly improved understanding of the long-term changes that occur in the receptors and pathways that control the activity of parasympathetic CVNs after CIH, as well as cellular targets that potentially could restore and maintain cardio-protective parasympathetic activity in patients with OSA.

Public Health Relevance

One major, yet poorly understood cardiovascular health risk that occurs in as many as ~24% of males and 9% of females (between 30-60 years of age) within the United States population is obstructive sleep apnea (OSA). While OSA impairs the baroreflex control of heart rate and diminishes cardioprotective parasympathetic activity to the heart, little is known about the mechanisms responsible. This work will not only address hypotheses fundamental to understanding the basis and mechanisms of impaired parasympathetic cardiac activity in a model of OSA, but will also suggest which receptors and processes are altered and likely involved in the generation and progression of cardiovascular diseases with OSA, and will help identify promising targets to restore parasympathetic activity to the heart to increase survival.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-VH-B (02))
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Lathrop, David A
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George Washington University
Schools of Medicine
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