One major, yet poorly understood cardiovascular health risk that occurs in as many as ~24% of males and 9% of females within the United States population is obstructive sleep apnea (OSA). OSA can participate in both the initiation and progression of several cardiovascular diseases including sudden death, hypertension, arrhythmias, myocardial ischemia and stroke. Treatment of OSA is primarily continuous positive airway pressure (CPAP), and while this treatment is marginally effective in reducing elevated arterial pressure (~2 mmHg) CPAP is intrusive, poorly tolerated and often discontinued despite the risks of OSA. Recent work has suggested activity in neurons within the paraventricular nucleus of the hypothalamus (PVN) that are critical for the cardiovascular responses to challenges such as stress and dehydration are not impaired, but rather possess augmented activity in models of OSA and are involved in the maintenance and/or generation of OSA induced hypertension. However the PVN is a heterogeneous nucleus. Whereas vasopressin (AVP) neurons in the PVN are sympathoexcitatory, and activation of vasopressin receptors inhibits cardioprotective parasympathetic cardiac vagal neurons (CVNs), recent work has provided exciting new evidence that the neuropeptide oxytocin, released from a different population of PVN neurons, is cardioprotective. Oxytocin reduces the adverse cardiovascular consequences of anxiety and stress and, as this study will test, perhaps the deleterious consequences of chronic nocturnal intermittent hypoxia/hypercapnia. This project challenges the paradigm that the PVN is solely sympathoexcitatory, and will test that there are two contrasting pathways from the PVN, one that co-releases oxytocin, activates CVNs and is cardioprotective, and another pathway in which vasopressin inhibits CVNs and increases adverse cardiovascular changes. Furthermore this work will test if these pathways are altered and if these two populations of PVN neurons can be differentially controlled to mitigate or enhance the adverse cardiovascular changes that occur in a model of OSA. This project will address major gaps in our knowledge and hopefully constitute a foundation for appraising new potential treatments and targets for patients with cardiovascular diseases including OSA.

Public Health Relevance

This work will test if there are two contrasting pathways from the hypothalamus to parasympathetic cardiac neurons that control heart rate, and if these pathways are altered in a model of a prevalent cardiovascular disease, obstructive sleep apnea (OSA). This work seeks to identify promising targets to restore cardiac vagal activity and reduce adverse cardiovascular changes that occur in diseases such as OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Lathrop, David A
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George Washington University
Schools of Medicine
United States
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Dergacheva, Olga; Mendelowitz, David (2018) Combined hypoxia and hypercapnia, but not hypoxia alone, suppresses neurotransmission from orexin to hypothalamic paraventricular spinally-projecting neurons in weanling rats. Brain Res 1679:33-38
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