Obstructive sleep apnea (OSA), a relatively common condition that causes nightly exposure to intermittent hypoxia, has emerged as a risk factor for hypertension;however, the underlying mechanisms are incompletely understood. The current concept is that sympathetic nervous system overactivity and vascular endothelial dysfunction play important roles. The proposed research will test our hypothesis that the intermittent hypoxia of OSA activates the renin-angiotensin-system (RAS) in the carotid body, resulting in increased production of superoxide ion by NADPH oxidase (NOX) and xanthine oxidase (XO). Excess superoxide in the carotid body, in turn, augments chemoreflex control of sympathetic outflow and ventilation. At the same time, activation of RAS and XO in resistance arteries leads to impairment in endothelium- dependent vasodilation. We further hypothesize that both of these consequences of intermittent hypoxia worsen the severity of sleep disordered breathing, in selected subjects, by increasing respiratory control system gains leading to ventilatory instability. The objective of this trial is to translate our previous mechanistic findings in rats into pharmacologic strategies for preventing or reversing carotid chemoreflex hypersensitivity, thereby ameliorating the cardiovascular consequences of OSA and, if our hypothesis is correct, perhaps even lessening the severity of sleep disordered breathing events. Our long-range goal is to elucidate pathophysiologic mechanisms for cardiovascular disease in patients with OSA and identify interventions that minimize associated complications, morbidity and mortality.
The specific aims of this application are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness;and 2) Determine if these Interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure. This research is innovative because it may identify novel targets and interventions to be used with CPAP that reduce sympathetic overactivity, potentially reduce OSA severity, and minimize associated cardiovascular abnormalities in patients with OSA.

Public Health Relevance

Sleep apnea, a relatively common condition that results in nightly exposure to intermittent hypoxia, has emerged as a risk factor for hypertension. The proposed research will investigate, in humans and rats, whether inhibition of XO and angiotensin II can decrease negative chemoreflex, sympathetic and vascular effects of OSA. These interventions are novel, relevant, unobtrusive, relatively inexpensive, and could drasticallv change the treatment and possible prevention of cardiovascular disease in OSA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL105365-02
Application #
8322512
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Twery, Michael
Project Start
2011-08-19
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$856,383
Indirect Cost
$286,338
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Morgan, Barbara J; Adrian, Russell; Bates, Melissa L et al. (2014) Quantifying hypoxia-induced chemoreceptor sensitivity in the awake rodent. J Appl Physiol (1985) 117:816-24
Willis, Daniel N; Liu, Boyi; Ha, Michael A et al. (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J 25:4434-44