Obstructive sleep apnea (OSA) is a significant, but often overlooked, problem in today's society. OSA is defined by interrupted breathing during sleep, most often due to a collapse of the soft tissues in the upper airway. It has been estimated that more than 25% of the adult population in the Western world suffers from clinically significant OSA. In addition to being the underlying cause of mood and behavioral disorders, OSA is an independent risk factor for cardiovascular disease and stroke. Currently, animal models of OSA predominately consist of exposing rodents to intermittent hypoxia during the sleep cycle. The physiological response to apnea differs from intermittent hypoxia in a number of significant ways.
In Specific Aim 1, we propose to develop a rat model of obstructive sleep apnea. We will obstruct the airway during the sleep cycle in unanesthetized, freely-moving rats. The frequency and/or duration of apnea can be controlled to vary the severity of OSA. Inclusion of obstructive apnea will more closely model OSA in the human. While OSA is an independent risk factor for stroke and may be responsible for cognitive decline, very little is known about the effects of OSA on cerebral circulation. We have previously shown that nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF) are important dilatory mechanisms involved with the endothelial control of cerebral circulation. During pathological conditions such as ischemia/reperfusion and traumatic brain injury, dilations through endothelium- derived NO are diminished, whereas, EDHF-mediated dilations are enhanced. The effects of OSA on endothelial mechanisms of dilation in cerebral arteries have not been studied.
In Specific aim 2 we will use our model to test the hypothesis that OSA attenuates dilation through endothelium- derived NO and upregulates EDHF mediated dilations. For studies in Specific Aim 2, we will use isolated pressurized and perfused middle cerebral arteries from rats after 1 month of OSA. This R21 Grant proposal involves """"""""exploratory and developmental research"""""""" in the """"""""early and conceptual stages"""""""" of developing an improved animal model for OSA and determining the effects of OSA on cerebral arteries. The improved model will better mimic OSA as it occurs in the human and will help to provide a more complete understanding of the pathological events associated with OSA in cardiac function and control of the cerebral circulation.
We propose to (a) improve the current rodent models of obstructive sleep apnea to more closely mimic the human condition and (b) study the effects of obstructive sleep apnea on the cerebral circulation using our newly developed model. Very little is known about the effects of obstructive sleep apnea on the cerebral circulation. The proposed studies will provide an important foundation for understanding cerebrovascular dysfunction related to obstructive sleep apnea.
