A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries

Abstract

Obstructive sleep apnea (OSA), a condition in which the upper airway collapses during sleep, is strongly associated with metabolic and cardiovascular diseases. Little is known how OSA affects the cerebral circulation. The goals of this study were 1) to develop a rat model of chronic OSA that involved apnea and 2) to test the hypothesis that 4 wk of apneas during the sleep cycle alters endothelium-mediated dilations in middle cerebral arteries (MCAs). An obstruction device, which was chronically implanted into the trachea of rats, inflated to obstruct the airway 30 times/h for 8 h during the sleep cycle. After 4 wk of apneas, MCAs were isolated, pressurized, and exposed to luminally applied ATP, an endothelial P2Y2 receptor agonist that dilates through endothelial-derived nitric oxide (NO) and endothelial-dependent hyperpolarization (EDH). Dilations to ATP were attenuated ~30% in MCAs from rats undergoing apneas compared with those from a sham control group (P < 0.04 group effect; n = 7 and 10, respectively). When the NO component of the dilation was blocked to isolate the EDH component, the response to ATP in MCAs from the sham and apnea groups was similar. This finding suggests that the attenuated dilation to ATP must occur through reduced NO. In summary, we have successfully developed a novel rat model for chronic OSA that incorporates apnea during the sleep cycle. Using this model, we demonstrate that endothelial dysfunction occurred by 4 wk of apnea, likely increasing the vulnerability of the brain to cerebrovascular related accidents.

Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

“…It is important to note that these measured changes in ET-1 signaling occurred in OSA rats at a time that preceded any chronic alterations in systemic BP, inflammation, or oxidative state. 6 The first major finding of this study is that OSA increased the sensitivity of PCAs by 23-fold to ET-1 applied to the abluminal surface. Removal of the endothelium led to an enhanced baseline contractile state of PCAs.…”

“…Thus, BP was not significantly changed after 2 or 4 weeks of apneas with AHIs of 60 (this study) or 30 (previous study). 6 Obstructive Sleep Apnea Increases Cerebrovascular Sensitivity to Abluminal Endothelin-1 Maximum diameters for rat PCAs were 263 ± 9 μm (n = 24) and 266 ± 7 μm (n = 20) for sham and OSA rats, respectively (P = 0.79). After developing spontaneous tone, diameters of PCAs from the two groups were 184 ± 9 μm and 180 ± 6 μm, respectively (P = 0.74).…”

“…An obstruction device or balloon, which was fabricated from silicone tubing, was inserted into the lumen of the trachea caudal to the thyroid. 6 The silicone obstruction device was attached to PE-50 tubing that was tunneled under the skin and exited the back of the neck. The externalized PE-50 tubing was passed through a spring attached to the rat by a harness at one end and a swivel mounted at the top of the cage at the other end ( Figure 1A).…”

“…4 In an effort to more closely recapitulate the physiologic consequences observed in OSA patients, we have developed a model of OSA that incorporates apneas during the sleep cycle in rats. 6 Apneas were produced by inflating a balloon in the trachea. The severity of OSA in our model was equivalent to moderate OSA in humans.…”

“…Furthermore, we showed that endothelial dilations involving nitric oxide production were attenuated in the middle cerebral artery after 4 weeks of apneas. 6 Systolic Pressure (mmHg) Figure 1. Diagram of tethered rat with implanted obstruction device and system controlling apneas.…”