Reactive oxygen species contribute to sleep apnea-induced hypertension in rats

Abstract

In clinical studies, sleep apnea is associated with hypertension, oxidative stress, and increased circulating endothelin-1 (ET-1). We previously developed a model of sleep apnea by exposing rats to eucapnic intermittent hypoxia (IH-C) during sleep, which increases both blood pressure and plasma levels of ET-1. Because similar protocols in mice increase tissue and plasma markers of oxidative stress, we hypothesized that IH-C generation of reactive oxygen species (ROS) contributes to the development of ET-1-dependent hypertension in IH-C rats. To test this, male Sprague-Dawley rats were instrumented with indwelling blood pressure telemeters and drank either plain water or water containing the superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 1 mM). Mean arterial pressure (MAP) and heart rate (HR) were recorded for 3 control days and 14 treatment days with rats exposed 7 h/day to IH-C or air/air cycling (Sham). On day 14, MAP in IH-C rats treated with Tempol (107 ± 2.29 mmHg) was significantly lower than in untreated IH-C rats (118 ± 9 mmHg, P < 0.05). Tempol did not affect blood pressure in sham-operated rats (Tempol = 101 ± 3, water = 101 ± 2 mmHg). Immunoreactive ET-1 was greater in plasma from IH-C rats compared with plasma from shamoperated rats but was not different from Sham in Tempol-treated IH-C rats. Small mesenteric arteries from IH-C rats but not Tempol-treated IH-C rats had increased superoxide levels as measured by ferric cytochrome c reduction, lucigenin signaling, and dihydroethidium fluorescence. The data show that IH-C increases ET-1 production and vascular ROS levels and that scavenging superoxide prevents both. Thus oxidative stress appears to contribute to increases in ET-1 production and elevated arterial pressure in this rat model of sleep apnea-induced hypertension. Keywords Tempol; endothelinThe repeated episodes of cessation of breathing that occur during sleep apnea have been linked to the increased generation of reactive oxygen species (ROS) with an associated increase in cardiovascular morbidity (1). Since it is estimated that up to one in five adults in Western countries suffer from sleep apnea (36), this condition appears to be a significant cause of cardiovascular disease. Several longitudinal studies of sleep apnea patients conclude that the greatest health risk of sleep apnea is the increased incidence of cardiovascular disease (24,42), with the most consistent alteration being increased mean arterial pressure (MAP) (26,30). Thus almost 50% of people suffering from sleep apnea also suffer from hypertension (13), and it is of great relevance to better understand the role of oxidative stress in sleep apnea-associated hypertension.Repeated apneic episodes are reported to increase oxidative stress in sleep apnea patients (16,21), in animal models of sleep apnea (31, 41), and in cultured cells exposed to cyclical hypoxia (43). However, debate continues on the consequences of this elevated oxidative stress. One potential consequence is an incr...

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

“…Numerous lines of evidence indicate that oxidative stress affects the vascular tone, on one hand through decreased NO bioavailability contributing to endothelial dysfunction and, on the other hand, by promoting vascular cell proliferation, inflammation, and extracellular matrix remodeling 8. Our results are in accordance with previous studies demonstrating that long‐term exposure to IH induces vascular oxidative stress13, 14 (ie, superoxide anion production) and inflammation10, 11, 12, 44, 46 (ie, NF‐κB, F4/80, CD45, and interferon‐γ expression). In addition, using in vitro transendothelial electrical resistance measurement, we demonstrated that IH also induces endothelial barrier dysfunctions, confirming recent data from Prabhakar's group that demonstrates in endothelial cell cultures a central role of reactive oxygen species in promoting IH‐associated endothelial barrier dysfunctions 47.…”

“…In OSA, it has been shown that venous endothelial cells from apneic patients exhibited local oxidative stress and inflammation associated with decreased NO bioavailability and reduced flow‐mediated dilation 9. Experimental studies in rodents demonstrated that chronic IH per se represents a causal factor of vascular remodeling and hypertension,10, 11, 12, 13, 14 in part through vascular inflammation10, 11, 12 and oxidative stress 13, 14…”

Oxidative Stress in the Carotid Body: Implications for the Cardioventilatory Alterations Induced by Obstructive Sleep Apnea

“…Increased plasmatic levels of ROS and ET-1 have been also implicated in the hypertension induced by intermittent hypoxia. Troncoso-Brindeiro et al, (2007) reported that the concurrent treatments of rats exposed to intermittent hypoxia with the SOD mimetic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), prevents the increased ROS plasmatic level and the hypertension. However, it is worth noting that intermittent hypoxia increases the expression of ET-1 in the rat CB during the first week of hypoxia, and later the ET-1 levels returned back to the control levels (Del Rio et al, 2011), suggesting that ET-1 may contribute to the enhanced carotid body responsiveness to hypoxia in the early phase of the intermittent hypoxic exposures.…”

Constant daily hypoxia leads to different degrees of pulmonary hypertension in two different rat strains

“…The latter approach is proposed for the study of the hypoxic consequences of sleep apnea, and such various short-cycle hypoxia reoxygenation paradigms are accompanied by metabolic effects on lipid metabolism [17] and glucose intolerance [18]. These effects are in part secondary to the development of free oxygen radicals formed in the hypoxia reoxygenation process [19]. The common approach to model the hypoxia of chronic lung disease is a 23 -24 hour exposure to hypoxia for 2 -3 weeks.…”