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...