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1 Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, New Mexico, United States
2 Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, New Mexico, United States; Departament de Fisiologia e Biofisica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
3 Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
4 Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
* To whom correspondence should be addressed. E-mail: nkanagy{at}salud.unm.edu.
In clinical studies, sleep apnea is associated with hypertension, oxidative stress and increased circulating endothelin (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 (4-2,2,6,6-tetramethyl-piperidine 1-oxyl, 1mM). Mean arterial pressure (MAP) and heart rate (HR) were recorded for 3 control days and 14 treatment days with rats exposed 7 hrs/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 rats (tempol=101±3, water=101±2). Immunoreactive ET-1 was greater in plasma from IH-C rats compared to plasma from Sham 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.
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