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

Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. Am J Physiol Heart Circ Physiol 293: H2971-H2976, 2007. First published August 31, 2007; doi:10.1152/ajpheart.00219.2007. - 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 sham-operated 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.