Time course of intermittent hypoxia-induced impairments in resistance artery structure and function
Introduction
Exposure to chronic intermittent hypoxia (CIH) in rats causes vascular dysfunction. Specifically, we have documented that 14 days of CIH attenuates acetylcholine (ACh)- and hypoxia-induced vasodilation in the skeletal muscle and cerebral circulations (Phillips et al., 2004), increases stiffness of skeletal muscle resistance arteries (Phillips et al., 2006), and causes blood pressure and heart rate elevations that are apparent not only during the CIH exposures but also during the portion of the day when the rats are normoxic (Marcus et al., 2009a). These same impairments have been observed in patients with moderate to severe obstructive sleep apnea (OSA) (Carlson et al., 1996, Becker et al., 2003, Phillips et al., 2008). In such patients, the duration of OSA prior to diagnosis typically cannot be ascertained; therefore, the time course for development of impairments in vascular function is unknown. In addition, the mechanisms underlying these impairments are not completely understood. The purpose of this investigation was to perform in vitro assessment of resistance artery function and structure after 3, 14, 28, and 56 days of exposure to CIH in Sprague–Dawley rats, an established model of OSA. In addition, because oxidative stress and inflammation are putative contributors to OSA-related vascular dysfunction in humans (Lavie, 2009), we assessed the effects of CIH on urinary isoprostane excretion and expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and nitrotyrosine (NT) in the arterial wall.
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Animals
Adult male Sprague–Dawley rats (Harlan, Madison, WI) were used for all experiments. They had ad libitum access to standard rat chow (Purina) and drinking water during exposure to either CIH or normoxia (see below). Room temperature and relative humidity were maintained at 24 ± 1 °C. and 20–70%, respectively. Rats were housed in accordance with recommendations set forth in the National Institutes of Health Guide for the Care of Laboratory Animals (NIH Pub. No. 85-23, Revised 1985). All protocols
Baseline characteristics at time of study (Table 1)
Two-way ANOVA revealed a main effect of CIH on body weight; however, posttests did not indicate statistically significant between-group differences at any point in time. CIH and NORM rats did not differ in age at any point in time; however, the rats exposed to both conditions for 14 days were somewhat younger than the rats studied at 3, 28, and 56 days of exposure. There was a small effect of CIH on hematocrit that was of borderline statistical significance (p = 0.05). Baseline tone in gracilis
Discussion
This study confirms our previous observations, made in rats exposed to CIH for 2 weeks, that CIH attenuates endothelium-dependent vasodilation in skeletal muscle resistance arteries and extends them by demonstrating that 3 days of CIH exposure is insufficient to consistently produce this impairment and that longer exposures (i.e. 4 weeks and 8 weeks) do not exacerbate it. The observed CIH-induced impairment in vasodilator function was accompanied by evidence of new collagen deposition in the
Acknowledgements
The authors thank Joseph A. Hardin for performing the immunohistochemical staining and Dr. Yi-Hua Xu for assistance with the stain separation for NOS and NT measurements. We would also like to acknowledge the assistance of Dr. Julian H. Lombard for his thoughtful review of the manuscript. This work was supported by grants from the National Heart Lung and Blood Institute [grant numbers HL 074072 to BJM, T32 HL07654 to NJM].
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