Abstract
Obstructive sleep apnoea (OSA) is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH) to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk), and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1) and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.
Highlights
Humans are exposed to hypoxia in a variety of circumstances
In pulmonary arteries of every group, ACh relaxed the PE-induced contraction, and the relaxation effects were attenuated in endothelium-denuded rings, no matter from normoxia or cyclic intermittent hypoxia (CIH) rats
In pulmonary arteries from CIH rats, the ACh-induced relaxation was significantly decreased when compared with endothelium-intact normoxia rats, indicating that endothelial function was damaged
Summary
Humans are exposed to hypoxia in a variety of circumstances. Frequently, the exposure is continuous, as with exposure to altitude, but often the exposure is intermittent, with certain disease states. Of the disease states that provide exposure to intermittent hypoxia, the most prevalent is obstructive sleep apnoea (OSA), a condition affecting as many as 10% of working age males and 4% of working age females [1,2]. When exposed to intermittent hypoxia for several hours per day to mimic OSA, animals have been shown to develop sustained pulmonary hypertension and pulmonary vascular remodeling within a few weeks [3,4]. Intermittent hypoxia is a risk factor for cardiovascular disorders and in some cases is a complication of pulmonary vascular diseases [4,5], as the endothelium is affected [6]. Diminished production of NO and aggravated release of ET-1 are believed to be key initiators of endothelial injury [12]
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