Chronic Intermittent Hypoxia Alters Rat Ophthalmic Artery Reactivity Through Oxidative Stress, Endothelin and Endothelium-Derived Hyperpolarizing Pathways

Abstract

PURPOSE. Obstructive sleep apnea recently has been associated with a higher frequency of ischemic optic neuropathies. Intermittent hypoxia (IH) has been proposed as a major component of obstructive sleep apnea cardiovascular consequences. However, there currently are no pathophysiologic data regarding the effect of IH on the ocular vascular system. Thus, we assessed the impact of chronic IH exposure on the morphology and vascular reactivity of the rat ophthalmic artery (OA). METHODS. Rats were exposed to 14 days of IH or normoxia (NX). Ophthalmic artery reactivity was studied using wire myography in rats treated or not with tempol (1 mM/day). Expression of endothelin-1 (ET-1) and its receptors, and of the three nitric oxide synthase (NOS) isoform genes was quantified using quantitative polymerase chain reaction (qPCR) in the retina and optic nerve. Structural alterations (optical and electron microscopy) and superoxide anion production were studied in OA sections. RESULTS. Superoxide ion expression in the OA wall was increased by 23% after IH exposure. Ophthalmic artery contractile response to 3.10 À8 M ET-1 was increased by 18.6% and nitric oxide-mediated relaxation was significantly delayed in IH compared to NX rats. In the absence of nitric oxide, cytochrome P450 blockade increased relaxation to acetylcholine in IH rats and delayed it in NX rats. Tempol treatment abolished the IH-induced changes in OA reactivity. CONCLUSIONS. These results strongly suggest that chronic IH induces oxidative stress in the rat OA, associated with endothelial dysfunction through alterations of nitric oxide and endothelium-derived hyperpolarising factors (EDHF) pathways.

Effect of obstructive sleep apnoea on retinal microvascular function: a randomised controlled trial

“…Fourteen days of exposure to intermittent hypoxia in rats showed oxidative stress in the ophthalmic artery associated with endothelial dysfunction mediated through nitric oxide and endothelium-derived hyperpolarising factor pathways [ 24 ]. However, the role of oxidative stress in OSA-mediated ocular vascular disease is contentious [ 25 , 26 ], and such animal models often induce more marked intermittent hypoxia than seen in human OSA, and do not model for the correct associated rises in carbon dioxide levels that would generate vasodilation [ 27 ].…”

Association between Upper-airway Surgery and Ameliorative Risk Markers of Endothelial Function in Obstructive Sleep Apnea

“…Our findings are consistent with results of experimental studies reporting vascular hyperpermeability, hypercoagulability, and unbalance of the steady endovascular environment in response to chronic intermittent hypoxia 46,47 and impaired sleep architecture 48 . Potential physiological pathways may include oxidative stress, inflammation, and sympathetic activation 49–51 .…”

The Associations of Obstructive Sleep Apnea and Eye Disorders: Potential Insights into Pathogenesis and Treatment

“…When rats were exposed to 14 days of IH, superoxide ion expression in the ophthalmic artery (OA) wall and OA contractile response to endothelin-1 both increased, and nitric oxide-mediated relaxation was significantly delayed [191]. This shows the induction of oxidative stress in rat OA by chronic IH, combined with endothelial cell and nitric oxide synthase dysfunction.…”