Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats

Abstract

Although intermittent hypoxia is often associated with hypertension, experimental and clinical studies have demonstrated definite antihypertensive effects of some intermittent hypoxia conditioning (IHC) regimens. Mechanisms of this antihypertensive response are unknown. Endothelial dysfunction related to disturbed synthesis and/or reduced availability of nitric oxide (NO) has been linked to hypertension. Thus, experiments were conducted to determine if IHC can improve endothelium-dependent relaxation and formation of releasable vascular NO stores of young (4-8-week-old) spontaneously hypertensive rats (SHR). Rats were subjected to either IHC (9.5-10% O(2), 5-10 min, 5-8 times per day, 20 d) or to sham conditioning. Endothelium-dependent relaxation to acetylcholine was measured in norepinephrine-precontracted, isolated aortic rings, and the size of NO stores was evaluated by percent relaxation to N-acetylcysteine (NAC), which releases stored NO. The capacity of aortic rings for NO storage was evaluated by the relaxation to NAC after prior incubation with an NO donor. IHC significantly suppressed the development of hypertension in young SHR. Endothelial function decreased from 54.7 ± 4.6% to 28.1 ± 6.4% relaxation to acetylcholine after 20 d of sham IHC, whereas endothelial function was sustained (60.3 ± 6.0% relaxation) in IHC rats. IHC also induced formation of available NO stores and enhanced the capacity of aortic rings to store NO. Therefore, the antihypertensive effect of IHC in young SHR is associated with prevention of endothelial dysfunction and with increased accumulation of NO stores in vascular walls.

Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

“…Akt activation may also provide protection via increased eNOS and augmented NO stores. In fact, the anti-hypertensive effect of IH in young spontaneously hypertensive rats is associated with prevention of endothelial dysfunction and with increased accumulation of NO stores in vascular walls due to augmented eNOS activity [62]. The ability of IH to increase eNOS is shared also in OSA-like models at the level of the carotid body [63].…”

Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension

“…Animal experiments have shown that, among various types of adaptation, hypoxic conditioning is the most effective in stimulating nitric oxide synthesis and storage [9,12]. Beneficial effects on nitric oxide metabolism apparently underlie hypoxiainduced prevention of endothelial dysfunction and the antihypertensive effect of hypoxia observed in spontaneously hypertensive rats [10,[13][14][15]. Thus, the present study was designed to evaluate the effect of normobaric intermittent hypoxia conditioning (IHC) on BP and nitric oxide production in patients with stage 1 arterial hypertension.…”

The polymorphic and contradictory aspects of intermittent hypoxia

“…IH can protect the heart against ischemia-reperfusion injury (197) by improving against ischemia-induced contractile dysfunction (31, 127), endothelial dysfunction (110,111), arrhythmias (110,116,209), and cell death (45, 89). Also, IH treatment can promote higher resistance to arrhythmias during acute myocardial ischemia and prevent the development of atherosclerosis in rabbits (88).…”

“…This protection has been ascribed to the higher myocardial vascularity, coronary blood flow, cardiomyoglobin, and expression of antioxidant proteins induced by IH (211). Other investigators have reported antihypertensive effects of conditioning IH exposures (9 -10% O 2 , 5-10 min, 5-8 times per day) in young spontaneous hypertensive rats, which have been associated with prevention of endothelial dysfunction and with increased accumulation of nitric oxide (NO) in vasculature (111). In addition, IH appears to provide a therapeutic effect on permanent coronary artery ligation-induced myocardial infarction by reducing the infarct size, myocardial fibrosis, and apoptosis (202).…”