During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.

Hypoxia is one of the most frequently encountered stresses in health and disease. The duration, frequency, and severity of hypoxic episodes are critical factors determining whether hypoxia is beneficial or harmful. Adaptation to intermittent hypoxia has been demonstrated to confer cardiovascular protection against more severe and sustained hypoxia, and, moreover, to protect against other stresses, including ischemia. Thus, the direct and cross protective effects of adaptation to intermittent hypoxia have been used for treatment and prevention of a variety of diseases and to increase efficiency of exercise training. Evidence is mounting that nitric oxide (NO) plays a central role in these adaptive mechanisms. NO-dependent protective mechanisms activated by intermittent hypoxia include stimulation of NO synthesis as well as restriction of NO overproduction. In addition, alternative, nonenzymic sources of NO and negative feedback of NO synthesis are important factors in optimizing NO concentrations. The adaptive enhancement of NO synthesis and/or availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. Understanding the role of NO in mechanisms of adaptation to hypoxia will support development of therapies to prevent and treat hypoxic or ischemic damage to organs and cells and to increase adaptive capabilities of the organism.

IHC exerted a robust, persistent therapeutic effect and can be considered as an alternative, nonpharmacological treatment for patients with stage 1 arterial hypertension. The antihypertensive action of IHC is associated with normalization of nitric oxide production.

Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso-and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

The calibrated application of limited-duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion and, in many cases, improve contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease and produced robust, persistent, antihypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on β-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that use protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC clearly merits further evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions.

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Heat shock potentiated the nitric oxide production (EPR assay) in the liver, kidney, heart, spleen, intestine, and brain. The heat shock-induced sharp transient increase in the rate of nitric oxide production preceded the accumulation of heat shock proteins (HSP70) (Western blot analysis) as measured in the heart and liver. In all organs the nitric oxide formation was completely blocked by the NO-synthase inhibitor /V%nitro-Larginine (L-NNA). L-NNA also markedly attenuated the heat shock-induced accumulation of HSP70. The results suggests that nitric oxide is involved in the heat shock-induced activation of HSP70 synthesis.

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