Intermittent Hypoxia 2: Cardiovascular and Metabolism
Intermittent Hypoxia 2: Cardiovascular and Metabolism
The purpose of this study is to compare cardiovascular physiological adaptation to
 intermittent hypoxia (IH) of nonobese healthy subjects. The exposure will be two periods of
 two weeks (IH versus exposure "placebo hypoxia"). The investigators will use pharmacological
 tools, peripheral vasodilator (amlodipine) or specific blocker of angiotensin receptor
 (valsartan) versus the taking of a placebo. The allocation of the tool and the exhibition
 will be randomized (HI / placebo, valsartan / amlodipine). The outcome measures evaluated
 concern the cardiovascular system, systemic inflammation and tissular and glucose metabolism.

 The investigators assume an increase in arterial resistance during the intermittent hypoxia
 compared to the control group, these being dependent on sympathetic tone.

 The investigators hypothesize that the metabolic alterations that will be observed after
 experimental simulation (IH and fragmentation of sleep for 15 consecutive nights) will be
 less severe in the valsartan group than in the amlodipine group in comparison with the
 placebo group.

 A serum bank and a gene bank will be performed for the requirements of subsequent studies if
 necessary.
There are many physiological situations in which the organism is exposed to hypoxia, such as
 exercise and altitude. In addition some pathological situations also involve hypoxia, such as
 obesity, heart failure, respiratory failure and sleep apnea syndrome.

 Hypoxia associated with altitude is frequently marked by the presence of sleep during
 periodic breathing induces a particular pattern of hypoxia called intermittent hypoxia. Also
 some subjects are "intolerant altitude" and develop specific pathologies at high altitude
 (acute mountain evil, pulmonary edema ...).

 We recently demonstrated that subjects tolerate the altitude had just intermittent hypoxia
 while they were sleeping during the simulated altitude. The protective role of intermittent
 hypoxia in the mechanisms of occurrence of intolerance to altitude remains to be understood
 more precisely. In fact those who were intolerant to altitude has no periodic breathing and
 therefore intermittent hypoxia during the oxygen-deficient atmosphere.

 Conversely, the sleep apnea syndrome (SAS) also characterized by a HI. It is produced by
 repeated episodes of airway obstruction during sleep, producing a sequence: respiratory
 effort, hypoxia / re-oxygenation and sleep interruption.

 The HI is associated with both a well established cardiovascular morbidity but also to
 cardioprotection. This relates to cardiovascular morbidity rise in blood pressure can
 certainly promote the development after many years of hypertension. On the other hand the
 presence of sleep apnea syndrome is advanced as a factor favoring the coronary collateral
 circulation and therefore will bring a cardioprotective effect for patients.

 Understanding the mechanisms of physiological adaptations to intermittent hypoxia by passing
 a deleterious evolution of a protective HI is therefore critical.

 Exposure to altitude or OSAS induces the activation of intermediary mechanisms such as
 sympathetic activation, altered vascular reactivity, systemic inflammation and low-grade
 oxidative stress. The direct involvement of these mechanisms is dependent mainly intermediate
 of intermittent hypoxia. The shift in equilibrium between activator and inhibitor factors
 will evolve either to a protective mode (adaptation to altitude) or pathologic
 (cardiovascular complication of OSA).

 Sympathetic activation has been demonstrated in patients with OSAS, reversible with effective
 treatment. The importance of cardiovascular sympathetic activation in elevating blood
 pressure by intermittent hypoxia is shown in animal models of HI. We also found an increase
 in sympathetic activation in our reversible model of HI in healthy subjects.

 The elevation of that sympathetic activity is assumed to be multifactorial. An increase in
 tone but also a central potentiation thereof by an increase in peripheral chemoreflex
 sensitivity (sensitive to hypoxia) and against a lack of regulation by the arterial
 baroreflex.

 Moreover angiotensin system modulates the central sympathetic tone and peripheral chemoreflex
 sensitivity. These actions are complementary in a signaling pathway of particular interest in
 exposure to intermittent hypoxia.
Inclusion Criteria:

 -  Healthy subject

 -  Subject aged of 18 years-old at least

 -  Diagnostic AHI<15/h and <5% of total sleep time spent with a SaO2<90%

 -  Free and informed consent signed

 -  Subject covered by social security

 -  Negative pregnancy test

 Exclusion Criteria:

 -  Subject with a medical pathology (respiratory, cardiovascular, renal, metabolic,
 neurological...)

 -  Tobacco consumption > 5 cigarettes/days

 -  Alcohol consumption > 3 units/days (1 unit=1 drink)

 -  Subject under trusteeship or guardianship

 -  Subject unaffiliated with the social security

 -  Person deprived of their liberty, adult protected by laws, person hospitalized

 -  Ongoing participation in another clinical research study

 -  Subject non-cooperative or respectful of obligations inherent in the participation in
 the study