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% O2, 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.
MullerB, KleschyovAL, AlencarJL, VaninA, StocletJC. Nitric oxide transport and storage in the cardiovascular system. Ann NY Acad Sci2002;962:131–9
3.
VaninAF. Dinitrosyl iron complexes and S-nitrosothiols are two possible forms for stabilization and transport of nitric oxide in biological systems. Biochemistry1998;63:782–93
4.
VaninAF. Dinitrosyl iron complexes with thiolate ligands: physico-chemistry, biochemistry and physiology. Nitric Oxide2009;2:1–13
5.
ManukhinaEB, VaninAF, MarkovKM, MalyshevIYu. Formation and role of nitric oxide stores in adaptation to hypoxia. Adv Med Biol2006;578:35–40
6.
ManukhinaEB, VaninAF, MalyshevIYu, MalletRT, DowneyHF. Intermittent hypoxia-induced cardio- and vasoprotection: role of NO stores. In: XiL, SerebrovskayaTV, eds. Intermittent Hypoxia: From Molecular Mechanisms to Clinical Applications. Hauppauge: Nova Science Publishers, 2009:113–46
7.
MokhVP, PoltorakovAP, SerezhenkovVA, VaninAF. On the nature of a compound formed from dinitrosyl-iron complexes with cysteine and responsible for a long-lasting vasorelaxation. Nitric Oxide2010;22:266–74
8.
YangY, LoscalzoJ. S-Nitrosated proteins: formation, metabolism and function. In: van FaassenE, VaninAF, eds. Radicals for Life: The Various Forms of Nitric Oxide. Amsterdam: Elsevier, 2007:201–21
9.
ManukhinaEB, DowneyHF, MalletRT. Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Exp Biol Med2006;231:343–65
10.
SerebrovskayaTV, ManukhinaEB, SmithML, DowneyHF, MalletRT. Intermittent hypoxia: cause of or therapy for systemic hypertension?Exp Biol Med2008;233:627–50
11.
Vorob'evLP, ChizhovAIa, PotievskaiaVI. The possibilities of using intermittent normobaric hypoxia for treating hypertension patients. Ter Arkh1994;66:12–5[Russian]
12.
MukharliamovFIu, SmirnovaMI, BedritskiiSA, LiadovKV. Interval hypoxic training in arterial hypertension. Vopr Kurortol Fizioter Lech Fiz Kult2006;2:5–6[Russian]
13.
SimonenkoVB, ErmolaevAL, PotievskaiaVI, StepaniantsOS. Hypoxic therapy of arterial hypertension in patients with different variability of arterial pressure. Klin Med (Mosk)2003;81:35–8[Russian]
14.
BalykinMV, VinogradovSN, GeningTP. Effect of normobaric hypoxia and physical load on the functional indices of cardiorespiratory system in overweight people. Vopr Kurortol Fizioter Lech Fiz Kult2004;1:18–21[Russian]
15.
LyaminaNP, SenchikhinVN, PokidyshevDA, ManukhinaEB. Disturbed NO production in patients with essential hypertension and a non-drug method of its correction. Kardiologiia2001;41:17–21[Russian]
16.
ZongP, SettyS, SunW, MartinezR, TuneJD, EhrenburgIV, TkatchoukEN, MalletRT, DowneyHF. Intermittent hypoxic training protects canine myocardium from infarction. Exp Biol Med2004;229:806–12
17.
SerebrovskayaTV. Intermittent hypoxia research in the former Soviet Union and the Commonwealth of Independent States: history and review of the concept and selected applications. High Alt Med Biol2002;3:205–21
18.
VaninAF, SaninaNA, SerezhenkovVA, BurbaevDSh, LozinskyVI, AldoshinSM. Dinitrosyl-iron complexes with thiol-containing ligands: spatial and electronic structures. Nitric Oxide2007;16:82–93
19.
VaninAF, PoltorakovAP, MikoyanVD, KubrinaLN, BurbaevDS. Polynuclear water-soluble dinitrosyl iron complexes with cysteine or glutathione ligands: electron paramagnetic resonance and optical studies. Nitric Oxide2010;23:136–49
20.
VlasovaMA, SmirinBV, PokidyshevDA, MashinaSY, VaninAF, MalyshevIY, ManukhinaEB. Mechanism of adaptation of the vascular system to chronic changes in nitric oxide level in the organism. Bull Exper Biol Med2006;142:670–4
21.
VlasovaMA, VaninAF, MullerB, SmirinBV, MalyshevIY, ManukhinaEB. Detection and description of various stores of nitric oxide store in vascular wall. Bull Exp Biol Med2003;136:226–30
22.
SmirinBV, VaninAF, MalyshevIY, PokidyshevDA, ManukhinaEB. Nitric oxide depot in blood vessels in vivo. Biull Eksp Biol Med1999;127:629–32[Russian]
23.
ManukhinaEB, MalyshevIIu, MaleniukEB, ZeninaTA, PokidyshevDA, MikoianVD, KubrinaLN, VaninAF. Hypotensive effect and tissue distribution of the dinitrosyl iron complexes, a nitric oxide donor. Bull Exp Biol Med1998;1:23–5
24.
FosterGE, PoulinMJ, HanlyPJ. Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp Physiol2007;92:51–65
25.
SmithML. Sleep apnoea and hypertension: physiological bases for a causal relation themed issue. Exp Physiol2007;92:19–20
26.
KanagyN. Vascular effects of intermittent hypoxia. ILAR J2009;50:282–8
27.
NeubauerJA. Physiological and pathophysiological responses to intermittent hypoxia. J Appl Physiol2001;90:1593–9
28.
BrooksD, HornerRL, KozarLF, Render-TeixeiraCL, PhillipsonEA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest1997;99:106–9
29.
FletcherEC, LesskeJ, QianW, MillerCC3rd, UngerT. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension1992;19:555–61
30.
TahawiZ, OrolinovaN, JoshuaIG, BaderM, FletcherEC. Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. J Appl Physiol2001;90:2007–13
31.
PhillipsSA, OlsonEB, MorganBJ, LombardJH. Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol2004;286:H388–H93
32.
CaiY, DengX, ZhouX, ZhengY, WangX, LiangB, CaiQ, YangY. The hypoxic moderation of systemic hypertension in spontaneously hypertensive rats. Chin Med Sci J1993;8:125–8
33.
ObrezchikovaMN, KharchenkoIB, TarasovaOS, KoshelevVB. Intermittent hypoxic training in an altitude chamber decelerates but not prevents development of genetically determined hypertension in rats. Hypox Med J1997;5:3–7
34.
ManukhinaEB, MashinaSIu, SmirinBV, LyaminaNP, SenchikhinVN, VaninAF, MalyshevIY. Role of nitric oxide in adaptation to hypoxia and adaptive defense. Physiol Res2000;49:89–97
35.
LlorensS, FernándezAP, NavaE. Cardiovascular and renal alterations on the nitric oxide pathway in spontaneous hypertension and ageing. Clin Hemorheol Microcirc2007;37:149–56
36.
NavaE, FarreAL, MorenoC, CasadoS, MoreauP, CosentinoF, LuscherTF. Alterations to the nitric oxide pathway in the spontaneously hypertensive rat. J Hypertens1998;16:609–15
37.
RacasanS, Branko BraamB, KoomansHA, JolesJA. Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon. Am J Physiol Renal Physiol2005;288:F626–36
38.
HongH-J, LohS-H, YenM-H. Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase. Br J Pharmacol2000;131:631–7
39.
PudduP, PudduGM, ZacaF, MuscariA. Endothelial dysfunction in hypertension. Acta Cardiol2000;55:p221–32
40.
FörstermannU. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch2010;459:923–39
MullerB, KleschyovAL, StocletJC. Evidence for N-acetylcysteine-sensitive nitric oxide storage as dinitrosyl iron complexes in lipopolysaccharide-treated rat aorta. Br J Pharmacol1996;119:1281–5
43.
MülschA, MordvintcevP, VaninAF, BusseR. The potent vasodilating and guanylyl cyclase activating dinitrosyl–iron(II) complex is stored in a protein-bound form in vascular tissue and is released by thiols. FEBS Lett1991;294:252–6
44.
AndrewsKL, McGuireJJ, TriggleCR. A photosensitive vascular smooth muscle store of nitric oxide in mouse aorta: no dependence on expression of endothelial nitric oxide synthase. Br J Pharmacol2003;138:932–40
45.
ChauhanS, RahmanA, NilssonH, ClappL, MacAllisterR, AhluwaliaA. NO contributes to EDHF-like responses in rat small arteries: a role for NO stores. Cardiovasc Res2003;57:207–16
46.
ManukhinaEB, MalyshevIY, SmirinBV, MashinaSY, SaltykovaVA, VaninAF. Production and storage of nitric oxide in adaptation to hypoxia. Nitric Oxide1999;5:393–401
47.
ManukhinaEB, VaninAF, VlasovaMA, SmirinBV, MashinaSY, MalyshevIY, DowneyHF. Modulation of NO stores: a new mechanism of vascular adaptation to chronic changes in plasma NO. J Physiol Sci2009;59:406(abstract)
48.
DowneyHF, ManukhinaEB, BarlowM, VaninAF, MikoyanVD, CaffreyJL. Metabolic syndrome depresses NO storage in canine coronary arteries. J Physiol Sci2009;59:325(abstract)
49.
RyouMG, SunJ, OguayoKN, ManukhinaEB, DowneyHF, MalletRT. Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion. Exp Biol Med2008;233:766–74
50.
MalletRT, RyouM-G, ManukhinaEB, DowneyHF. Beta-adrenergic signaling and ROS: pivotal roles in intermittent, normobaric hypoxia-induced cardioprotection. In: XiL, SerebrovskayaTV, eds. Intermittent Hypoxia: From Molecular Mechanisms to Clinical Applications. Hauppauge: Nova Science Publishers, 2009:189–212
51.
MalletRT, RyouM-G, ManukhinaEB, DowneyHF. Intermittent hypoxic conditioning of canine myocardium: robust protection against ischemia-reperfusion injury. In: LukyanovaL, TakedaN, SingalPK, eds. Adaptation Biology and Medicine: Health Potentials. Vol. 5. New Delhi: Narosa Publishers, 2008:59–78
52.
ManukhinaEB, DowneyHF, MalletRT, GoryachevaAV, MalyshevIY, VaninAF. Role of nitric oxide (NO) stores in adaptive defense against NO overproduction. In: WangP, KuoC-H, TakedaN, SingalPK, eds. Adaptation Biology and Medicine, Vol. 6: Cell Adaptations and Challenges. New Delhi: Narosa Publishing House Ltd, 2010:293–315
