Introduction
The brain and heart have high metabolic rates and therefore high oxygen requirements [1]. These features determine their sensitivity to ischaemia–reperfusion (I/R). Neurons die after more than two minutes of ischaemia [2], while irreversible cardiomyocyte damage develops after more than ten minutes of I/R [3]. This sensitivity accounts for cardiac and brain injuries during surgery with cardiopulmonary bypass [4–8]. Hypothermia, ischaemic and remote preconditioning can prevent or attenuate such injuries [6–10]. Ischaemic preconditioning exposes the target organ, brain or heart, to brief ischaemia lasting 2–15 minutes and reperfusion lasting 5–10 minutes before prolonged ischaemia [2, 11, 12].
Ischaemic preconditioning has two important disadvantages: it increases I/R resistance only in the conditioned organ, and may itself cause damage. Brief cardiac I/R can trigger life-threatening ventricular tachycardia or fibrillation [13]. Researchers therefore seek alternatives, including remote [14–16] and hypoxic preconditioning [16, 17]. Remote preconditioning applies five-minute ischaemia and five-minute reperfusion to one organ, usually limb skeletal muscle, to increase I/R tolerance in another, such as the heart [10, 14, 15].
Hypoxic preconditioning (HP) increases resistance to severe prolonged hypoxia or ischaemia through a preceding single 1–6-hour exposure [18–22] or several brief hypoxia/reoxygenation sessions of 2–10 minutes each [16, 17, 23]. It differs from interval hypoxic training, involving daily exposures for 5–14 days [24, 25], and adaptation involving 30 [26] or 45 days [27, 28]. Some authors nevertheless call 28-day [29] or two-month [30] adaptation preconditioning, while St Petersburg physiologists use the term for two-hour daily exposures over three days [31, 32]. Thus terminology is not standardised. Here HP means a single exposure or several hypoxia–reoxygenation sessions within a few hours.
Delayed or late HP is best studied: resistance rises 16–24 hours after hypoxia–reoxygenation [18–20, 22, 33]. Early HP, producing increased tolerance immediately after exposure, is less studied [16, 17, 23, 34, 35].
All these studies used experimental animals; clinical applications remain largely unstudied. High-ranking Russian, Ukrainian and international journals contain no experimental data on HP nephroprotection, so this review examines experimentally demonstrated neuroprotective and cardioprotective effects only.
Cardioprotective effect
The first HP studies showed that cardiac I/R tolerance could increase immediately after brief hypoxia [34, 35]. However, Z. Cai and colleagues found no increase in tolerance to 30-minute ischaemia and reperfusion 30 minutes after in vivo HP [36].
Most studies concern delayed cardioprotection 24 hours after brief hypoxia [19, 20, 22, 36–39], reflected by a smaller infarct-size/area-at-risk ratio (IS/AAR); the risk area is the ischaemic myocardium during coronary occlusion. US investigators used four hours of 10% inspired O₂ 24 hours beforehand and reduced this ratio from 30% in controls to 20% in mice [22]. Cai and colleagues used five cycles of 6% O₂ and 21% O₂ 24 hours before isolating mouse hearts; after 30-minute ischaemia and two-hour reperfusion, IS/AAR fell from 42% to 21% [36]. French researchers found ratios of 21.8% versus 33.5% in rats 24 hours after four-hour exposure to 10% O₂ [20].
Our three-hour protocol reduced the ratio almost 40% in isolated hearts conditioned 24 hours earlier [19]. Chinese investigators found an almost twofold reduction after HP 24 hours before coronary occlusion in vivo [39].
HP also improves reperfusion pump function. Cai’s five six-minute hypoxia/six-minute reoxygenation cycles 24 hours before mouse-heart isolation doubled reperfusion left-ventricular developed pressure versus I/R controls [36]. Wu found that coronary occlusion nearly halved contraction and relaxation rates in rats in vivo; HP 24 hours earlier almost eliminated these changes [39]. German physiologists in 2008 exposed rats to 10.5% O₂ for 24 hours and found improved right-ventricular contractility during isolated-heart I/R [40]. Egyptian investigators used ten cycles of three minutes at 10% O₂ and three minutes at 21% O₂ 24 hours before isolation, followed by 30-minute global ischaemia.
Reperfusion developed pressure was almost threefold greater, contraction rate 1.5-fold greater and end-diastolic pressure twofold lower [38]. These findings support better pump function in vitro and in vivo. However, L. Xi and colleagues found no effect of in vivo HP on isolated-heart pumping during global ischaemia and reperfusion [22].
Delayed HP therefore prevents cardiomyocyte necrosis and improves reperfusion pump function after prolonged I/R, but whether early HP limits infarction or improves inotropy is unclear. Major cardiac I/R manifestations include necrosis, apoptosis, contractile dysfunction, arrhythmias and no-reflow [41]. Direct proof of an antiapoptotic HP effect is lacking. We found 75% lower cardiomyocyte caspase-3 activity after delayed HP in isolated rat-heart I/R, an indirect antiapoptotic sign, and 56% fewer ventricular reperfusion arrhythmias [42]. We found no literature on HP effects on no-reflow.
Neuroprotective effect
In 1999 Beijing investigators found that HP increased mouse survival at 2.7 kPa from 1.6 to 15.3 minutes, and after potassium cyanide from 2.2 to 9.4 minutes [43]. Since the brain is most hypoxia-sensitive, protection may involve glycolytic energy production, reduced expenditure or suppression of irreversible neuronal injury. Survival despite cytochrome oxidase inhibition suggests no dependence on altered mitochondrial function. Protection appeared immediately after four hypoxia–reoxygenation sessions, indicating early HP [43]. The same group later found reduced respiratory and heart rates and 1.6-fold lower oxygen consumption, supporting energy conservation [44]. Taie and colleagues used three hours at 8% O₂ and repeated hypoxia 24 hours later.
Delayed HP prevented the fall in brain tissue pO₂, also suggesting an energy-saving mechanism [45].
Clinical prospects require knowing whether HP protects against cerebral I/R. A 1994 study unilaterally ligated a carotid artery in seven-day-old rats and exposed them to 8% O₂ for three hours, measuring necrosis gravimetrically seven days later. Some underwent HP 24 hours before the occlusion described in the source as coronary. Controls lost 34% of hemisphere weight to necrosis, whereas no infarct was detected after HP [46]. Feng used a similar model and found a fivefold reduction, not complete elimination [47]. US investigators gave mice two hours at 11% O₂, then 48 hours later a 90-minute middle cerebral artery (MCA) occlusion.
Necrosis measured one day after reperfusion was 60% smaller [48]. Bernaudin in 2002 used one, three or six hours at 8% O₂, permanent left MCA occlusion 24 hours later and planimetry after another 48 hours. One- and six-hour HP were strongest, reducing necrosis about 40%; protection was absent 78 hours after HP [49]. Thus delayed HP can limit infarction during both I/R and persistent cerebral ischaemia. This differs from myocardial infarction, whose limitation requires restored coronary perfusion [41], indicating different pathogenesis. In 2003 Prass used 30, 60, 180, 300 or 360 minutes at 8% O₂ and 45-minute MCA occlusion three days later.
Only three- and five-hour exposures protected. After five-hour HP, no protection appeared immediately or at 24 hours; it peaked at three days and disappeared at six days [49]. Five-hour HP protected against 30-, 45-, 60- and 120-minute occlusions but not permanent occlusion, contradicting Bernaudin’s findings [50] for unclear reasons. Moscow State University investigators used four ten-minute exposures to 10% O₂ separated by five-minute reoxygenation, then MCA coagulation and damage assessment 72 hours later. HP given one, 24 or 72 hours before stroke protected only at 24 hours; remote preconditioning did not protect [51]. These results favour HP’s clinical prospects and show no early infarct limitation during 72-hour local persistent ischaemia.
Indiana investigators exposed newborn rats to 8% O₂ for three hours, then 24 hours later coagulated the left carotid and applied 2.5 hours at 8% O₂. Semiquantitative histopathology five days later showed marked neuroprotection [52], confirmed independently in Sweden [53] and the USA [54].
Swedish physiologists also found that HP reduced the cerebral blood-flow fall caused by carotid coagulation (p<0.01), indicating vascular as well as neural protection. Improved collaterals may explain protection during permanent MCA occlusion [50]. Chinese investigators used 8% O₂ for 30, 60, 120 or 180 minutes, then after one to five days induced ischaemia by vertebral-artery coagulation and transient carotid occlusion. Damage was assessed by hippocampal CA1 neuron loss [55]. Two days after HP, 30 minutes gave the greatest protection, whereas three hours did not improve tolerance. The 30-minute protocol was strongest after one day, minimal after four and undetectable after five [55].
No publication demonstrated infarct limitation by early HP. Whether HP neuroprotection limits necrosis or apoptosis is also unclear, making antiapoptotic studies particularly relevant.
Cantagrel and colleagues in 2003 exposed newborn rats to 8% O₂ for three hours, then one day later unilaterally electrocoagulated the carotid and applied two-hour hypoxia at 8% O₂. TUNEL-positive cells, identified by terminal deoxynucleotidyl transferase-mediated UTP nick end-labelling, were counted in striatum, hippocampus and cortex after 24 hours, 48 hours and 14 days [56]. HP almost completely prevented apoptotic brain-cell death. Chinese investigators independently confirmed this [57].
Neurological dysfunction is a recognised manifestation of ischaemic brain injury [58]. HP substantially reduces neurological deficits in experimental stroke [52, 53, 57] and prevents learning and memory disturbances arising 24 hours after transient MCA occlusion [59].
Thus HP increases tolerance of prolonged severe hypoxia, limits experimental cerebral infarction, suppresses ischaemia-induced apoptosis, prevents reduced cerebral blood flow after carotid coagulation and eliminates neurological deficits in injury models. These positive effects, however, concern delayed HP; early neuroprotection remains unclear.
Clinical application
In our clinical observations, HP was induced after partial cardiopulmonary bypass began and lung ventilation stopped, before aortic clamping [60–62]. Before global cardiac ischaemia, the oxygenator received a 10–12% O₂ gas mixture for ten minutes, followed by five-minute reoxygenation. Arterial PaO₂ fell to 30–35 mmHg, SaO₂ to 55–65% and cerebral regional rSO₂ to 52–59%. We did not allow values below critical arterial haemoglobin saturation of 50% and corresponding PaO₂ of 27 mmHg. Controls were 40 patients undergoing coronary artery bypass grafting with bypass without HP; the HP group comprised 46 [60, 62]. Myocardial protection was assessed from plasma creatine kinase (CK), CK-MB and troponin I after perfusion and early postoperatively.
CK maxima occurred at six, 24 and 48 hours; HP significantly reduced CK at six and 48 hours. CK-MB peaked immediately after bypass and at six, 24 and 48 hours; HP patients had significantly lower levels at six and 24 hours. Troponin I peaked at 16 hours in both groups but was lower after HP [60]. This indicates cardioprotection during bypass surgery. Plasma lactate served as an indirect myocardial hypoxia and anaerobic glycolysis marker. It peaked one hour after unclamping in both groups but was lower with HP [60], indicating reduced myocardial anaerobic glycolysis, another positive effect.
Recovery of cardiac activity and inotropic requirements are principal indicators of protection after global ischaemia [63]. HP patients required adrenaline and dopamine less often in the immediate postperfusion and early postoperative periods [60]. Spontaneous cardiac recovery was more frequent with HP. Patients without HP more often required electrical cardioversion and pacing after perfusion [60].
Neurospecific S-100B is an early brain-injury marker [64]. Baseline plasma levels were normal in all groups. Maximal increases occurred after bypass discontinuation in both groups, but were less pronounced with HP [62]. Cognitive decline occurred in 67% of controls versus 32% of HP patients [62].
We therefore demonstrated cardioprotective and neuroprotective effects, improved reperfusion pump function and prevention of cognitive dysfunction with HP.
Cardioprotective signalling in vivo
Xi and colleagues in 2002 studied delayed HP in mice using one or two cycles at 10% O₂ for 30 minutes, two hours or four hours, followed by 24-hour reoxygenation. Isolated hearts underwent Langendorff perfusion and I/R. Only one or two four-hour cycles reduced IS/AAR. The inducible nitric oxide synthase inhibitor S-methylisothiourea, given before HP or heart isolation, abolished infarct limitation in both cases [22], identifying iNOS as both trigger and mediator. Our results show myocardial iNOS induction and involvement in HP effects [19, 33]. The selective blocker phenylene-1,3-bis(ethane-2)-isothiourea completely abolished antiarrhythmic protection [19, 33].
Thus iNOS triggers and mediates late HP; the roles of NOS and NO• in early HP remain unknown.
Protein kinases are important in ischaemic preconditioning [11]. French investigators induced HP in rats in vivo, then after 24 hours isolated hearts for 30-minute global ischaemia and two-hour reperfusion [37]. HP limited infarction. Wortmannin, a PI3-kinase inhibitor given 30 minutes before HP, did not alter protection [37]. Data on other kinases in HP in vivo are lacking.
In 2008 we showed that late in vivo cardioprotection involves ATP-sensitive K⁺ channels (KATP) and Ca²⁺-sensitive K⁺ channels (KCa). Selective blockers 24 hours after conditioning completely abolished infarct limitation [19], suggesting these channels are final effectors.
In vivo signalling data remain too limited for a clear receptor/signalling model. The firm conclusion is that iNOS, KATP and KCa channels have important roles in delayed HP.
Neuroprotective signalling in vivo
Adenosine increases brain hypoxia resistance [65]. Beijing investigators in 1999 found threefold higher cerebral adenosine after HP, lower A1-receptor density but higher affinity, suggesting adenosine as a trigger [66]. This interpretation requires caution: no receptor blockers were used, so protection might merely coincide with higher adenosine. Erythropoietin enhances erythropoiesis and brain tolerance [67]. Prass in 2003 found sixfold greater cerebral erythropoietin mRNA after HP. Intracerebroventricular soluble erythropoietin receptors, which bind the hormone, two hours after HP abolished infarct limitation [49]. Receptor evidence consists only of these two studies [49, 66], suggesting adenosine and erythropoietin involvement.
Protein kinases regulate cerebral ischaemic tolerance [68, 69] and are considered activated by phosphorylation [11]. Protein kinase C (PKC) activation involves phosphorylation and membrane translocation. Beijing researchers found cortical and hippocampal PKCγ translocation after HP without altered PKCα activity [70]. Another Beijing group confirmed this and found more membrane-associated PKCε and PKCβ, while other isoenzymes were unchanged, concluding that ε, β and γ participate [71]. We consider this premature because neither study assessed neuroprotection or used PKC inhibitors; translocation need not directly mediate cytoprotection.
Zhan and colleagues in 2010 found increased Akt phosphorylation after HP; Akt was originally isolated from an AKR thymoma cell line. PI3-kinase blockade with LY294002 prevented phosphorylated Akt and abolished neuroprotection [55]. US investigators confirmed Akt phosphorylation [47], supporting the PI3–Akt pathway. Others, however, did not detect phosphorylation after HP [52].
Indiana investigators in 2004 found ERK1/2 (extracellular signal-regulated kinase) phosphorylation after HP. U0126 inhibition abolished protection [52]. Beijing investigators instead found less phosphorylated ERK1/2 in brain tissue [73]. The reason for these opposite findings is unclear.
The groups also disagree on JNK, c-Jun N-terminal kinase. Indiana found no effect on phosphorylation [52], whereas Beijing found increased phosphorylation [72]. Without a JNK inhibitor in the Beijing study, its role in neuroprotection remains unclear.
No accepted consensus therefore identifies the receptors and kinases involved. Erythropoietin is the most likely trigger, with PI3–Akt and ERK1/2 the most likely mediators.
Final effector of brain protection
The final effector protein increasing cellular hypoxia–reoxygenation tolerance remains unidentified. Candidates are KATP channels [74] and the mitochondrial permeability transition pore (MPT), an oligomeric protein complex on inner and outer mitochondrial membranes [75]. Opening releases cytochrome c, which activates apoptosis in the cytoplasm. Proteins inhibiting the pore therefore suppress apoptosis, while those promoting opening induce it.
Chinese investigators found increased Bcl-2, B-cell lymphoma protein-2, which inhibits the MPT pore, and suppressed Bax, Bcl-2-associated X-protein, which promotes opening [57]. Zhang and colleagues confirmed this in 2008 [76]. No study using the pore opener atractyloside was found, leaving its actual contribution unclear. We also found no in vivo studies assessing KATP channels in HP.
Conclusion
The literature indicates that late HP substantially increases cardiac and cerebral I/R resistance. Experimental evidence for early neuroprotection in vivo is absent, while clinical observations show early cardiac and neural protection. A few studies link delayed cardioprotection to inducible NOS, KATP and KCa activation. Neuroprotection results from erythropoietin-receptor stimulation and increased PI3–Akt and ERK1/2 activity. The MPT pore is the proposed final cerebral effector.
Support and acknowledgements
Supported by Ministry of Education and Science grants 2.1.1/530 and 2.1.1/211, Russian Foundation for Basic Research grant 10-04-00288-a and Federal Agency for Science and Innovation contract 02.740.11.0714. The authors thank N.A. Danilchenko, G. Badziunas, V. Klyucharyov, I.S. Khokhlova, A. Tomashevsky and R.A. Sidorov for technical assistance.
References
1. Ньюсхолм Э., Старт К. Регуляция метаболизма. М.: Мир. 1977. 408.
2. Hiraide T., Katsura K., Muramatsu H., Asano G., Katayama Y. Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil. Brain Res. 2001; 910: 1–2: 94–98.
3. Trost S.U., Omens J.H., Karlon W.J. et al. Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70. J. Clin. Invest. 1998; 101: 4: 855–862.
4. Gazzolo D., Abella R., Marinoni E. et al. Circulating biochemical markers of brain damage in infants complicated by ischemia reperfusion injury. Cardiovasc. Hematol. Agents Med. Chem. 2009; 7: 2: 108–126.
5. Su X.W., Undar A. Brain protection during pediatric cardiopulmonary bypass. Artif. Organs. 2010; 34: 4: E91-E102.
6. Thielmann M., Kottenberg E., Boengler K. et al. Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res. Cardiol. 2010; 105: 5: 657–664.
7. Thiengburanatham S. Hyperhomocysteinemia-induced myocardial injury after coronary artery bypass. Asian Cardiovasc. Thorac. Ann. 2009; 17: 5: 483–489.
8. Walsh S.R., Sadat U., Boyle J.R. et al. Remote ischemic preconditioning for renal protection during elective open infrarenal abdominal aortic aneurysm repair: randomized controlled trial. Vasc. Endovascular Surg. 2010; 44: 5: 334–340.
9. Rees K., Beranek-Stanley M., Burke M., Ebrahim S. Hypothermia to reduce neurological damage following coronary artery bypass surgery. Cochrane Database Syst. Rev. 2001; 1: CD002138.
10. Zhou W., Zeng D., Chen R. et al. Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants. Pediatr. Cardiol. 2010; 31: 1: 22–29.
11. Маслов Л.Н., Лишманов Ю.Б., Соленкова Н.В. Адаптация миокарда к ишемии. Первая фаза ишемического прекондиционирования. Успехи физиол. наук. 2006; 37: 3: 25–41.
12. Маслов Л.Н. Новые подходы к профилактике и терапии ишемических и реперфузионных повреждений сердца при остром инфаркте миокарда. Сиб. мед. жур. Томск. 2010; 25: 2: 17–24.
13. Lu H.R., Yang P., Remeysen P. et al. Ischemia/reperfusioninduced arrhythmias in anaesthetized rats: a role of Na+ and Ca2+ infl ux. Eur. J. Pharmacol. 1999; 365(2–3): 233–239.
14. Маслов Л.Н., Колар Ф., Криг Т. Дистантное ишемическое прекондиционирование. Успехи физиол. наук. 2009; 40: 4: 64–78.
15. Venugopal V., Hausenloy D..J, Ludman A. et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart. 2009; 95: 19: 1567–1571.
16. Lukyanova L.D., Germanova E.L., Kopaladze R.A. Development of resistance of an organism under various conditions of hypoxic preconditioning: role of the hypoxic period and reoxygenation. Bull. Exp. Biol. Med. 2009; 147: 4: 400–404.
17. Park A.M., Nagase H., Vinod Kumar S., Suzuki Y.J. Acute intermittent hypoxia activates myocardial cell survival signaling. Am. J. Physiol. Heart Circ. Physiol. 2007; 292: 2: H751–H757.
18. Портниченко А.Г., Розова К.В., Василенко М.I., Мойбенко О.О. Вiковi особливостi ультраструктурних змiн мiокарда при гiпоксичному прекондицiюваннi та iшемii-реперфузii iзольованого сердця щурiв. Фiзiол. журн. 2007; 53: 4: 27–34.
19. Портниченко А.Г., Василенко М.I., Мойбенко О.О. Роль калiэвих каналiв в ефекторних механiзмах кардiопротекцii при пизньому прекондицiюваннi сердця щурiв. Патологiя 2008а; 5: 3: 61–62.
20. Beguin P.C., Joyeux-Faure M., Godin-Ribuot D., Lévy P., Ribuot C. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. J. Appl. Physiol. 2005; 99: 3: 1064–1069.
21. Bernaudin M., Sharp F.R. Methods to detect hypoxia-induced ischemic tolerance in the brain. Methods Enzymol. 2004; 381: 399–416.
22. Xi L., Tekin D., Gursoy E. et al. Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. Am. J. Physiol. Heart Circ. Physiol. 2002; 283: 1: H5–H12.
23. Khoury J., Ibla J.C., Neish A.S., Colgan S.P. Antiinfl ammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation. J. Clin. Invest. 2007; 117: 3: 703– 711.
24. Казаченко А.В., Кирпатовский В.И., Яненко Э.К., Коваленко Е.А. Интервальная нормобарическая гипоксическая тренировка в профилактике интраоперационного ишемического повреждения почек кроликов. Hyp. Med. 1996; 4: 1: 3–7.
25. Коваленко Е.А. Гипоксическая тренировка в медицине. Hyp. Med. J. 1993; 1(1): 2–4.
26. Neckar J., Papousek F., Novakova O., Ost’adal B., Kolar F. Cardioprotective eff ects of chronic hypoxia and ischaemic preconditioning are not additive. Basic Res. Cardiol. 2002; 97: 2: 161–167.
27. Meerson F.Z., Ustinova E.E., Orlova E.H. Prevention and elimination of heart arrhythmias by adaptation to intermittent high altitude hypoxia. Clin. Cardiol. 1987; 10: 12: 783–789.
28. Meerson F.Z., Ustinova E.E., Manukhina E.B. Prevention of cardiac arrhythmias by adaptation to hypoxia: regulatory mechanisms and cardiotropic effect. Biomed. Biochim. Acta. 1989; 48: 2–3: S83–S88.
29. Yang C.C., Lin L.C., Wu M.S., Chien C.T., Lai M.K. Repetitive hypoxic preconditioning attenuates renal ischemia/ reperfusion induced oxidative injury via upregulating HIF-1 -dependent bcl-2 signaling. Transplantation. 2009; 88: 11: 1251–1260.
30. Chen W.J., Chen H.W., Yu S.L. et al. Gene expression profiles in hypoxic preconditioning using cDNA microarray analysis: altered expression of an angiogenic factor, carcinoembryonic antigen-related cell adhesion molecule 1. Shock. 2005; 24: 2: 124–131.
31. Rybnikova E., Gluschenko T., Tulkova E. et al. Preconditioning induces prolonged expression of transcription factors pCREB and NF-κB in the neocortex of rats before and following severe hypobaric hypoxia. J. Neurochem. 2008; 106: 3: 1450–1458.
32. Semenov D.G., Samoilov M.O., Lazarewicz J.W. Preconditioning reduces hypoxia-evoked alterations in glutamatergic Ca2+ signaling in rat cortex. Acta Neurobiol. Exp. 2008; 68: 2: 169–179.
33. Портниченко А.Г., Василенко М.И., Мойбенко А.А. Влияние острой гипоксической гипоксии на индукцию синтазы оксида азота у крыс. Фiзiол. журн. 2003; 49: 3: 47–49.
34. Shizukuda Y., Mallet R.T., Lee S.C., Downey H.F. Hypoxic preconditioning of ischaemic canine myocardium. Cardiovasc. Res. 1992; 26: 5: 534–542.
35. Shizukuda Y., Iwamoto T., Mallet R.T., Downey H.F. Hypoxic preconditioning attenuates stunning caused by repeated coronary artery occlusions in dog heart. Cardiovasc. Res. 1993; 27: 4: 559–564.
36. Cai Z., Manalo D.J., Wei G. et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003; 108: 1: 79–85.
37. Beguin P.C., Belaidi E., Godin-Ribuot D., Lévy P., Ribuot C. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2. J. Mol. Cell. Cardiol. 2007; 42: 2: 343–351.
38. Bin-Jaliah I., Ammar H.I., Mikhailidis D.P. et al. Cardiac adaptive responses after hypoxia in an experimental model. Angiology. 2010; 61: 2: 145–156.
39. Wu X., Liu X., Zhu X., Tang C. Hypoxic preconditioning induces delayed cardioprotection through p38 MAPK-mediated calreticulin upregulation. Shock. 2007; 27: 5: 572–577.
40. Wasserfuhr D., Cetin S.M., Yang J. et al. Protection of the right ventricle from ischemia and reperfusion by preceding hypoxia. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2008; 378: 1: 27–32.
41. Ostadal B., Kolar F. Cardiac Ischemia: From Injury to Protection. Boston, Dordrecht, London: Kluwer Academic Publishers, 1999, 173.
42. Портниченко А.Г. Феномен позднего прекондиционирования миокарда, или фенотипическая кардиопротекция. В кн.: Эндогенные механизмы кардиопротекции как основа патогенетической терапии заболеваний сердца. Под ред. А.А. Мойбенко, В.Е. Досенко, А.Н. Пархоменко. Киев: НВП «Видавництво «Наукова думка» НАН України», 2008б; 305–331.
43. Lu G., Ding D., Shi M. Acute adaptation of mice to hypoxic hypoxia. Biol. Signals Recept. 1999; 8: 4–5: 247–255.
44. Lu G.W., Liu H.Y. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J. Appl. Physiol. 2001; 91: 3: 1193–1198.
45. Taie S., Ono J., Iwanaga Y. et al. Hypoxia-inducible factor- 1 has a key role in hypoxic preconditioning. J. Clin. Neurosci. 2009; 16: 8: 1056–1060.
46. Gidday J.M., Fitzgibbons J.C., Shah A.R., Park T.S. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci. Lett. 1994; 168: 1–2: 221–224.
47. Feng Y., Rhodes P.G., Bhatt A.J. Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor A, preserves the phosphorylation of Akt- Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic-ischemic model. Brain Res. 2010; 1325: 1–9.
48. Miller B.A., Perez R.S., Shah A.R. et al. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport. 2001; 12: 8: 1663–1669.
49. Prass K., Scharff A., Ruscher K. et al. Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke. 2003; 34: 8: 1981–1986.
50. Bernaudin M., Nedelec A.S., Divoux D. et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxiainducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J. Cereb. Blood Flow Metab. 2002; 22: 4: 393–403.
51. Самойленкова Н.С., Гаврилова С.А., Кошелев В.Б. Защитный эффект гипоксии и ишемического прекондиционирования при локальной ишемии мозга крыс. Доклады АН. Биологические науки. 2007; 414: 2: 283–285.
52. Jones N.M., Bergeron M. Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2 signaling. J. Neurochem. 2004; 89: 1: 157–167.
53. Gustavsson M., Mallard C., Vannucci S.J. et al. Vascular response to hypoxic preconditioning in the immature brain. J. Cereb. Blood Flow Metab. 2007; 27: 5: 928–938.
54. Freiberger J.J., Suliman H.B., Sheng H. et al. A comparison of hyperbaric oxygen versus hypoxic cerebral preconditioning in neonatal rats. Brain Res. 2006; 1075: 1: 213–222.
55. Zhan L., Wang T., Li W. et al. Activation of Akt/FoxO signaling pathway contributes to induction of neuroprotection against transient global cerebral ischemia by hypoxic pre-conditioning in adult rats. J. Neurochem. 2010; 114: 3: 897–908.
56. Cantagrel S., Krier C., Ducrocq S. et al. Hypoxic preconditioning reduces apoptosis in a rat model of immature brain hypoxia-ischaemia. Neurosci. Lett. 2003; 347: 2: 106–110.
57. Gao X., Chang C., Duan D., Ru L., Yin G. Eff ect of hypoxic preconditioning on neural cell apoptosis and expression of Bcl-2 and Bax in cerebral ischemia-reperfusion in rats. J. Huazhong Univ. Sci. Technolog Med. Sci. 2006; 26: 1: 17–20.
58. Виберс Д.О., Фейгин В., Браун Р.Д. Инсульт. Клиническое руководство. Пер. с англ. 2-е изд. – М.: Изд-во «БИНОМ»; СПб.: Изд-во «Диалект», 2005; 608.
59. Lu N., Li X.J., Li C.Z. et al. Eff ect of hypoxic preconditioning on the learning and memory ability and expressions of survivin and HSP-70 proteins in rats with focal cerebral ischemia/reperfusion injury. J. South. Med. Univ. 2007; 27: 12: 1856–1859.
60. Емельянова Т.В., Прут Д.А., Подоксенов Ю.К. Ишемическое прекондиционирование как фактор защиты миокарда при проведении кардиохирургических операций. Сиб. мед. жур. Томск. 2009; 24: 1: 120–122.
61. Подоксенов Ю.К., Емельянова Т.В., Шипулин В.М. и др. Патент №2398600 «Способ защиты жизненно важных органов кардиохирургических пациентов, оперированных в условиях искусственного кровообращения». Приоритет изобретения 05 ноября 2008 г.
62. Шишнева Е.В., Подоксенов Ю.К., Емельянова Т.В., Шипулин В.М., Лебедева Е.В. Оптимизация защиты головного мозга путем применения методики гипоксического прекондиционирования и анестезии ксеноном у кардиохирургических пациентов. Патология кровообр. и кардиохирургия. 2010; 3: 40–44.
63. Руководство по кардиоанестезиологии. под ред. Н.А. Трековой, А.А. Бунятяна.- М.: Медицинское информационное агентство. 2005; 688.
64. Ramlawi B., Rudolph J.L., Mieno S. et al. Serologic markers of brain injury and cognitive function after cardiopulmonary bypass. Ann. Surg. 2006; 244: 4: 593–601.
65. Williams-Karnesky R.L., Stenzel-Poore M.P. Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant. Curr. Neuropharmacol. 2009; 7: 3: 217–227.
66. Zhang W.L., Lu G.W. Changes of adenosine and its A1 receptor in hypoxic preconditioning. Biol. Signals Recept. 1999; 8: 4–5: 275–280.
67. Маслов Л.Н. Роль эритропоэтина в ишемическом прекондиционировании, посткондиционировании и регенерации мозга после ишемии. Росс. Физиол. жур. 2010; 96: 1: 26–41.
68. Della-Morte D., Raval A.P., Dave K.R., Lin H.W., Perez-Pinzon M.A. Post-ischemic activation of protein kinase C epsilon protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood fl ow. Neurosci. Lett. 2011; 487: 2: 158-162.
69. Wang S., Dai Z.G., Dong X.W. et al. Duplicate preconditioning with sevofl urane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase. Neurosci. Bull. 2010; 26: 6: 437–444.
70. Cui X.Y., Li J.F., Han S., Zu P.Y. Hypoxic preconditioning increases cPKCγ membrane translocation in murine brain.
71. Li J., Niu C., Han S. et al. Identifi cation of protein kinase C isoforms involved in cerebral hypoxic preconditioning of mice. Brain Res. 2005; 1060: 1–2: 62–72.
72. Zhang N., Gao G., Bu X. et al. Neuron-specifi c phosphorylation of c-Jun N-terminal kinase increased in the brain of hypoxic preconditioned mice. Neurosci. Lett. 2007; 423: 3: 219–224.
73. Long C., Gao Y., Gao G. et al. Decreased phosphorylation and protein expression of ERK1/2 in the brain of hypoxic preconditioned mice. Neurosci. Lett. 2006; 397: 3: 307– 312.
74. Соленкова Н.В., Маслов Л.Н., Дауни Дж. АТФ-зависимые К+-каналы и регуляция устойчивости сердца к ишемическим и реперфузионным воздействиям. Пат. физиол. экспер. тер., 2006; 2: 28–31.
75. Halestrap A.P. A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem. Soc. Trans. 2010; 38: 4: 841–860.
76. Zhang Y.B., Lu G.W., Yang M.F., Niu J.Z., Sun B.L. Changes in Bcl-2 and Caspase-3 expressions in cortex of hypoxic preconditioning mice. Acta Physiol. Sin. 2008; 60: 2: 249–253.
Full main-text translation of: Маслов Л.Н., Лишманов Ю.Б., Емельянова Т.В., Прут Д.А., Колар Ф., Портниченко А.Г., Подоксёнов Ю.К., Халиулин И.Г., Ванг Х., Пей Ж.-М. Гипоксическое прекондиционирование как новый подход к профилактике ишемических и реперфузионных повреждений головного мозга и сердца. Ангиология и сосудистая хирургия. 2011;17(3):27–36.
Related resources
Related resources cover technology, equipment and applications.