Chronic hypoxia protects the heart against injury caused by acute oxygen deprivation, but its salutary mechanism is poorly understood. The aim was to find out whether cardiomyocytes isolated from chronically hypoxic hearts retain the improved resistance to injury and whether the mitochondrial large-conductance Ca2+-activated K+ (BKCa) channels contribute to the protective effect. Adult male rats were adapted to continuous normobaric hypoxia (inspired O2 fraction 0.10) for 3 wk or kept at room air (normoxic controls). Myocytes, isolated separately from the left ventricle (LVM), septum (SEPM), and right ventricle, were exposed to 25-min metabolic inhibition with sodium cyanide, followed by 30-min reenergization (MI/R). Some LVM were treated with either 30 μM NS-1619 (BKCa opener), or 2 μM paxilline (BKCa blocker), starting 25 min before metabolic inhibition. Cell injury was detected by Trypan blue exclusion and lactate dehydrogenase (LDH) release. Chronic hypoxia doubled the number of rod-shaped LVM and SEPM surviving the MI/R insult and reduced LDH release. While NS-1619 protected cells from normoxic rats, it had no additive salutary effect in the hypoxic group. Paxilline attenuated the improved resistance of cells from hypoxic animals without affecting normoxic controls; it also abolished the protective effect of NS-1619 on LDH release in the normoxic group. While chronic hypoxia did not affect protein abundance of the BKCa channel regulatory β1-subunit, it markedly decreased its glycosylation level. It is concluded that ventricular myocytes isolated from chronically hypoxic rats retain the improved resistance against injury caused by MI/R. Activation of the mitochondrial BKCa channel likely contributes to this protective effect.

Centre for Cardiovascular Research Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

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Aldakkak M, Stowe DF, Cheng Q, Kwok WM, Camara AKS. Mitochondrial matrix K PubMed PMC

Aon MA, Cortassa S, Wei AC, Grunnet M, O'Rourke B. Energetic performance is improved by specific activation of K PubMed PMC

Asemu G, Papousek F, Ostadal B, Kolar F. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K PubMed

Bautista L, Castro MJ, Lopez-Barneo J, Castellano A. Hypoxia inducible factor-2α stabilization and maxi-K PubMed

Bentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M. Activation of big conductance Ca PubMed

Borchert GH, Giggey M, Kolar F, Wong TM, Backx PH, Escriba PV. 2-Hydroxyoleic acid affects cardiomyocyte [Ca PubMed

Buhl SN, Jackson KY. Optimal conditions and comparison of lactate dehydrogenase catalysis of the lactate-to-pyruvate and pyruvate-to-lactate reactions in human serum at 25, 30, and 37°C. Clin Chem 24: 823–831, 1978 PubMed

Cao CM, Chen M, Wong TM. The K PubMed PMC

Cao CM, Xia Q, Gao Q, Chen M, Wong TM. Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning. J Pharmacol Exp Ther 312: 644–650, 2005 PubMed

Cheng Y, Gu XQ, Bednarczyk P, Wiedemann FR, Haddad GG, Siemen D. Hypoxia increases activity of the BK-channel in the inner mitochondrial membrane and reduces activity of the permeability transition pore. Cell Physiol Biochem 22: 127–136, 2008 PubMed

Eells JT, Henry MM, Gross GJ, Baker JE. Increased mitochondrial K PubMed

Essop MF. Cardiac metabolic adaptations in response to chronic hypoxia. J Physiol 584: 715–726, 2007 PubMed PMC

Friehs I, del Nido PJ. Increased susceptibility of hypertrophied hearts to ischemic injury. Ann Thorac Surg 75: S678–S684, 2003 PubMed

Gaspar T, Katakam P, Snipes JA, Kis B, Domoki F, Bari F, Busija DW. Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels. J Neurochem 105: 1115–1128, 2008 PubMed PMC

Hagen BM, Sanders KM. Deglycosylation of the β1-subunit of the BK channel changes biophysical properties. Am J Physiol Cell Physiol 291: C750–C756, 2006 PubMed

Hartness ME, Brazier SP, Peers C, Bateson AN, Ashford MLJ, Kemp PJ. Post-transcriptional control of human maxiK potassium channel activity and acute oxygen sensitivity by chronic hypoxia. J Biol Chem 278: 51422–51432, 2003 PubMed

Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J. Mitochondrial Ca PubMed

Kolar F, Ostadal B. Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia. Physiol Res 53, Suppl 1: S3–S13, 2004 PubMed

Kopecky M, Daum S. [Tissue adaptation to anoxia in rat myocardium] (in Czech). Cesk Fysiol 7: 518–521, 1958 PubMed

Mallet RT, Ryou MG, Williams AG, Howard L, Downey HF. β PubMed

Neckar J, Szarszoi O, Koten L, Papousek F, Ostadal B, Grover GJ, Kolar F. Effects of mitochondrial K PubMed

Neckar J, Ostadal B, Kolar F. Myocardial infarct size-limiting effect of chronic hypoxia persists for five weeks of normoxic recovery. Physiol Res 53: 621–628, 2004 PubMed

Ohya S, Kuwata Y, Sakamoto K, Muraki K, Imazumi Y. Cardioprotective effects of estradiol include the activation of large-conductance Ca PubMed

Orio P, Rojas P, Ferreira G, Latorre R. New disguises for an old channel: MaxiK channel β-subunits. News Physiol Sci 17: 156–161, 2002 PubMed

Ostadal B, Kolar F. Cardiac adaptation to chronic high-altitude hypoxia: Beneficial and adverse effects. Respir Physiol Neurobiol 158: 224–236, 2007 PubMed

Park WS, Kang SH, Son YK, Kim N, Ko JH, Kim HK, Ko EA, Kim CD, Han J. The mitochondrial Ca PubMed

Redel A, Lange M, Jazbutyte V, Lotz C, Smul TM, Roewer N, Kehl F. Activation of mitochondrial large-conductance calcium-activated K PubMed

Rodrigo GC, Samani NJ. Ischemic preconditioning of the whole heart confers protection on subsequently isolated ventricular myocytes. Am J Physiol Heart Circ Physiol 294: H524–H531, 2008 PubMed

Sato T, Saito T, Saegusa N, Nakaya H. Mitochondrial Ca PubMed

Shi Y, Jiang MT, Su J, Hutchins W, Konorev E, Baker JE. Mitochondrial big conductance K PubMed

Skalska J, Piwonska M, Wyroba E, Surmacz L, Wieczorek R, Koszela-Piotrowska I, Zielinska J, Bednarczyk P, Dolowy K, Wilczynski GM, Szewczyk A, Kunz WS. A novel potassium channel in skeletal muscle mitochondria. Biochim Biophys Acta 1777: 651–659, 2008 PubMed

Wang X, Fisher PW, Xi L, Kukreja R. Essential role of mitochondrial Ca PubMed

Wang X, Yin C, Xi L, Kukreja RC. Opening of Ca PubMed

Wu S, Li HY, Wong TM. Cardioprotection of preconditioning by metabolic inhibition in the rat ventricular myocyte. Involvement of κ-opioid receptor. Circ Res 84: 1388–1395, 1999 PubMed

Xie Y, Zhu Y, Zhu WZ, Chen L, Zhou ZN, Juan WJ, Yang HT. Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 288: H2594–H2602, 2005 PubMed

Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O'Rourke B. Cytoprotective role of Ca PubMed

Yang CT, Zeng XH, Xia XM, Lingle CJ. Interactions between β subunits of the KCNMB family and Slo3: β4 selectively modulates Slo3 expression and function. PLoS One 4: e6135, 2009 PubMed PMC

Zhu HF, Dong JW, Zhu WZ, Ding HL, Zhou NZ. ATP-dependent potassium channels involved in the cardiac protection induced by intermittent hypoxia against ischemia/reperfusion injury. Life Sci 73: 1275–1287, 2003 PubMed

Zoratti M, De Marchi U, Gulbins E, Szabo I. Novel channels in the inner mitochondrial membrane. Biochim Biophys Acta 1787: 351–363, 2009 PubMed

Cardioprotective Effect of Chronic Hypoxia Involves Inhibition of Mitochondrial Permeability Transition Pore Opening

Sixty Years of Heart Research in the Institute of Physiology of the Czech Academy of Sciences