| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS
1Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Graduate School of the CAS, Shanghai; 2Laboratory of Molecular Cardiology, Institute of Health Sciences, SJTUSM and SIBS, CAS, Shanghai; and 3Physiological Laboratory of Hypoxia, SIBS, CAS, Shanghai, China
Submitted 19 October 2005 ; accepted in final form 17 November 2005
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
intracellular Ca2+ concentration; Ca2+ transients; Ca2+ transporters; myofilament Ca2+ sensitivity
Cytosolic free Ca2+ concentration ([Ca2+]i) plays a crucial role in determining cardiac contraction and relaxation in both physiological and pathophysiological conditions. Intracellular Ca2+ overload due to abnormal Ca2+ homeostasis in cardiomyocytes is one of the main factors involved in I/R injury (7, 27). Because the sarcoplasmic reticulum (SR) is the major source and sink of cytosolic Ca2+ and plays a critical role in regulating [Ca2+]i and subsequent contraction, the dysfunction of SR due to I/R (34, 35), particularly the impaired SR Ca2+ release channels/ryanodine receptors (RyRs) and SR Ca2+-pump ATPase (SERCA2), may contribute to Ca2+ overload and thereby affect contractility after ischemia (34, 35, 37). In cardiomyocytes, the Na+/Ca2+ exchanger (NCX) works with SERCA2 to exclude cytosolic Ca2+ during diastole by mediating most of the trans-sarcolemmal efflux, triggering SR (17), and directly activating the contractile elements (23). It also plays an important role in Ca2+ overload during I/R, leading to cellular injury and cell death (19, 20). Recently, we demonstrated that IHA hypoxia can protect the heart against lethal Ca2+ overload injury induced by Ca2+ paradox (36) and prevent the increase in resting [Ca2+]i due to I/R (41). More recently, we observed (37) that IHA hypoxia mitigates I/R-induced depression in SERCA2 activity by upregulating dual-site phospholamban (PLB) phosphorylation and that these effects are associated with improved recovery of contractile relaxation. We therefore hypothesized that IHA hypoxia may maintain Ca2+ homeostasis and result in better recovery of contractility during I/R via its protection of the SR and sarcolemmal Ca2+-handling proteins. To elucidate this issue in the present study, we have compared the time-dependent changes in Ca2+ transients and cell contraction at baseline and during I/R in cardiomyocytes in normoxic rats with those from IHA hypoxic rats and investigated the influence of IHA hypoxia on the changes in the protein contents and activities of SR RyRs, SERCA2, and sarcolemmal NCX during these processes.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
IHA hypoxic animals. Male Sprague-Dawley rats were exposed to IHA hypoxia in a hypobaric chamber (equivalent to an altitude of 5,000 m; barometric pressure PB = 404 mmHg, PO2 = 84 mmHg) for one 6-h period each day for 42 days as previously described (36, 37). Their body weight during this period rose from 100–130 g to 310–340 g. Age-matched normoxic animals were maintained in the normoxic environment for a corresponding period. Their body weights and weight gains were identical to those of rats exposed to IHA hypoxia. All animals had free access to water and to a standard laboratory diet.
Isolation of ventricular myocytes. Left ventricular myocytes were isolated from the heart using a standard enzymatic method described previously (3), and >90% of isolated, rod-shaped myocytes were Ca2+ tolerant.
I/R protocol in isolated cardiomyocytes. To determine directly the effects of IHA hypoxia on alterations of Ca2+ transients and contractions due to I/R, a cellular model of simulated I/R in isolated ventricular myocytes was used as previously described (9, 41). Briefly, myocytes were equilibrated in modified Krebs-Henseleit (K-H) solution at 35°C, pH 7.4. Subsequently, the solution was switched to ischemic solution containing (in mM) 123.0 NaCl, 8.0 KCl, 6.0 NaHCO3, 0.9 NaH2PO4, 0.5 MgSO4, 20.0 Na+-lactate, and 1.8 CaCl2, and was then gassed with 95% N2-5% CO2 (pH 6.8) for 20 min, followed by 30-min reperfusion with modified K-H solution. Left ventricular myocytes from the same heart were harvested for protein extraction at preischemia, after 20 min of ischemia (I20), and after 3 min (R3) and 30 min of reperfusion (R30), respectively.
Simultaneous measurement of Ca2+ transients and cell shortening. Ca2+ transients and cell shortening were detected simultaneously as previously described (3). Cells were incubated with a Ca2+ indicator, indo-1 AM (5 µM; Molecular Probes, Carlsbad, CA), at 25°C for 10 min. Loaded cells were electrically stimulated at 0.5 Hz, except during ischemia. The ratio of emitted fluorescence at 405 and 485 nm was recorded as an indicator of [Ca2+]i (3). Simultaneously, the cells were illuminated with a red light (650–750 nm) through the bright-field path of the microscope, and cell shortening was detected using an optical edge detector, collected using a charge-coupled device camera, and analyzed using IonWizard 4.4 software in length mode (IonOptix; Milton, MA).
To estimate the SR Ca2+ content and the involvement of NCX, caffeine-induced Ca2+ transients was measured as previously described (3) at preischemia, I20, and R30, but not at R3, because the cells died soon afterward as a result of severe hypercontracture. Because Na+-lactate was used to simulate acidosis due to ischemia and therefore could not be eliminated in the present study, Ni2+ (5 mM) was applied to block NCX just before and during the addition of caffeine (10 mM) (28). The time constants (
) representing a decay rate of Ca2+ transients and cell shortening were determined as previously described (3).
Measurement of electrogenic NCX currents.
The Ni2+-sensitive currents were recorded as electrogenic NCX currents (INa/Ca) using the standard whole cell patch-clamp technique as previously described (32). Briefly, membrane currents were assessed using an Axopatch multiclamp model 700B amplifier and a 1/100 CV-3 head stage (Axon Instruments, Sunnyvale, CA). The electrode resistance ranged from 2 to 5 M
. When INa/Ca was measured, K+ in the external solution was replaced by Cs+ (to abolish inwardly rectifying K+ current), and 10 µM nifedipine and 20 µM ouabain (to inhibit L-type Ca2+ currents and the Na+ pump, respectively) were added. Glibenclamide (2 µM) and hexamethyleneamiloride (2 µM) were also added to the ischemic solution to block the ATP-sensitive K+ (KATP) channel and Na+/H+ exchange, respectively. Ni2+ (5 mM) was added to define the fraction of currents derived from INa/Ca (total current remaining after subtraction of post-Ni2+ trace). A Cs+-based internal dialysis solution was used for all recordings, which contained (in mM) 65 CsCl, 20 NaCl, 5 MgATP, 6 CaCl2, 4 MgCl2, 10 HEPES, 20 tetraethyl ammonium chloride (TEA), and 21 EGTA (pH 7.2 adjusted with CsOH) (32). INa/Ca was elicited using ramp voltage-clamp pulses from holding potential –40 mV to +80 and then to –120 mV (100 mV/s) at 0.1 Hz. Membrane capacitance was read directly from the membrane test function of pCLAMP 9.0 software (Axon Instruments) before compensating series resistance and membrane capacitance.
Preparation of SR vesicles and cell sarcolemmal membrane samples. Harvested cells were homogenated in a lysis buffer containing (in mM) 15 Tris·HCl, 10 NaHCO3, 5 NaN3, 250 sucrose, and 1 EDTA (2°C, pH 7.0) using a homogenizer (Polytron PT 3100; Kinematica, Littau-Lucerne, Switzerland). The homogenate was centrifuged for 5 min at 3,000 g to remove cellular debris. For cell membrane preparation (25), the supernatant was centrifuged at 100,000 g for 60 min and then discarded. The pellet representing the sarcolemma-enriched fraction was resuspended in the solution with (in mM) 100 NaCl, 50 LiCl, 6 KCl, and 20 HEPES-Tris, pH 7.4, for Western blot analysis of NCX. For SR vesicle isolation (25, 35), the 3,000 g supernatant was further centrifuged at 48,000 g for 75 min and then discarded. The pellet was suspended in a mixture of 0.6 mM KCl and 20 mM Tris·HCl (pH 7.0) and centrifuged at 48,000 g for 60 min. The final pellet was rehomogenized in 250 mM sucrose and 40 mM imidazole-HCl and stored at –70°C. All solutions contained three protease inhibitors: soybean trypsin inhibitor (40 µg/ml), 0.1% PMSF, and leupeptin (0.5 µg/ml). The concentration of the proteins was determined using the method of Bradford.
Measurement of 45Ca2+ uptake of SR. Ca2+ uptake activity of SR was determined using 45Ca2+ (Amersham, Piscataway, NJ) and the Millipore (Billerica, MA) filtration technique as described previously (25, 35). The uptake conditions for SR protein (50 µg) were as follows: 22°C for 10 min in 40 imidazole-HCl (pH 7.0), 100 KCl, 20 NaCl, 5 MgCl2, 4 ATP-Na2, 1.3 µCi 45CaCl2, 5 µM Ru-360, and 5 µM calmidazolium (to inhibit Ca2+ uptake of mitochondria and SERCA2, respectively). The 45Ca2+ uptake by SERCA2 was defined as the difference between the rate of 45Ca2+ uptake in a 5 mM K+-oxalate-containing solution in the presence and absence of 5 µM cyclopiazonic acid, a specific inhibitor of SERCA2. The difference in uptake in the presence and absence of 20 µM ryanodine, a special blocker of RyRs, was defined as Ca2+ release via the RyRs (25).
Western blot analysis of RyRs, SERCA2, and NCX. The protein contents of RyRs and SERCA2 in the SR (25) and NCX in the sarcolemmal membrane (18) were determined using Western blot analysis. SR samples (50 µg) and membrane samples (30 µg) were subjected to 10% and 7.5% SDS-PAGE, respectively. Proteins were electrophoretically transferred to polyvinylidene difluoride membranes and probed with anti-RyR antibody (1:500 dilution; ABR, Golden, CO), anti-SERCA2 antibody (1:1,000 dilution; Santa Cruz Biotechnology, Santa Cruz, CA), and anti-NCX1 (1:400 dilution; Abcam, Cambridge, UK), respectively. The membranes were then incubated with horseradish peroxidase-conjugated goat anti-mouse IgG (1:2,500 dilution; Sigma, St. Louis, MO). The immunoreactions were visualized using an ECL detection kit (Amersham), exposed to X-ray film, and quantified using a video documentation system (Gel Doc 2000; Bio-Rad Laboratories, Hercules, CA).
Data presentation and statistical analysis. Data are presented as means ± SE. Significant differences were evaluated using ANOVA or paired and unpaired t-tests as appropriate. P < 0.05 was regarded as statistically significant.
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
values of Ca2+ transients and cell shortening, which represent the decay from the peak and are reverse indicators of the speed of Ca2+ removal from the cytosol or of relaxation in contractility, were significantly prolonged at R3 and R30 in the normoxic group, whereas in hypoxic group, the prolonged of the Ca2+ transients at R3 was significantly improved and returned completely to preischemia level at R30, accompanied by resumed of cell shortening during reperfusion (Fig. 2, E and F). These results demonstrate that the IHA hypoxia-induced prevention of Ca2+ overload due to I/R is associated with improved postischemic Ca2+ transients and contractile function.
|
|
|
|
|
during the preischemia phase (Fig. 5, A and B). Addition of 5 mM Ni2+ before caffeine led to similar increases in at preischemia in both groups, but increased significantly at I20 and R30 in the IHA hypoxia group compared with the normoxia group (Fig. 5, C and D). These data indicate that NCX is involved in Ca2+ efflux during I/R and in the cardioprotection induced by IHA hypoxia upon Ca2+ exclusion. Protein content and activity of NCX in ventricular myocytes from normoxic and IHA hypoxic rats during ischemia. To gain further insight into the changes in NCX during ischemia and the effect of IHA hypoxia on it, we examined INa/Ca. Figure 6A shows a set of typical recordings of INa/Ca at preischemia and I20 in myocytes from normoxia and IHA hypoxia groups. There was no difference in the cell capacitance between the normoxia group (126.54 ± 17.53 pF, n = 12) and the IHA hypoxia group (127.37 ± 18.86 pF, n = 10; P > 0.05). During the preischemia phase, no difference between the two groups was observed regarding INa/Ca (Fig. 6B). Ischemia at 20 min in normoxic myocytes significantly decreased both the inward and outward directed INa/Ca and shifted the apparent reversal potential to a positive direction (from –45.96 ± 3.56 mV to –34.63 ± 4.50 mV; P < 0.05) (Fig. 6, C and E). IHA hypoxia totally reserved these changes, with the similar apparent reversal potential of –46.17 ± 4.69 mV at preischemia and –46.26 ± 3.48 mV at I20 (P > 0.05) (Fig. 6, D and E). NCX protein content was not altered by I/R in both groups (Fig. 6F). These data indicate that IHA hypoxia relieves the ischemia-induced depression of NCX activity.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
Influence of IHA hypoxia on Ca2+ transients and cell shortening during I/R. We have shown that Ca2+ overload that occurred during I/R was accompanied by increases in the amplitude of Ca2+ transients and cellular contracture at the early phase of reperfusion and by decreases in Ca2+ transients and cell shortening at the late phase of reperfusion. These observations are basically similar to previous findings in acidosis (12), anoxia/reoxygenation (29), and I/R (27).
Several mechanisms have been proposed for the cardioprotective effects of IHA hypoxia against I/R injury, such as increases in the oxygen uptake and antioxidative ability (39), activation of PKC isoforms (10), and opening of a mitochondrial ATP-sensitive K+ channel (mitoKATP) (1, 41), but knowledge of target proteins that regulate Ca2+ homeostasis during IHA hypoxia is limited. Our current finding that IHA hypoxia preventing I/R-induced increase in resting [Ca2+]i levels is consistent with findings reported in a previous study (41). The novel findings in this study are that at the late phase of reperfusion, IHA hypoxia attenuates I/R-induced depression of Ca2+ transients and cell shortening without affecting baseline levels of these parameters. This direct evidence indicates that maintaining relatively normal Ca2+ homeostasis plays a crucial role in the cardioprotective effects of IHA hypoxia. This view is supported by our previous data indicating that IHA hypoxia protects the heart against lethal Ca2+ overload injury (36). It has been shown that continuous, chronic hypoxia lasting 2–3 wk decreases the amplitude of Ca2+ transients in association with the prolongation of time to peak and (25). Interestingly, longer IHA hypoxia lasting 6 wk did not alter baseline parameters, indicating that intermittent hypoxia may have better tolerance to counteract ischemic insults because it provides cells sufficient time to recover from acute damage while deriving the endogenous protective mechanisms.
IHA hypoxia maintains Ca2+ homeostasis during I/R by preventing alterations in major SR Ca2+-handling proteins RyR and SERCA2. The activator Ca2+ is released mainly by RyRs and is taken up by SERCA2 (5). We confirmed the previous observations of the activities and/or protein contents of RyRs and SERCA2 being decreased during I/R (24, 33–35). IHA hypoxia attenuated the above changes without affecting the baseline levels of these parameters. The depressed SR Ca2+ uptake due to I/R can be interpreted as the result of decreased protein content of SERCA2 and activity of the pump. Previous studies conducted by us (37) and by others (30) demonstrated that the decreased phosphorylation of PLB, an intrinsic protein of the cardiac SR that reversibly inhibits SERCA2 activity (14) is correlated to the depression of SERCA2 activity and relaxation recovery. Improved SR Ca2+ uptake stimulated by IHA hypoxia is ascribed at least in part to the preserved protein content and upregulated dual-site PLB phosphorylation induced by PKA and CaMKII (37). We previously observed that in rat myocardium, the abbreviation of action potential duration induced by I/R could be improved by IHA hypoxia (38). Because the action potential duration modulates the extent of SR Ca2+ loading (4), the electrophysiological alteration may also contribute to the improvement of SR Ca2+ uptake due to IHA hypoxia during I/R. Consistent with the decreased SR Ca2+ uptake during I/R, SR Ca2+ release from RyRs also decreased at the end of reperfusion. Although the latter may alleviate Ca2+ overload (24, 27), the reduced activity of RyRs would be detrimental to the contractility due to the depression of Ca2+ release from the SR. This notion is supported by our observation that IHA hypoxia-protected activity of RyRs correlates with the improved amplitude and rise of Ca2+ transients and cell shortening. It is also noteworthy that I/R-increased SR load remains unchanged in the IHA hypoxia group. Altogether, these findings indicate that 1) depression in SR Ca2+ handling due to I/R accounts for the decreased amplitude and delayed rise and decay of Ca2+ transients and cell contraction during reperfusion, and 2) IHA hypoxia may suppress I/R-induced cytosolic Ca2+ overload by reserving the protein content and function of RyRs and SERCA2, which could enhance the SR's capability of dealing with transiently overloaded cytosolic Ca2+ during I/R and maintaining a better balance of Ca2+ homeostasis, leading to improvement in contractility.
IHA hypoxia prevents alteration of NCX currents due to ischemia. On the basis mainly of pharmacological studies, it is generally thought that NCX causes Ca2+ overload during I/R (18, 31). The decreased inward and outward INa/Ca, with a shift of apparent reversal potential to a positive direction observed at the late phase of ischemia, may contribute to delayed cytosolic Ca2+ efflux (Fig. 5D) and, as others suggested (32), may lead to Ca2+ overload. Suppression of INa/Ca may be mediated by ischemia-induced intracellular acidosis (32) and decreases in cytosolic ATP levels (8) but not by alterations of protein content (18).
IHA hypoxia totally reversed ischemia-induced inhibition of the inward and outward INa/Ca as well as the shift of apparent reversal potential. This effect may be helpful for cells to alleviate the Ca2+ overload during ischemia by extruding cytosolic Ca2+ more quickly (Fig. 5B), consequently contributing to better relaxation observed in the IHA hypoxia group. The protected function of NCX, together with the improved contents and activities of RyRs and SERCA2 by IHA hypoxia during I/R, indicates that IHA hypoxia increases the capacity of cells to cope with Ca2+ overload by accelerating the removal of cytosolic Ca2+ into the SR and out of cells.
IHA hypoxia can maintain the mitochondrial integrity of both structure and function during Ca2+ overload or I/R by activating mitoKATP (1, 36, 41) and inhibiting the opening of mitochondrial permeability transition pores (40). Thus it significantly improves energy supply to reoxygenated myocardium after acute anoxia (15) and suppresses mitochondrial Ca2+ overload caused by I/R (40). Because the metabolism of mitochondria may affect the function of SR Ca2+-handling proteins (42) and the protection of IHA hypoxia against lethal Ca2+ overload injury can be abolished by inhibiting mitoKATP (36), the beneficial effects of IHA hypoxia on mitochondria may play an important role in its protection of the SR and sarcolemmal Ca2+-handling proteins and also in better recovery of postischemic contractility during I/R.
Beneficial effect of IHA hypoxia on the depressed Ca2+ sensitivity of myofilaments during reperfusion. We also observed that the decreased Ca2+ sensitivity of myofilaments due to I/R is largely suppressed by IHA hypoxia. Because Ca2+ overload directly decreases the Ca2+ sensitivity of myofilaments and depresses contractility during reperfusion (11, 16), improved contraction may be directly related to IHA hypoxia-induced suppression of Ca2+ overload. In addition, mitochondrial reactivation, such as production of energy, also influences the function of myofibrillar enzymes (26). IHA hypoxia protects the mitochondria and ATP production in anoxic reoxygenated myocardium (15) and in I/R myocytes (40); therefore, this mechanism also may be involved in the beneficial effect of IHA hypoxia on the resumed myofilament sensitivity and contractility during reperfusion. Moreover, ischemia preconditioning (2) could reduce acidosis-induced depression of myofilament Ca2+ sensitivity and maximum force (13). Thus the contribution of this mechanism to the beneficial effect of IHA hypoxia requires further future study.
In conclusion, our findings demonstrate that 1) IHA hypoxia does not alter baseline Ca2+ transients, cell shortening, and the contents and function of major Ca2+ handling proteins; 2) IHA hypoxia-attenuated cytosolic Ca2+ overload during I/R is associated with improved dynamics of Ca2+ transients and cell shortening; and 3) these beneficial effects of IHA hypoxia may be ascribed to the maintained contents and activities of RyRs and SERCA2 and the activity of NCX, which contribute to improved cellular contraction and relaxation during reperfusion.
|
GRANTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
ek F, Ot'ádal B, and Kolá
F. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias: involvement of mitochondrial KATP channel. J Mol Cell Cardiol 31: 1821–1831, 1999.[CrossRef][ISI][Medline]2. Babsky A, Hekmatyar S, Wehrli S, Doliba N, Osbakken M, and Bansal N. Influence of ischemic preconditioning on intracellular sodium, pH, and cellular energy status in isolated perfused heart. Exp Biol Med (Maywood) 227: 520–528, 2002.
3. Bassani JW, Bassani RA, and Bers DM. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol 476: 279–293, 1994.
4. Bassani RA, Altamirano J, Puglisi JL, and Bers DM. Action potential duration determines sarcoplasmic reticulum Ca2+ reloading in mammalian ventricular myocytes. J Physiol 559: 593–609, 2004.
5. Bers DM. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 87: 275–281, 2000.
6. Bolli R. The late phase of preconditioning. Circ Res 87: 972–983, 2000.
7. Carrozza JP Jr, Bentivegna LA, Williams CP, Kuntz RE, Grossman W and Morgan JP. Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. Circ Res 71: 1334–1340, 1992.
8. Collins A, Somlyo AV, and Hilgemann DW. The giant cardiac membrane patch method: stimulation of outward Na+-Ca2+ exchange current by MgATP. J Physiol 454: 27–57, 1992.
9. Cordeiro JM, Howlett SE, and Ferrier GR. Simulated ischaemia and reperfusion in isolated guinea pig ventricular myocytes. Cardiovasc Res 28: 1794–1802, 1994.
10. Ding HL, Zhu HF, Dong JW, Zhu WZ, and Zhou ZN. Intermittent hypoxia protects the rat heart against ischemia/reperfusion injury by activating protein kinase C. Life Sci 75: 2587–2603, 2004.[CrossRef][ISI][Medline]
11. Gao WD, Atar D, Backx PH, and Marban E. Relationship between intracellular calcium and contractile force in stunned myocardium: direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ Res 76: 1036–1048, 1995.
12. Harrison SM, Frampton JE, McCall E, Boyett MR, and Orchard CH. Contraction and intracellular Ca2+, Na+, and H+ during acidosis in rat ventricular myocytes. Am J Physiol Cell Physiol 262: C348–C357, 1992.
13. Kentish JC and Allen DG. Is force production in the myocardium directly dependent upon the free energy change of ATP hydrolysis? J Mol Cell Cardiol 18: 879–884, 1986.[CrossRef][ISI][Medline]
14. Kim HW, Steenaart NA, Ferguson DG, and Kranias EG. Functional reconstitution of the cardiac sarcoplasmic reticulum Ca2+-ATPase with phospholamban in phospholipid vesicles. J Biol Chem 265: 1702–1709, 1990.
15. Kopylov IuN, and Golubeva LIu. Effect of adaptation to periodic hypoxia on the resistance of the indicators of energy metabolism and myocardial contraction in acute anoxia and reoxygenation (Article in Russian). Biull Eksp Biol Med 111: 22–25, 1991.[Medline]
16. Kusuoka H, Porterfield JK, Weisman HF, Weisfeldt ML, and Marban E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts. J Clin Invest 79: 950–961, 1987.[ISI][Medline]
17. Leblanc N and Hume JR. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science 248: 372–376, 1990.
18. Matsumoto T, Miura T, Miki T, Genda S, and Shimamoto K. Blockade of the Na+-Ca2+ exchanger is more efficient than blockade of the Na+-H+ exchanger for protection of the myocardium from lethal reperfusion injury. Cardiovasc Drugs Ther 16: 295–301, 2002.[CrossRef][ISI][Medline]
19. Mochizuki S and MacLeod KT. Effects of hypoxia and metabolic inhibition on increases in intracellular Ca2+ concentration induced by Na+/Ca2+ exchange in isolated guinea-pig cardiac myocytes. J Mol Cell Cardiol 29: 2979–2987, 1997.[CrossRef][ISI][Medline]
20. Murphy E, Cross HR, and Steenbergen C. Is Na/Ca exchange during ischemia and reperfusion beneficial or detrimental? Ann NY Acad Sci 976: 421–430, 2002.[ISI][Medline]
21. Murry CE, Jennings RB, and Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136, 1986.
22. Neckár J, Marková I, Novák F, Nováková O, Szárszoi O, Otádal B, and Kolá F. Increased expression and altered subcellular distribution of PKC-
in chronically hypoxic rat myocardium: involvement in cardioprotection. Am J Physiol Heart Circ Physiol 288: H1566–H1572, 2005.
23. Nuss HB and Houser SR. Sodium-calcium exchange-mediated contractions in feline ventricular myocytes. Am J Physiol Heart Circ Physiol 263: H1161–H1169, 1992.
24. Osada M, Netticadan T, Tamura K, and Dhalla NS. Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning. Am J Physiol Heart Circ Physiol 274: H2025–H2034, 1998.
25. Pei JM, Kravtsov GM, Wu S, Das R, Fung ML, and Wong TM. Calcium homeostasis in rat cardiomyocytes during chronic hypoxia: a time course study. Am J Physiol Cell Physiol 285: C1420–C1428, 2003.
26. Piper HM, Abdallah Y, and Schafer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res 61: 365–371, 2004.
27. Piper HM, Meuter K, and Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg 75, Suppl: S644–S648, 2003.
28. Quinn FR, Currie S, Duncan AM, Miller S, Sayeed R, Cobbe SM, and Smith GL. Myocardial infarction causes increased expression but decreased activity of the myocardial Na+-Ca2+ exchanger in the rabbit. J Physiol 553: 229–242, 2003.
29. Ralenkotter L, Dales C, Delcamp TJ, and Hadley RW. Cytosolic [Ca2+], [Na+], and pH in guinea pig ventricular myocytes exposed to anoxia and reoxygenation. Am J Physiol Heart Circ Physiol 272: H2679–H2685, 1997.
30. Said M, Vittone L, Mundiña-Weilenmann C, Ferrero P, Kranias EG, and Mattiazzi A. Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants. Am J Physiol Heart Circ Physiol 285: H1198–H1205, 2003.
31. Satoh H, Ginsburg KS, Qing K, Terada H, Hayashi H, and Bers DM. KB-R7943 block of Ca2+ influx via Na+/Ca2+ exchange does not alter twitches or glycoside inotropy but prevents Ca2+ overload in rat ventricular myocytes. Circulation 101: 1441–1446, 2000.
32. Shigematsu S and Arita M. Anoxia depresses sodium-calcium exchange currents in guinea-pig ventricular myocytes. J Mol Cell Cardiol 31: 895–906, 1999.[CrossRef][ISI][Medline]
33. Temsah RM, Kawabata K, Chapman D, and Dhalla NS. Preconditioning prevents alterations in cardiac SR gene expression due to ischemia-reperfusion. Am J Physiol Heart Circ Physiol 282: H1461–H1466, 2002.
34. Temsah RM, Netticadan T, Chapman D, Takeda S, Mochizuki S, and Dhalla NS. Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am J Physiol Heart Circ Physiol 277: H584–H594, 1999.
35. Wu QY and Feher JJ. Effect of ischemia on the fraction of ryanodine-sensitive cardiac sarcoplasmic reticulum. J Mol Cell Cardiol 29: 1363–1373, 1997.[CrossRef][ISI][Medline]
36. Xie Y, Zhu WZ, Zhu Y, Chen L, Zhou ZN, and Yang HT. Intermittent high altitude hypoxia protects the heart against lethal Ca2+ overload injury. Life Sci 76: 559–572, 2004.[CrossRef][ISI][Medline]
37. Xie Y, Zhu Y, Zhu WZ, Chen L, Zhou ZN, Yuan WJ, and 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.
38. Zhang Y, Zhong N, and Zhou ZN. Effects of intermittent hypoxia on action potential and contraction in non-ischemic and ischemic rat papillary muscle. Life Sci 67: 2465–2471, 2000.[CrossRef][ISI][Medline]
39. Zhang Y, Zhong N, Zhu HF, and Zhou ZN. Antiarrhythmic and antioxidative effects of intermittent hypoxia exposure on rat myocardium (Article in Chinese). Sheng Li Xue Bao 52: 89–92, 2000.[Medline]
40. Zhu WZ, Xie Y, Chen L, Yang HT, and Zhou ZN. Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol 40: 96–106, 2006.[CrossRef][ISI][Medline]
41. Zhu HF, Dong JW, Zhu WZ, Ding HL, and Zhou ZN. ATP-dependent potassium channels involved in the cardiac protection induced by intermittent hypoxia against ischemia/reperfusion injury. Life Sci 73: 1275–1287, 2003.[CrossRef][ISI][Medline]
42. Zima AV, Copello JA, and Blatter LA. Effects of cytosolic NADH/NAD+ levels on sarcoplasmic reticulum Ca2+ release in permeabilized rat ventricular myocytes. J Physiol 555: 727–741, 2004.
This article has been cited by other articles:
|
|
 |
|
  M. E. Jung, J. W. Simpkins, A. M. Wilson, H. F. Downey, and R. T. Mallet Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats J Appl Physiol, August 1, 2008; 105(2): 510 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Y. Lu, L. Chen, X.-L. Cai, and H.-T. Yang Overexpression of heat shock protein 27 protects against ischaemia/reperfusion-induced cardiac dysfunction via stabilization of troponin I and T Cardiovasc Res, August 1, 2008; 79(3): 500 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Essop Cardiac metabolic adaptations in response to chronic hypoxia J. Physiol., November 1, 2007; 584(3): 715 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gao, L. Chen, and H.-T. Yang Activation of {alpha}1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes Cardiovasc Res, August 1, 2007; 75(3): 584 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Yeung, G. M. Kravtsov, K. M. Ng, T. M. Wong, and M. L. Fung Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2046 - C2056. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
