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Effects of superoxide donor menadione in adult Rat myocardium are associated with increased diastolic intracellular calcium

Effects of superoxide donor menadione in adult Rat myocardium are associated with increased... BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzt012 Research article Eec ff ts of superoxide donor menadione in adult Rat myocardium are associated with increased diastolic intracellular calcium Luke J. Rogers*, Andrew John Lake, Katherine White, Matthew Hardy and Ed White School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK *Corresponding author: Luke J. Rogers, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. Email: ljrogers@doctors.org.uk Supervisor: Ed White, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. Superoxide anions have been associated with many aspects of cardiovascular disease. Menadione is a superoxide anion donor that alters the heart’s electrical and mechanical functions. The aim of this study was to demonstrate simultaneous changes in 2+ 2+ intracellular Ca ([Ca ]i) and mechanical activity in intact adult cardiac myocytes, and mechanical activity and electrical activ- ity in isolated whole hearts in order to provide greater insight into the mechanisms associated with the detrimental effects of menadione on the myocardium. Isolated hearts from adult male Wistar rats (n = 11, 200–250 g) were Langendorff perfused at 38°C with a Krebs–Henseleit solution. A saline-filled balloon was placed in the left ventricle (LV) in order to measure diastolic and developed pressure. Monophasic action potentials were simultaneously recorded from the epicardial surface. External stimulation at 5 Hz and intrinsic pacing were used throughout a 10 min control period and 30 min exposure to 50 µ M mena- dione. Single LV myocytes (n = 7 from n = 4 animals) were loaded with the Ca -indicator Fura4-AM, stimulated at 1 Hz and 2+ 2+ exposed to 50 µ M menadione. Myocyte length was simultaneously measured with [Ca ]i using a video edge detection sys- tem. In isolated hearts, exposure to menadione significantly decreased contractility and action potential duration (with a simi - lar time course); intrinsic heart rate and rhythmicity. Diastolic pressure was significantly increased. In single adult myocytes, 2+ menadione caused a significant increase in diastolic [Ca ]i and a decrease in resting cell length and led to spontaneous release 2+ of [Ca ]i. We conclude that the effects of menadione upon electrical and mechanical activity of the heart are at least in part a 2+ 2+ 2+ consequence of dysregulation of [Ca ]i handling and the subsequent increase in diastolic [Ca ] alterations in [Ca ]i are consistent with the generation of delayed after depolarization arrhythmias. Key words: menadione, calcium, rat, superoxide, contractility, electrophysiology Received 22 July 2013; revised 3 December 2013; accepted 16 December 2013 Introduction streptokinase and percutaneous coronary interventions has led to the characterization of a paradoxical phenomenon Cardiovascular disease is a major contributor to mortality known as ‘reperfusion injury’. This is believed to occur as a and morbidity throughout the world (Roger et al., 2012). In result of the rapid production of reactive oxygen species the case of acute ischaemic events current treatment guidelines (ROS), which overwhelm the endogenous antioxidant sys- prioritize the rapid restoration of circulatory function to tems leading to cell death via necrosis and apoptotic path- reverse cardiomyocyte injury and limit cell death, thus signifi - ways. The superoxide anion in particular is believed to have a cantly reducing cardiac mortality and morbidity (Pollack, critical role as a mediator of post-ischaemic contractile dys- Antman, and Hollander, 2008). However, the advent of function, dysrhythmias and chronic cardiovascular disease cardiac thrombolysis through the use of agents such as (Kevin, Novalija and Stowe, 2005). © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Research article Bioscience Horizons • Volume 7 2014 Menadione is a potent superoxide donor (Choi et al., edge detection system (Crescent Electronics, Sandy, UT, 2+ 2005) that has a negative inotropic effect on isolated hearts, USA). [Ca ]i transients and cell shortening were analysed 2+ which, it has been suggested, is linked to intracellular Ca with pClamp 9 (Axon Instruments). 2+ ([Ca ]i) regulation (Anderson and Dutta, 1991). In addi- Solutions tion, it has been demonstrated that menadione alters the electrical response of cardiac tissue preparations (Choi et al., The K–H solution contained (in mM) NaCl 118.5; NaHCO 2005; Ha et al., 2007). However, the simultaneous measure- 25.0; KCl 4.2; KH PO 1.2 mM; MgSO 7H O 1.2; glucose 2 4 4 2 ment of the mechanical and electrical effects of menadione 11.1 and CaCl 2.0. Menadione was dissolved in methanol to 2+ has not previously been reported, nor has its effects on [Ca ] make a 50 mM stock solution which was added to K–H solu- i transients in intact adult myocytes been measured. The tion to give a final concentration of 50 µ M menadione and objective was to test the hypothesis that the mechanical and 0.1% methanol. Glibenclamide, at a final concentration of electrical effects of the superoxide anion donor menadione 50 µ M, was dissolved in 0.1% methanol. Exposure to 0.1% 2+ can be explained by the presence of dysfunctional [Ca ]i methanol in K–H solution had no statistically significant regulation. effects on isolated whole hearts or single myocytes. The effects of menadione were not reversible on removal of the agent. Materials and Methods Statistical analysis Isolated whole hearts Statistical significance was tested using one-way repeated Adult male Wistar rats (n = 13, 200–250 g) were killed by measures ANOVA (RMANOVA) unless stated otherwise, P stunning and cervical dislocation in accordance with the UK values < 0.05 were regarded as significant. Data are expressed Home Office regulations (Animal [Scientific Procedures] Act as mean ± SEM. 1986). Hearts were isolated, weighed and Langendorff per- fused (Stones et al., 2009) with a Krebs–Henseleit (K–H) −1 −1 solution at 38°C at a constant flow rate of 7 ml min g Results heart weight. A saline-filled balloon, connected to a pressure transducer, was placed in the left ventricle (LV) via the dis- Isolated whole hearts sected left atrium to measure diastolic and developed pres- Menadione caused a significant increase in diastolic pressure sure (DP). The balloon was inflated (typically to a volume of approximately 10 min after exposure compared to vehicle 0.1 ml) until diastolic pressure began to register and transient alone (Fig. 1). The end-diastolic pressure (EDP) rose from systolic pressures were visible. Monophasic action potentials 19.7 ± 12.84 mmHg, prior to exposure, to 50.7 ± 9.9 mmHg, (MAPs) were simultaneously recorded from the epicardial (P < 0.001) after 25 min. As a consequence of this, DP fell surface of the LV (Benoist et al., 2011). Alternating, 5 min from 76.5 ± 15.72 to 17.5 ± 3.0 mmHg over the same time periods of external stimulation, delivered via platinum con- period (P < 0.001). The mean changes for EDP and DP are tact electrodes at a frequency of 5 Hz and intrinsic pacing (no shown in Fig. 2A and B, respectively. external stimulation), were used throughout a 10 min control and 30 min exposure to 50-µ M menadione (Sigma, Aldrich) Exposure to menadione for 25 min also significantly followed by a return to menadione-free solution. Alternatively, reduced the rate of peak pressure development (max dP/dT) after 10 min control solution, hearts (n = 2) were exposed to −1 (from 4037.0 ± 446.2 to 2254.2 ± 98.0 mmHg s , P < 0.001) glibenclamide (a blocker of ATP-modulated potassium cur- and the peak rate of relaxation (min dP/dT) (from rent, I ) for 10 min followed by glibenclamide plus mena- KATP −1 −3126.6 ± 259.0 to −2240.0 ± 36.5 mmHg s , P < 0.001). dione for 30 min. Pressure values and rates of pressure The mean changes of max and min dP/dT are shown in development and MAP durations were measured with Lab Fig. 2C and D, respectively. Chart 7 software (ADInstruments, Australia). MAP durations at 20, 50 and 80% repolarization (APD , APD , APD , respectively) were simultaneously Single LV myocytes 20 50 80 recorded with LV pressure (Fig. 3A). There was a significant LV myocytes were isolated from n = 4 adult Wistar rat hearts reduction in APD after 25 min exposure to menadione as described previously by McCrossan, Billeter and White (Fig. 3B and C). (2004). Myocytes selected for study were quiescent when not In the absence of external stimulation, menadione affected stimulated and had clear and regular striations. Myocytes 2+ the rate and rhythmicity of intrinsic pacing (Fig. 4A). Heart were loaded with the Ca -indicator Fura4-AM (2 µ M for rate was significantly reduced after 20 min of exposure (Fig. 20 min) stimulated at 1 Hz and exposed to 50 µ M menadi- 4B, P < 0.05, paired t-test). There was a significant decrease one (n = 7). Cells were alternately excited by light at 340 and in rhythmicity, indicated by an increase in the standard devia- 380 nm (optoscan monochromator, Cairn Research, UK) and 2+ tion of beat-to-beat periodicity (an established index of the ratio of emitted light at 510 nm was our index of [Ca ]i. rhythmicity, Fig. 4C, P < 0.05, Wilcoxon signed rank test). Myocyte length was simultaneously measured using a video 2 Bioscience Horizons • Volume 7 2014 Research article Figure 1. Representative trace of LV pressure before and after exposure to vehicle (A) or 50 µ M menadione (B). Arrow indicates addition of agents. Figure 2. Mean changes in (A) EDP, (B) DP, (C) maximum rate of pressure development (contraction) and (D) minimum rate of pressure development (relaxation). Arrow denotes addition of vehicle or 50 µ M menadione. ***P < 0.001 vs. pre-drug, 1-way RMANOVA, n = 7 hearts. To test whether action potential duration (APD) short- 59 and 38%; increase in EDP 52 and 8 mmHg; decrease in ening was dependent upon the activation of I , hearts DP 27 and 70 mmHg; decrease in max dP/dt 1641 and KATP −1 (n = 2) were exposed to the I blocker glibenclamide. 1856 mm Hg s ; decrease in min dP/dT 859 and KATP −1 This did not prevent the mechanical responses or APD 1216 mm Hg s ) these observations are consistent with the shortening upon exposure to menadione (APD shortening changes in these parameters reported in Figs 2 and 3. 3 Research article Bioscience Horizons • Volume 7 2014 Figure 3. MAP duration following exposure to menadione. (A) Representative MAP traces illustrating APD , APD and APD . (B) APD prior to 20 50 80 80 (control) and during exposure to menadione. (C) Mean percentage change in MAP duration after 25 min exposure to menadione for APD , APD 20 50 and APD . ***P < 0.001, 1-way RM ANOVA vs. pre-exposure, n = 7 hearts. (Floreani, Santi, and Carpenedo, 1989; Anderson and Dutta, Single LV myocytes 1991). We observed decreased DP, as a result of increased dia- 2+ The effect of menadione on [Ca ]i handling was tested in stolic pressure, rather than decreased systolic pressure, consis- single myocytes (Fig. 5A). Exposure to 50 µ M menadione tent with the findings of Anderson and Dutta (1991). Our caused a significant increase in diastolic calcium (Fig. 5B, data provide evidence that exposure to menadione results in a P < 0.05). There was also a significant reduction in resting reduction in ventricular DP as a consequence of increased cell length (Fig. 5C, P < 0.05). Exposure to menadione caused 2+ diastolic [Ca ]i, as observed in single myocytes. In this 2+ the generation of spontaneous oscillations of [Ca ]i and cell respect, it is interesting to note that the rise in the diastolic shortening (Fig. 5A). These effects were not seen in four cells pressure in whole hearts (Figs 1 and 2) had a similar time exposed to vehicle alone. 2+ course to the rise in diastolic [Ca ]i and fall in resting cell length (Fig. 5). Discussion In a previous study, a reduction in myocyte contractility induced by exposure to an alternative ROS donor, H O , was 2 2 The negative inotropic effect of menadione 2+ attributed to a fall in myofilament Ca sensitivity (Luo et al., 2+ 2006). However, in our study a fall in myofilament Ca sen- A novel aspect of our study is that while previous studies have sitivity is not consistent with the maintained systolic pressure predicted the diastolic contracture provoked by menadione is 2+ or a decreased rate of relaxation. Alternatively, in isolated associated with a rise in diastolic [Ca ]i, our observation in sarcoplasmic reticular (SR) preparations, menadione has intact, adult myocytes is the first to show directly a simultane - 2+ been reported to inhibit the function of the SR Ca -uptake ous increase in these parameters. Menadione has been shown pump (SERCA) (Floreani and Carpenedo, 1989; Floreani, to have both positive and negative inotropic effects depending Santi, and Carpenedo, 1989; Shneyvays et al., 2005). This upon concentration (Floreani, Santi, and Carpenedo, 1989). 2+ inhibition could explain the increased level of diastolic [Ca ]i; We used a concentration designed to provoke the nega - decreased contractility and decreased rate of relaxation. tive inotropic effect associated with ROS-induced injury 4 Bioscience Horizons • Volume 7 2014 Research article Figure 4. (A) Representative, simultaneous recording of LV MAPs (upper trace) and LV pressure (lower trace) in a heart exposed to 50 µ M menadione for 20 min, note the dysrhythmic behaviour. (B) Intrinsic heart rate and (C) standard deviation of heart rate (beat-to-beat periodicity), an index of rhythmicity, before and after 20 min exposure to menadione, n = 7 hearts, *P < 0.05; B, paired t-test; C, Wilcoxon signed rank test. Similar findings have been reported in rat ventricular myo - The effect of menadione on APD cytes using H O ( Greensmith, Eisner and Nirmalan, 2010). 2 2 and heart rate Exposure to free radicals has been shown to reduce the activ- + + ity of Na and K -ATPase (Kim and Akera, 1987; Matsuoka, Menadione reduced the duration of APD in the LV of iso- Kato and Kako, 1990). It is therefore possible that cellular lated whole rat hearts. These findings are consistent with the + 2+ loading of Na could also contribute to Ca overload via findings of Choi et al. (2005) and Ha et al. (2007). However, + 2+ activation of the Na –Ca exchanger (Matsuura and Barrington, Meier and Weglicki (1988) provided evidence Shattock, 1991). that H O prolonged the APD of canine ventricular myocytes 2 2 and Cerbai et al. (1991) have shown that dihydroxyfumaric Previously, it has been shown that the reintroduction of acid (DHF), a general donor of ROS species, prolongs the molecular oxygen to ischaemic myocardium results in the APD of guinea pig ventricular myocytes. These study differ- production of oxygen-free radicals (Bolli et al., 1989). ences may arise from the varying effects of ROS species and Contraction band necrosis has been documented in histo- or related to differences in species studied or preparation, logical sections of human LV tissue following reperfusion e.g. single cells vs. multicellular preparations. after myocardial infarction and fibrinolysis ( Verma et al., 2002). It is therefore interesting that we observed myocyte Menadione also had a negative chronotropic effect on iso- death (e.g. Fig. 5A) in a number of the myocytes exposed to lated whole hearts and produced dysrhythmia. Cerbai et al. menadione. (1991) have shown that DHF causes guinea pig ventricular 5 Research article Bioscience Horizons • Volume 7 2014 2+ Figure 5. (A) Representative recording of cell length (upper trace) and [Ca ]i (lower trace) in a single myocyte exposed to 50 µ M menadione and 2+ stimulated at 1 Hz. Traces represent 1 min recordings at 5 min intervals. (B) Increase in diastolic [Ca ]i and (C) decrease in resting cell length during exposure to menadione. *P < 0.05, 1-way RM ANOVA vs. pre-exposure; n = 7 myocytes from n = 4 hearts. ROS production interferes with mitochondrial function. myocytes to exhibit early after depolarizations (EADs) or to 2+ This has been shown to cause a release of Ca from the mito- become unexcitable. Similarly, Matsuura and Shattock chondria (Saxena et al., 1995) and to reduce mitochondrial (1991) identified an oscillatory transient current that sponta - 2+ respiration (Nulton-Persson and Szweda, 2001; Long et al., neously triggered SR Ca release and automaticity, greatly + + 2004). Both SERCA, and Na and K -ATPase activity are ATP increasing the risk of dysrhythmias on exposure to rose 2+ dependent, it is therefore possible that increased [Ca ]i and Bengal (10–100 nM). This current was attributed to the Na – 2+ 2+ ATP depletion potentiate one another; as [Ca ]i rises so does Ca exchanger and is typically associated with delayed after the cell’s utilization of ATP, thus further depleting ATP stores. depolarizations (DADs) (Venetucci et al., 2008). Another novel finding of this study is the demonstration of spontane - 2+ ous [Ca ]i transients in intact adult myocytes on exposure to A reduction in ATP may trigger the opening of I chan- KATP menadione. It can be seen in Fig. 5A that after 20 min expo- nels and contribute to the APD shortening that we observed 2+ sure to menadione, Ca release became irregular and was (Brown and O’Rourke, 2010). However, our preliminary stud- not coupled to the stimulating pulse, these spontaneous ies (n = 2) found that 50 µ M glibenclamide was not effective at 2+ releases of Ca are typical of those thought to trigger DAD preventing the degree of APD shortening caused by menadi- type arrhythmias. In addition, the dysrhythmia shown in Fig. one. Oxygen-free radicals have been reported to have a direct 4A is consistent with DADs rather than EADs being the effect upon I channels decreasing their sensitivity to ATP KATP arrhythmic mechanism induced by menadione. (Ichinari et al., 1996; Tokube, Kiyosue and Arita, 1996). 6 Bioscience Horizons • Volume 7 2014 Research article cardiocytes, Journal of Molecular and Cellular Cardiology, 20, 1163– As modification of contractility and electrical activity are interrelated it is useful to measure these parameters simulta- neously. A further novel finding is that APD shortening Benoist, D., Stones, R., Drinkhill, M. et  al. (2011) Arrhythmogenic sub- occurs alongside the fall in DP and is likely to contribute to strate in hearts of rats with monocrotaline-induced pulmonary 2+ this effect because a shorter APD will lead to less Ca influx hypertension and right ventricular hypertrophy, American Journal 2+ 2+ through L-type Ca channels, a smaller SR Ca load and of Physiology Heart and Circulatory Physiology, 300, H2230–H2237. 2+ 2+ thus a smaller SR Ca release, in turn smaller SR Ca release + 2+ will generate less inward Na –Ca exchange current, short- Bolli, R., Jeroudi, M. O., Patel, B. S. et al. (1989) Direct evidence that oxy- ening the APD (Bouchard, Clark and Giles, 1995). gen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog, Proceedings of the National Academy Study limitations of Sciences of the United States of America, 86, 4695–4699. Due to the instability of physiological buffer solutions, there Bouchard, R. A., Clark, R. B., and Giles, W. R. (1995) Effects of action is currently no method of exposing cardiac tissue to a known potential duration on excitation-contraction coupling in rat ven- concentration of ROS. Consequently, the concentration of tricular myocytes. Action potential voltage-clamp measurements, menadione administered was a proxy for the concentration Circulation Research, 76, 790–801. of superoxide anions. Furthermore, although menadione is Brown, D. A. and O’Rourke, B. (2010) Cardiac mitochondria and arrhyth- the most specific superoxide anion donor ( Choi et al., 2005), − mias, Cardiovascular Research, 88, 241–249. potential effects relating to H O and OH cannot be 2 2 excluded. Cerbai, E., Ambrosio, G., Porciatti, F. et al. (1991) Cellular electrophysiolog- ical basis for oxygen radical-induced arrhythmias. A patch-clamp Conclusion study in guinea pig ventricular myocytes, Circulation, 84, 1773–1782. Choi, B. H., Ha, K. C., Park, J. A. et al. (2005) Regional differences of super - The data presented provide evidence that exposure to mena- oxide dismutase activity enhance the superoxide-induced electrical dione, at 50 µ M, exerts a negative inotropic effect as a conse- heterogeneity in rabbit hearts, Basic Research in Cardiology, 100, quence of an increase in diastolic pressure. Moreover, we 355–364. have shown that in single LV myocytes this decrease in rest- 2+ ing cell length occurs in parallel with an increase in [Ca ]i, Floreani, M. and Carpenedo, F. (1989) Inhibition of cardiac sarcoplasmic which we suggest is a result of the actions of superoxide on reticulum Ca2 + -ATPase activity by menadione, Archives of + 2+ Na –Ca exchange and SERCA function. Biochemistry and Biophysics, 270, 33–41. Floreani, M., Santi, S. E., and Carpenedo, F. (1989) Effects of 2-methyl- Funding 1,4-naphthoquinone (menadione) on myocardial contractility and Supported by the University of Leeds. cardiac sarcoplasmic reticulum Ca-ATPase, Naunyn-Schmiedeberg’s Archives of Pharmacology, 339, 448–455. Author biography Greensmith, D. J., Eisner, D. A., and Nirmalan, M. (2010) The effects of hydrogen peroxide on intracellular calcium handling and contractil- L.J.R. studied pharmacology in relation to medicine as part of an ity in the rat ventricular myocyte, Cell Calcium, 48, 341–351. intercalated degree; he subsequently completed his MBChB at the University of Leeds, passing with honours. He began work Ha, K. C., Kwak, Y. G., Piao, C. S. et al. (2007) Differential effects of super - as a Foundation Year 1 doctor in August 2013 and is currently oxide radical on the action potentials in ventricular muscles, considering an academic and research career in Cardiology or Purkinje fibers and atrial muscles in the heart of different aged rats, Cardiac Surgery. He contributed equally to the conduct of Archives of Pharmacal Research, 30, 1088–1095. experiments and analysis of data, alongside A.L. and K.W. He Ichinari, K., Kakei, M., Matsuoka, T. et al. (1996) Direct activation of the also wrote the paper and had primary responsibility for its final ATP-sensitive potassium channel by oxygen free radicals in guinea- content. Aside from the conduct of experiments and analysis of pig ventricular cells: its potentiation by MgADP, Journal of Molecular data A.L. and K.W. also edited the paper before final submis - and Cellular Cardiology, 28, 1867–1877. sion. A.L. provided the illustrations. Professor Ed White designed this project as a dissertation for L.J.R., A.L. and K.W. Kevin, L. G., Novalija, E. and Stowe, D. F. (2005) Reactive oxygen species as mediators of cardiac injury and protection: the relevance to anes- References thesia practise, Anesthesia & Analgesia, 101, 1275–1287. Kim, M. S. and Akera, T. (1987) O2 free radicals: cause of ischemia- Anderson, G. F. and Dutta, S. (1991) Electromechanical effects of mena - reperfusion injury to cardiac Na + -K + -ATPase, The American dione on isolated rat heart in relation to oxidative stress, Free Radical Journal of Physiology, 252, H252–H257. Biology & Medicine, 11, 169–177. Long, X., Goldenthal, M. J., Wu, G. M. et al. (2004) Mitochondrial Ca2+ flux Barrington, P. L., Meier, C. F., Jr., and Weglicki, W. B. (1988) Abnormal elec- and respiratory enzyme activity decline are early events in cardio- trical activity induced by free radical generating systems in isolated 7 Research article Bioscience Horizons • Volume 7 2014 myocyte response to H2O2, Journal of Molecular and Cellular with ST-segment elevation myocardial infarction: implications for Cardiology, 37, 63–70. emergency department practice, Annals of Emergency Medicine, 52, 344–355. Luo, J., Xuan, Y. T., Gu, Y. et al. (2006) Prolonged oxidative stress inverts the cardiac force-frequency relation: role of altered calcium han- Roger, V. L., Go, A. S., Lloyd-Jones, D. M. et al. (2012) Heart disease and dling and myofilament calcium responsiveness, Journal of Molecular stroke statistics–2012 update: a report from the American Heart and Cellular Cardiology, 40, 64–75. Association, Circulation, 125, e2–e220. Matsuoka, T., Kato, M., and Kako, K. J. (1990) Effect of oxidants on Saxena, K., Henry, T. R., Solem, L. E. et al. (1995) Enhanced induction of Na,K,ATPase and its reversal, Basic Research in Cardiology, 85, 330–341. the mitochondrial permeability transition following acute menadi- one administration, Archives of Biochemistry and Biophysics, 317, Matsuura, H. and Shattock, M. J. (1991) Membrane potential fluctua - 79–84. tions and transient inward currents induced by reactive oxygen intermediates in isolated rabbit ventricular cells, Circulation Shneyvays, V., Lesham, D., Shmist, Y. et al. (2005) Effects of menadione Research, 68, 319–329. and its derivative on cultured cardiomyocyes with mitochondrial disorders, Journal of Molecular and Cellular Cardiology, 39, 149–158. McCrossan, Z. A., Billeter, R., and White, E. (2004) Transmural changes in size, contractile and electrical properties of SHR left ventricular myo- Stones, R., Billeter, R., Zhang, H. et al. (2009) The role of transient out- cytes during compensated hypertrophy, Cardiovascular Research, 63, ward K+ current in electrical remodelling induced by voluntary 283–292. exercise in female rat hearts, Basic Research in Cardiology, 104, 643–652. Nulton-Persson, A. C. and Szweda, L. I. (2001) Modulation of mitochon- drial function by hydrogen peroxide, The Journal of Biological Tokube, K., Kiyosue, T., and Arita, M. (1996) Openings of cardiac KATP Chemistry, 276, 23357–23361. channel by oxygen free radicals produced by xanthine oxidase reac- tion, The American Journal of Physiology, 271, H478–H489. Pallandi, R. T., Perry, M. A., and Campbell, T. J. (1987) Proarrhythmic effects of an oxygen-derived free radical generating system on action potentials Venetucci, L. A., Trafford, A. W., O’Neill, S. C. et al. (2008) The sarcoplasmic recorded from guinea pig ventricular myocardium: a possible cause of reticulum and arrhythmogenic calcium release, Cardiovascular reperfusion-induced arrhythmias, Circulation Research, 61, 50–54. Research, 77, 285–292. Pollack, C. V., Jr., Antman, E. M., and Hollander, J. E. (2008) 2007 focused Verma, S., Fedak, P . W., Weisel, R. D. et al. (2002) Fundamentals of reperfusion update to the ACC/AHA guidelines for the management of patients injury for the clinical cardiologist, Circulation, 105, 2332–2336. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

Effects of superoxide donor menadione in adult Rat myocardium are associated with increased diastolic intracellular calcium

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzt012 Research article Eec ff ts of superoxide donor menadione in adult Rat myocardium are associated with increased diastolic intracellular calcium Luke J. Rogers*, Andrew John Lake, Katherine White, Matthew Hardy and Ed White School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK *Corresponding author: Luke J. Rogers, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. Email: ljrogers@doctors.org.uk Supervisor: Ed White, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. Superoxide anions have been associated with many aspects of cardiovascular disease. Menadione is a superoxide anion donor that alters the heart’s electrical and mechanical functions. The aim of this study was to demonstrate simultaneous changes in 2+ 2+ intracellular Ca ([Ca ]i) and mechanical activity in intact adult cardiac myocytes, and mechanical activity and electrical activ- ity in isolated whole hearts in order to provide greater insight into the mechanisms associated with the detrimental effects of menadione on the myocardium. Isolated hearts from adult male Wistar rats (n = 11, 200–250 g) were Langendorff perfused at 38°C with a Krebs–Henseleit solution. A saline-filled balloon was placed in the left ventricle (LV) in order to measure diastolic and developed pressure. Monophasic action potentials were simultaneously recorded from the epicardial surface. External stimulation at 5 Hz and intrinsic pacing were used throughout a 10 min control period and 30 min exposure to 50 µ M mena- dione. Single LV myocytes (n = 7 from n = 4 animals) were loaded with the Ca -indicator Fura4-AM, stimulated at 1 Hz and 2+ 2+ exposed to 50 µ M menadione. Myocyte length was simultaneously measured with [Ca ]i using a video edge detection sys- tem. In isolated hearts, exposure to menadione significantly decreased contractility and action potential duration (with a simi - lar time course); intrinsic heart rate and rhythmicity. Diastolic pressure was significantly increased. In single adult myocytes, 2+ menadione caused a significant increase in diastolic [Ca ]i and a decrease in resting cell length and led to spontaneous release 2+ of [Ca ]i. We conclude that the effects of menadione upon electrical and mechanical activity of the heart are at least in part a 2+ 2+ 2+ consequence of dysregulation of [Ca ]i handling and the subsequent increase in diastolic [Ca ] alterations in [Ca ]i are consistent with the generation of delayed after depolarization arrhythmias. Key words: menadione, calcium, rat, superoxide, contractility, electrophysiology Received 22 July 2013; revised 3 December 2013; accepted 16 December 2013 Introduction streptokinase and percutaneous coronary interventions has led to the characterization of a paradoxical phenomenon Cardiovascular disease is a major contributor to mortality known as ‘reperfusion injury’. This is believed to occur as a and morbidity throughout the world (Roger et al., 2012). In result of the rapid production of reactive oxygen species the case of acute ischaemic events current treatment guidelines (ROS), which overwhelm the endogenous antioxidant sys- prioritize the rapid restoration of circulatory function to tems leading to cell death via necrosis and apoptotic path- reverse cardiomyocyte injury and limit cell death, thus signifi - ways. The superoxide anion in particular is believed to have a cantly reducing cardiac mortality and morbidity (Pollack, critical role as a mediator of post-ischaemic contractile dys- Antman, and Hollander, 2008). However, the advent of function, dysrhythmias and chronic cardiovascular disease cardiac thrombolysis through the use of agents such as (Kevin, Novalija and Stowe, 2005). © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Research article Bioscience Horizons • Volume 7 2014 Menadione is a potent superoxide donor (Choi et al., edge detection system (Crescent Electronics, Sandy, UT, 2+ 2005) that has a negative inotropic effect on isolated hearts, USA). [Ca ]i transients and cell shortening were analysed 2+ which, it has been suggested, is linked to intracellular Ca with pClamp 9 (Axon Instruments). 2+ ([Ca ]i) regulation (Anderson and Dutta, 1991). In addi- Solutions tion, it has been demonstrated that menadione alters the electrical response of cardiac tissue preparations (Choi et al., The K–H solution contained (in mM) NaCl 118.5; NaHCO 2005; Ha et al., 2007). However, the simultaneous measure- 25.0; KCl 4.2; KH PO 1.2 mM; MgSO 7H O 1.2; glucose 2 4 4 2 ment of the mechanical and electrical effects of menadione 11.1 and CaCl 2.0. Menadione was dissolved in methanol to 2+ has not previously been reported, nor has its effects on [Ca ] make a 50 mM stock solution which was added to K–H solu- i transients in intact adult myocytes been measured. The tion to give a final concentration of 50 µ M menadione and objective was to test the hypothesis that the mechanical and 0.1% methanol. Glibenclamide, at a final concentration of electrical effects of the superoxide anion donor menadione 50 µ M, was dissolved in 0.1% methanol. Exposure to 0.1% 2+ can be explained by the presence of dysfunctional [Ca ]i methanol in K–H solution had no statistically significant regulation. effects on isolated whole hearts or single myocytes. The effects of menadione were not reversible on removal of the agent. Materials and Methods Statistical analysis Isolated whole hearts Statistical significance was tested using one-way repeated Adult male Wistar rats (n = 13, 200–250 g) were killed by measures ANOVA (RMANOVA) unless stated otherwise, P stunning and cervical dislocation in accordance with the UK values < 0.05 were regarded as significant. Data are expressed Home Office regulations (Animal [Scientific Procedures] Act as mean ± SEM. 1986). Hearts were isolated, weighed and Langendorff per- fused (Stones et al., 2009) with a Krebs–Henseleit (K–H) −1 −1 solution at 38°C at a constant flow rate of 7 ml min g Results heart weight. A saline-filled balloon, connected to a pressure transducer, was placed in the left ventricle (LV) via the dis- Isolated whole hearts sected left atrium to measure diastolic and developed pres- Menadione caused a significant increase in diastolic pressure sure (DP). The balloon was inflated (typically to a volume of approximately 10 min after exposure compared to vehicle 0.1 ml) until diastolic pressure began to register and transient alone (Fig. 1). The end-diastolic pressure (EDP) rose from systolic pressures were visible. Monophasic action potentials 19.7 ± 12.84 mmHg, prior to exposure, to 50.7 ± 9.9 mmHg, (MAPs) were simultaneously recorded from the epicardial (P < 0.001) after 25 min. As a consequence of this, DP fell surface of the LV (Benoist et al., 2011). Alternating, 5 min from 76.5 ± 15.72 to 17.5 ± 3.0 mmHg over the same time periods of external stimulation, delivered via platinum con- period (P < 0.001). The mean changes for EDP and DP are tact electrodes at a frequency of 5 Hz and intrinsic pacing (no shown in Fig. 2A and B, respectively. external stimulation), were used throughout a 10 min control and 30 min exposure to 50-µ M menadione (Sigma, Aldrich) Exposure to menadione for 25 min also significantly followed by a return to menadione-free solution. Alternatively, reduced the rate of peak pressure development (max dP/dT) after 10 min control solution, hearts (n = 2) were exposed to −1 (from 4037.0 ± 446.2 to 2254.2 ± 98.0 mmHg s , P < 0.001) glibenclamide (a blocker of ATP-modulated potassium cur- and the peak rate of relaxation (min dP/dT) (from rent, I ) for 10 min followed by glibenclamide plus mena- KATP −1 −3126.6 ± 259.0 to −2240.0 ± 36.5 mmHg s , P < 0.001). dione for 30 min. Pressure values and rates of pressure The mean changes of max and min dP/dT are shown in development and MAP durations were measured with Lab Fig. 2C and D, respectively. Chart 7 software (ADInstruments, Australia). MAP durations at 20, 50 and 80% repolarization (APD , APD , APD , respectively) were simultaneously Single LV myocytes 20 50 80 recorded with LV pressure (Fig. 3A). There was a significant LV myocytes were isolated from n = 4 adult Wistar rat hearts reduction in APD after 25 min exposure to menadione as described previously by McCrossan, Billeter and White (Fig. 3B and C). (2004). Myocytes selected for study were quiescent when not In the absence of external stimulation, menadione affected stimulated and had clear and regular striations. Myocytes 2+ the rate and rhythmicity of intrinsic pacing (Fig. 4A). Heart were loaded with the Ca -indicator Fura4-AM (2 µ M for rate was significantly reduced after 20 min of exposure (Fig. 20 min) stimulated at 1 Hz and exposed to 50 µ M menadi- 4B, P < 0.05, paired t-test). There was a significant decrease one (n = 7). Cells were alternately excited by light at 340 and in rhythmicity, indicated by an increase in the standard devia- 380 nm (optoscan monochromator, Cairn Research, UK) and 2+ tion of beat-to-beat periodicity (an established index of the ratio of emitted light at 510 nm was our index of [Ca ]i. rhythmicity, Fig. 4C, P < 0.05, Wilcoxon signed rank test). Myocyte length was simultaneously measured using a video 2 Bioscience Horizons • Volume 7 2014 Research article Figure 1. Representative trace of LV pressure before and after exposure to vehicle (A) or 50 µ M menadione (B). Arrow indicates addition of agents. Figure 2. Mean changes in (A) EDP, (B) DP, (C) maximum rate of pressure development (contraction) and (D) minimum rate of pressure development (relaxation). Arrow denotes addition of vehicle or 50 µ M menadione. ***P < 0.001 vs. pre-drug, 1-way RMANOVA, n = 7 hearts. To test whether action potential duration (APD) short- 59 and 38%; increase in EDP 52 and 8 mmHg; decrease in ening was dependent upon the activation of I , hearts DP 27 and 70 mmHg; decrease in max dP/dt 1641 and KATP −1 (n = 2) were exposed to the I blocker glibenclamide. 1856 mm Hg s ; decrease in min dP/dT 859 and KATP −1 This did not prevent the mechanical responses or APD 1216 mm Hg s ) these observations are consistent with the shortening upon exposure to menadione (APD shortening changes in these parameters reported in Figs 2 and 3. 3 Research article Bioscience Horizons • Volume 7 2014 Figure 3. MAP duration following exposure to menadione. (A) Representative MAP traces illustrating APD , APD and APD . (B) APD prior to 20 50 80 80 (control) and during exposure to menadione. (C) Mean percentage change in MAP duration after 25 min exposure to menadione for APD , APD 20 50 and APD . ***P < 0.001, 1-way RM ANOVA vs. pre-exposure, n = 7 hearts. (Floreani, Santi, and Carpenedo, 1989; Anderson and Dutta, Single LV myocytes 1991). We observed decreased DP, as a result of increased dia- 2+ The effect of menadione on [Ca ]i handling was tested in stolic pressure, rather than decreased systolic pressure, consis- single myocytes (Fig. 5A). Exposure to 50 µ M menadione tent with the findings of Anderson and Dutta (1991). Our caused a significant increase in diastolic calcium (Fig. 5B, data provide evidence that exposure to menadione results in a P < 0.05). There was also a significant reduction in resting reduction in ventricular DP as a consequence of increased cell length (Fig. 5C, P < 0.05). Exposure to menadione caused 2+ diastolic [Ca ]i, as observed in single myocytes. In this 2+ the generation of spontaneous oscillations of [Ca ]i and cell respect, it is interesting to note that the rise in the diastolic shortening (Fig. 5A). These effects were not seen in four cells pressure in whole hearts (Figs 1 and 2) had a similar time exposed to vehicle alone. 2+ course to the rise in diastolic [Ca ]i and fall in resting cell length (Fig. 5). Discussion In a previous study, a reduction in myocyte contractility induced by exposure to an alternative ROS donor, H O , was 2 2 The negative inotropic effect of menadione 2+ attributed to a fall in myofilament Ca sensitivity (Luo et al., 2+ 2006). However, in our study a fall in myofilament Ca sen- A novel aspect of our study is that while previous studies have sitivity is not consistent with the maintained systolic pressure predicted the diastolic contracture provoked by menadione is 2+ or a decreased rate of relaxation. Alternatively, in isolated associated with a rise in diastolic [Ca ]i, our observation in sarcoplasmic reticular (SR) preparations, menadione has intact, adult myocytes is the first to show directly a simultane - 2+ been reported to inhibit the function of the SR Ca -uptake ous increase in these parameters. Menadione has been shown pump (SERCA) (Floreani and Carpenedo, 1989; Floreani, to have both positive and negative inotropic effects depending Santi, and Carpenedo, 1989; Shneyvays et al., 2005). This upon concentration (Floreani, Santi, and Carpenedo, 1989). 2+ inhibition could explain the increased level of diastolic [Ca ]i; We used a concentration designed to provoke the nega - decreased contractility and decreased rate of relaxation. tive inotropic effect associated with ROS-induced injury 4 Bioscience Horizons • Volume 7 2014 Research article Figure 4. (A) Representative, simultaneous recording of LV MAPs (upper trace) and LV pressure (lower trace) in a heart exposed to 50 µ M menadione for 20 min, note the dysrhythmic behaviour. (B) Intrinsic heart rate and (C) standard deviation of heart rate (beat-to-beat periodicity), an index of rhythmicity, before and after 20 min exposure to menadione, n = 7 hearts, *P < 0.05; B, paired t-test; C, Wilcoxon signed rank test. Similar findings have been reported in rat ventricular myo - The effect of menadione on APD cytes using H O ( Greensmith, Eisner and Nirmalan, 2010). 2 2 and heart rate Exposure to free radicals has been shown to reduce the activ- + + ity of Na and K -ATPase (Kim and Akera, 1987; Matsuoka, Menadione reduced the duration of APD in the LV of iso- Kato and Kako, 1990). It is therefore possible that cellular lated whole rat hearts. These findings are consistent with the + 2+ loading of Na could also contribute to Ca overload via findings of Choi et al. (2005) and Ha et al. (2007). However, + 2+ activation of the Na –Ca exchanger (Matsuura and Barrington, Meier and Weglicki (1988) provided evidence Shattock, 1991). that H O prolonged the APD of canine ventricular myocytes 2 2 and Cerbai et al. (1991) have shown that dihydroxyfumaric Previously, it has been shown that the reintroduction of acid (DHF), a general donor of ROS species, prolongs the molecular oxygen to ischaemic myocardium results in the APD of guinea pig ventricular myocytes. These study differ- production of oxygen-free radicals (Bolli et al., 1989). ences may arise from the varying effects of ROS species and Contraction band necrosis has been documented in histo- or related to differences in species studied or preparation, logical sections of human LV tissue following reperfusion e.g. single cells vs. multicellular preparations. after myocardial infarction and fibrinolysis ( Verma et al., 2002). It is therefore interesting that we observed myocyte Menadione also had a negative chronotropic effect on iso- death (e.g. Fig. 5A) in a number of the myocytes exposed to lated whole hearts and produced dysrhythmia. Cerbai et al. menadione. (1991) have shown that DHF causes guinea pig ventricular 5 Research article Bioscience Horizons • Volume 7 2014 2+ Figure 5. (A) Representative recording of cell length (upper trace) and [Ca ]i (lower trace) in a single myocyte exposed to 50 µ M menadione and 2+ stimulated at 1 Hz. Traces represent 1 min recordings at 5 min intervals. (B) Increase in diastolic [Ca ]i and (C) decrease in resting cell length during exposure to menadione. *P < 0.05, 1-way RM ANOVA vs. pre-exposure; n = 7 myocytes from n = 4 hearts. ROS production interferes with mitochondrial function. myocytes to exhibit early after depolarizations (EADs) or to 2+ This has been shown to cause a release of Ca from the mito- become unexcitable. Similarly, Matsuura and Shattock chondria (Saxena et al., 1995) and to reduce mitochondrial (1991) identified an oscillatory transient current that sponta - 2+ respiration (Nulton-Persson and Szweda, 2001; Long et al., neously triggered SR Ca release and automaticity, greatly + + 2004). Both SERCA, and Na and K -ATPase activity are ATP increasing the risk of dysrhythmias on exposure to rose 2+ dependent, it is therefore possible that increased [Ca ]i and Bengal (10–100 nM). This current was attributed to the Na – 2+ 2+ ATP depletion potentiate one another; as [Ca ]i rises so does Ca exchanger and is typically associated with delayed after the cell’s utilization of ATP, thus further depleting ATP stores. depolarizations (DADs) (Venetucci et al., 2008). Another novel finding of this study is the demonstration of spontane - 2+ ous [Ca ]i transients in intact adult myocytes on exposure to A reduction in ATP may trigger the opening of I chan- KATP menadione. It can be seen in Fig. 5A that after 20 min expo- nels and contribute to the APD shortening that we observed 2+ sure to menadione, Ca release became irregular and was (Brown and O’Rourke, 2010). However, our preliminary stud- not coupled to the stimulating pulse, these spontaneous ies (n = 2) found that 50 µ M glibenclamide was not effective at 2+ releases of Ca are typical of those thought to trigger DAD preventing the degree of APD shortening caused by menadi- type arrhythmias. In addition, the dysrhythmia shown in Fig. one. Oxygen-free radicals have been reported to have a direct 4A is consistent with DADs rather than EADs being the effect upon I channels decreasing their sensitivity to ATP KATP arrhythmic mechanism induced by menadione. (Ichinari et al., 1996; Tokube, Kiyosue and Arita, 1996). 6 Bioscience Horizons • Volume 7 2014 Research article cardiocytes, Journal of Molecular and Cellular Cardiology, 20, 1163– As modification of contractility and electrical activity are interrelated it is useful to measure these parameters simulta- neously. A further novel finding is that APD shortening Benoist, D., Stones, R., Drinkhill, M. et  al. (2011) Arrhythmogenic sub- occurs alongside the fall in DP and is likely to contribute to strate in hearts of rats with monocrotaline-induced pulmonary 2+ this effect because a shorter APD will lead to less Ca influx hypertension and right ventricular hypertrophy, American Journal 2+ 2+ through L-type Ca channels, a smaller SR Ca load and of Physiology Heart and Circulatory Physiology, 300, H2230–H2237. 2+ 2+ thus a smaller SR Ca release, in turn smaller SR Ca release + 2+ will generate less inward Na –Ca exchange current, short- Bolli, R., Jeroudi, M. O., Patel, B. S. et al. (1989) Direct evidence that oxy- ening the APD (Bouchard, Clark and Giles, 1995). gen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog, Proceedings of the National Academy Study limitations of Sciences of the United States of America, 86, 4695–4699. Due to the instability of physiological buffer solutions, there Bouchard, R. A., Clark, R. B., and Giles, W. R. (1995) Effects of action is currently no method of exposing cardiac tissue to a known potential duration on excitation-contraction coupling in rat ven- concentration of ROS. Consequently, the concentration of tricular myocytes. Action potential voltage-clamp measurements, menadione administered was a proxy for the concentration Circulation Research, 76, 790–801. of superoxide anions. Furthermore, although menadione is Brown, D. A. and O’Rourke, B. (2010) Cardiac mitochondria and arrhyth- the most specific superoxide anion donor ( Choi et al., 2005), − mias, Cardiovascular Research, 88, 241–249. potential effects relating to H O and OH cannot be 2 2 excluded. Cerbai, E., Ambrosio, G., Porciatti, F. et al. (1991) Cellular electrophysiolog- ical basis for oxygen radical-induced arrhythmias. A patch-clamp Conclusion study in guinea pig ventricular myocytes, Circulation, 84, 1773–1782. Choi, B. H., Ha, K. C., Park, J. A. et al. (2005) Regional differences of super - The data presented provide evidence that exposure to mena- oxide dismutase activity enhance the superoxide-induced electrical dione, at 50 µ M, exerts a negative inotropic effect as a conse- heterogeneity in rabbit hearts, Basic Research in Cardiology, 100, quence of an increase in diastolic pressure. Moreover, we 355–364. have shown that in single LV myocytes this decrease in rest- 2+ ing cell length occurs in parallel with an increase in [Ca ]i, Floreani, M. and Carpenedo, F. (1989) Inhibition of cardiac sarcoplasmic which we suggest is a result of the actions of superoxide on reticulum Ca2 + -ATPase activity by menadione, Archives of + 2+ Na –Ca exchange and SERCA function. Biochemistry and Biophysics, 270, 33–41. Floreani, M., Santi, S. E., and Carpenedo, F. (1989) Effects of 2-methyl- Funding 1,4-naphthoquinone (menadione) on myocardial contractility and Supported by the University of Leeds. cardiac sarcoplasmic reticulum Ca-ATPase, Naunyn-Schmiedeberg’s Archives of Pharmacology, 339, 448–455. Author biography Greensmith, D. J., Eisner, D. A., and Nirmalan, M. (2010) The effects of hydrogen peroxide on intracellular calcium handling and contractil- L.J.R. studied pharmacology in relation to medicine as part of an ity in the rat ventricular myocyte, Cell Calcium, 48, 341–351. intercalated degree; he subsequently completed his MBChB at the University of Leeds, passing with honours. He began work Ha, K. C., Kwak, Y. G., Piao, C. S. et al. (2007) Differential effects of super - as a Foundation Year 1 doctor in August 2013 and is currently oxide radical on the action potentials in ventricular muscles, considering an academic and research career in Cardiology or Purkinje fibers and atrial muscles in the heart of different aged rats, Cardiac Surgery. He contributed equally to the conduct of Archives of Pharmacal Research, 30, 1088–1095. experiments and analysis of data, alongside A.L. and K.W. He Ichinari, K., Kakei, M., Matsuoka, T. et al. (1996) Direct activation of the also wrote the paper and had primary responsibility for its final ATP-sensitive potassium channel by oxygen free radicals in guinea- content. Aside from the conduct of experiments and analysis of pig ventricular cells: its potentiation by MgADP, Journal of Molecular data A.L. and K.W. also edited the paper before final submis - and Cellular Cardiology, 28, 1867–1877. sion. A.L. provided the illustrations. Professor Ed White designed this project as a dissertation for L.J.R., A.L. and K.W. Kevin, L. G., Novalija, E. and Stowe, D. F. (2005) Reactive oxygen species as mediators of cardiac injury and protection: the relevance to anes- References thesia practise, Anesthesia & Analgesia, 101, 1275–1287. Kim, M. S. and Akera, T. (1987) O2 free radicals: cause of ischemia- Anderson, G. F. and Dutta, S. 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Bioscience HorizonsOxford University Press

Published: Feb 12, 2014

Keywords: menadione calcium rat superoxide contractility electrophysiology

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