Calcium In Contraction Of The Heart

Calcium In Contraction Of The Heart In cardiac muscle, excitation-contraction coupling is mediated by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors that are activated by calcium entry through L-type calcium channels on the sarcolemmal membrane. Although Ca2+ induced Ca2+ release triggered by the L-typed calcium current is the primary pathway for triggering Ca2+ from the sarcoplasmic reticulum, there are many other mechanisms that can also activate Ca2 + release from the sarcoplasmic reticulum such as Calcium induced calcium release (CICR) induced by T-typed calcium current, CICR triggered by calcium influx through Na+/Ca2+ exchange, and CICR mediated by calcium through tetrodotoxin (TTX)-sensitive Ca2+ current (ICa,TTX). As calcium is an important second messenger which is essential in regulating cardiac electrical activity as well as being the main activator of the myofilaments to which cause cardiac contraction. Mishandling of calcium is thought to lead many pathophysiological conditions. Knowledge of the mechanisms involved in regulating intracellular calcium and therefore contraction of the heart, may help to prevent and/or treat pathological conditions such as cardiac hypertrophy, arrhythmias or heart failure by using therapeutic agents targeted at modulating intracellular calcium. ACKNOWLEDGEMENT Firstly, I would like to show my deepest gratitude to my supervisor, Dr. Munir Hussain, who is a Senior Lecturer in Biomedical Sciences in University of Bradford for his innovative, supportive, expert, professional, kind and careful supervision, constant guidance and, academic support. Without his advice and guidance, my dissertation will not be finished with great success. I would also like to show my sincere thank to all the lecturers from Management Development Institute of Singapore (MDIS) and teachers in my student life for letting me gain strong knowledge in biomedical science field and essential knowledge to be in this stage and my student coordinator and stuffs from Student Service Unit (SSU) for their kind arrangement, support, encouragement and care. I would like to thank to all my friends who supported me both physically and mentally during my preparation for the dissertation. Last but not least, I would like to convey my special deep thank to my parents who always give me tender love, care and all supports all the time. Without their guidance, support and love, nothing can be achieved by me. LIST OF FIGURES Figure 1: Calcium transport in ventricular myocytes 3 Figure 2: Six possible mechanism of cardiac excitation-contraction coupling 9 LIST OF ABBREVIATIONS LTCC = L-type calcium channels CICR = Calcium induced calcium release ECC = Excitation-contraction coupling NCX = Sodium-Calcium Exchange SR = Sarcoplasmic Recticulum ICa = Calcium current ICa,T = T-type calcium current ICa,L = L-type calcium current ICa,TTX = Tetrodotoxin-sensitive calcium current RyRs = Ryanodine Receptor [Ca2+]i = Intracellular calcium concentration [Ca2+]Tot = Total concentration of Calcium PKA = Protein Kinase A LVH = Left Ventricular Hypertrophy HOCM = Hypertrophic obstructive cardiomyopathy Introduction In heart muscle cell, the depolarization of action potential is due to the entering of Na+ ions via voltage gated Na+ channels and it is called fast inward current. The immediate repolarization is not possible due to rapidly inactivation of Na+ channel and initial depolarization allow the entering of calcium through voltage-grated Ca2+ channels and it is called second or the slow inward current. The rate of sodium channels inactivation is more rapid than that of calcium channels so that Ca2+ enters into the cell providing the membrane potential to close to 0mV for some part of action potential of heart muscle (Reuter, 1984). Excitation-contraction coupling (ECC) is the process in which an action potential triggers a myocyte to contract. In excitable muscle cells, the excitation signal causes rapid depolarization that produces the physiological response of contraction. Calcium is a ubiquitous second messenger, important in both, regulating the electrical activity of the heart as well as stimulating the myofilaments directly to cause contraction (Bers, 2001). In mammalian cardiac myocytes, the process of ECC is mediated by Ca2+ influx from the extracellular space that triggers Ca2+ Calcium induced Calcium release (CICR) from the sarcoplasmic reticulum (SR) (Bers, 1991; Stern Lakatta, 1992). When action potential reaches the myocyte, causing it to undergo depolarization, which causes calcium ions to enter the cell through L type calcium channel located on the sarcolemma and thereby trigger calcium release from the SR. Calcium influx and the intracellular calcium concentration trigger the contraction of heart due to binding of Ca2+ to cardiac muscle fiber protein, troponin C. For activation of SR calcium release, the L-type calcium current is the most widely accepted mechanism thought to be responsible for CICR. However, SR calcium release can also be triggered by calcium influx through sodium-calcium exchange, calcium influx via T-type Ca2+ current or through tetrodotoxin-sensitive Ca2+ current, or Inositol (1,4,5)-triphosphate (but not so much in cardiac muscle). Declining of calcium level in the cells cause the detachment of calcium from myofilament and resulting in relaxation of the heart. There are four main pathways for Ca2+ transport out of the cytosol including SR Ca2+ ATPase, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport and sarcolemmal Na+/Ca2+ exchange. (Bers, 2002). Since CICR is a positive-feedback mechanism, it has to be terminated which is essential for diastolic refilling of the heart. There are three main pathways for termination of calcium release such as local depletion of SR Ca2+, Ryanodine ( RyR) inactivation (or adaptation), and stochastic attrition. (Lukyanenko et al., 1998). Mutation in calcium channels can lead to life-threatening arrhythmias. The improper contractile function and abnormal heart rate associated with cardiac hypertrophy and heart failure is due to the mishandling of calcium in heart muscle cell (Pogwizd et al., 2001). In this dissertation, here I discuss about the key mechanism of how Ca2+ transport in cardiac ventricular myocytes. Moreover, I also discuss about how they are modulated and regulated as well as how they interact specifically. In addition, by knowing the subcellular mechanism of E-C coupling, here I discuss about how calcium is altering and getting mutated so as to cause cardiovascular diseases. The imp ortant molecular signaling pathways in contraction of heart will also be addressed. Figure 1. Calcium transport in ventricular myocytes. (Adapted from Bers, 2002) The figure shows the time course of an action potential, Ca2+ transient and contraction in rat ventricular myocytes, NCX, and other protein involved in contraction. Calcium channels in contraction of the heart In cardiac muscle, calcium has a role for the ability to make the cardiac cell to contract. There are five types of calcium channels; L, T, N, P/Q and R types. Among them, L-type and T-type calcium channels are two major types of calcium channels in the cells of cardiac tissues (Bean, 1989). L-type Ca2+ channels have many subunits in the heart such as ÃŽÂ ±1, ÃŽÂ ±2, ÃŽÂ ´ and ÃŽÂ ² subunits. The ÃŽÂ ±1 subunit is the dihydropyridine (DHP) receptors which are important for calcium entry into the cells (Liu et al., 2000). L-type calcium channels (long-lasting) can activates at more positive membrane potential (Em), at greater than -40mV and generate peak inward current at 0mV and slowly inactivated, and is sensitive to dihydropyridines (Tsien et al., 1987). Thus, the L-type Ca2+ channels are the majority of calcium channels responsible for entering of Ca2+ into the cardiac cell during phase 2 (plateau phase) of the action potential. On the other hand, T-type (tiny or tr ansient) Ca2+ channels cause the activation and inactivation at more negative membrane potential (Em) and dihydropyridines cannot block effectively (Nowycky et al., 1985). However T-type Ca2+ channels have faster kinetics than compared to L-type Ca2+ channels. During development and hypertrophy, T type calcium current is more prominent and the T-type current is typically small or absent in ventricular myocytes. The entering of Ca2+ into the cell by passing through I Ca,T is only responsible for smaller amount of Ca2+ than that passing through ICa,L. In most ventricular myocytes, T-type calcium current is almost negligible. It shows that the releasing and refilling is mainly provided by Ica,L. The amount of L-type calcium current and T-type calcium current is variable among cardiac myocytes. L-types calcium current is present in all cardiac myocytes whereas T-type calcium current have larger component in the canine Purkinje fiber (Zhou, 1998). Depolarization during the action potent ial causes activation of calcium current. During an action potential, the amount of calcium entry is limited by calcium dependent inactivation at the cytosolic side. L-type calcium channel is located at the sarcolemmal-SR junction where ryanodine receptors exist (Scriven et al., 2000). There is a negative feedback effect on Ca2+ influx and SR Ca2+ release during excitation-contraction mechanism. When there is increased Ca2+ influx or release, further release of Ca2+ is turned off. There are many isoforms of ryanodine receptors, (RyR1, RyR2, RyR3), among them, RYR2 is the cardiac isoform. RyR2 mediated release of Ca2+ from sarcoplasmic recticulum is an important step in cardiac E-C coupling in the heart. RyR2 is a Ca2+-gated channel (Nabauer et al, 1989). RyR2 is activated by Ca2+ influx through L-type Ca2+ channel or dihydropyridine receptor (Adachi-Akahane, 1996). Cytosolic Ca2+ is increased by the RyR2 opening and bind with contractile protein (troponin C) that trigger the contraction of heart. In ventricular myocytes, there are much more ryanodine receptors than dihydropyridine receptors. Therefore, four or ten RyRs can be associated with a single L-type Ca2+ channel (Bers et al., 1991). Defection in excitation- contraction coupling can occur due to either if RyRs channels sensitivity is altered for activation/inactivation or if the SR Ca2+ is depleted. There has been demonstrated in animal model of cardiomyopathy (Gomez et al, 1997). [Ca2+]i and Ca2+sparks [Ca2+]i and total [Ca2+] determine the development of contraction which produces both isometric force and rapid shortening (Moss, 2001). The strength of cardiac contraction can be changed by two ways: (1) by changing the extent and amplitude of the Ca2+ transient, (2) by altering the myofilament sensitivity to Ca2+. The sensitivity of myofilament calcium is increased by contracting the myofilament when the heart fills with blood resulting the contraction to be stronger. Caffeine and certain inotropic agents can enhance the myofilament sensitivity whereas the increased concentrations of phosphate and Mg2+ and acidosis reduce myofilament Ca2+ sensitivity. Ca2+ sparks is the process of spontaneous release of SR Ca2+ and it was described by using confocal fluorescence microscopy (Cheng et al., 1993). The release of SR Ca2+ via single L-type Ca2+ channel or RyRs openings generates Ca2+ sparks (Song et al., 1997). Ca2+ spark is activated by the Ca2+ entery through ICa (Cannell et al, 1995) . Ca2+ spark is triggered by the opening of single channel opening. There have been reported that spark probability can be depend on binding of two Ca2+ ions to the RyR (Santana et al., 1996). Thus, local cytosolic [Ca2+]i is important in the frequency of Ca2+ sparks and SR Ca2+ release. Moreover, the frequency of Ca2+ spark depends on the SR Ca2+ load (Cheng et al, 1993). When there is increased SR Ca2+ load, this may lead to increase the amplitude of Ca2+ spark. Therefore SR Ca2+ load is an important factor for Ca2+ release from SR. Role of Sarcoplamic Recticulum ECC and intracellular Ca2+ homeostasis are primarily regulated by sarcoplasmic recticulum (Bers, 1991). Once stimulation, calcium enters the cell, thereby stimulating the release of larger amount of calcium from SR resulting in activation of contractile protein and contraction of the heart. During cardiac relaxation, Ca2+ is taken up by SR by SR Ca2+ ATPase pump and Na+/Ca2+ exchange pump. The key SR Ca2+ release channel involved in cardiac contraction is RyRs and RyR2 is the cardiac isoform. The amount and fraction of Ca2+ release that depends on the level of SR Ca2+ load can release for a given ICa trigger (Shannon et al., 2000). Sensitivity of RyRs receptor to [Ca2+]i at high load of SR Ca2+ leads to increase spontaneous SR Ca2+ release. On the other hand, decrease in SR Ca2+ release (which is induced by ICa ) can be due to low SR[Ca2+] content. The lower the amount of the SR Ca2+ release, the more amount of Ca2+ enter the cells through Na+/Ca2+ exchange. When there is low concent ration in SR Ca2+, Ca2+ release from SR is turned off during E-C coupling. Furthermore, SR Ca2+ content depends on the heart rate and duration of action potential. Ca2+ concentration release from SR can be increased by more mount of Ca2+ enter into the cell, by decreasing Ca2+ efflux or increasing SR Ca2+ uptake. Phospholamben, an endogenous inhibitor of SR Ca2+ ATPase, is triggered by activation of cAMP-dependent or calmodulin-dependent protein kinase. When this phospholamben becomes phosphorylated, Ca2+ uptake by SR is increased and allows faster cardiac relaxation and declining of [Ca2+]i. Targeted knockout of phospholamben leads to hyperdynamic hearts with negative effects (Brittsan Kranias, 2000). Interestingly, lower SR Ca2+ uptake, reduced SR Ca2+ATPase gene and protein expression were seen in failing human heart (Pieske et al., 1995). On the other hand, there has been demonstrated that increased gene expression of sarcolemmal Na+/Ca2+ exchanger was seen in human failing hea rt (Reinecke et al., 1996). Regulation of Calcium current Ica can be variable physiologically and pharmacologically. During physiological sympathetic stimulation of heart, catecholamine stimulate beta-adrenegic receptors, which improve the force of contraction (inotropic effects) and relaxation (lusitorpic effects) and declining of [Ca2+]i. In addition, stimulation of ÃŽÂ ²-adrenergic receptor stimulates a GTP-binding protein that accelerates adenylyl cyclase for the cAMP production. cAMP activates PKA, which phospharylates severe protein such as phospholamban, RyR, L-types Ca2+ channels, myocin binding protein C and troponin I ( which are related to ECC). Activation and phosphorylation of L-type Ca2+ channels will cause Ca2+ release from SR causing contraction of the heart. Phosphorylation of troponin I and phospholamban stimulate the reuptake of Ca2+ release from SR and Ca2+ is dissociated from the myofilament and develops to cardiac relaxation (Lusitropic effect). The inotrophic effect of PKA (protein kinase A) activation is triggered by the combination greater availability of SR Ca2+ and increased calcium current. Open probability of RyR channels can also be modulated by protein kinase A. RyRs receptors are hyperphosphorylated in heart failure causing a diastolic leak of SR Ca2+. However, whether PKA-dependent phosphorylation will alter during excitation-contraction or not still remain controversial. Moreover, phosphorylation of L-type Ca2+ channels, phospholamban and troponin I are paralleled with activation of ß1-adrenergic receptors in ventricular myocytes that produce inotrophic and lusitropic effects. On the other hand, ß2-adrenergic receptors activation can give more restricted to the enhancement of ICa (Kushel et al., 1999). cAMP production can also be stimulated by the G-protein-coupled receptors such as prostaglandin E and histamine that will lead to little or no effect of inotropic effects (Vila Petroff et al, 2001). Other receptors will also regulate the signaling pathway. For instance, M2-musc arinic receptors activation can decrease cAMP and activation of PKA thereby decreasing Ca2+ entry and release. In addition, this pathway also enhances repolarization. The pharmacological effects of L-type Ca2+ channels are in which calcium sensitivity to dihydropyridines (nephedipine, amlodipine, nitrendine, nimodipine, nisoldipine). Ica is inhibited by most of DHPs and they are called Ca2+-channel blockers. In DHPs, there are two other types of specific L-type Ca2+ channel blockers (1) phenyalkylamines (eg. verapamil, D600) and (2) benzothiazepines (eg, diltiazem), and those agents can act together directly with the Ca2+ channel (Glossmann et al., 1985). Verapamil can inhibit the calcium channel in the open state but it require depolarization pulse) and this is called use dependent. The neutral ligands such as nitrendipine and nisoldipine inhibit ICa depend on the calcium channel whether they are in the opening state or inactivated state , and does not require depolarization pulse as they are voltage dependent than use dependent. Figure 2. Six possible mechanism of cardiac excitation-contraction coupling. (Adapted from Bers, 1999) The figure shows Ca2+ influx via ICa,L, Ca2+ influx via ICa,T,Ca2+influx through NCX, Ca2+ influx via IP3 ,Ca2+ influx via ICa,TTX and depolarization dependent Ca2+ influx. Calcium induced calcium release during E-C coupling There have been demonstrated that CICR in skinned ventricular myocytes (Fabiato and Fabiato, 1975). There was been proved that main pathway of E-C coupling in cardiac myocytes is by Ca entry through L-type Ca2+ channels and triggers SR Ca2+ release (Bers, 1991). When calcium channel becomes deactivates, before calcium channels close, calcium transient is induced by a large and short-lived ICa causing contraction. Moreover, Ca2+ channel activation in the absence of Ca2+ influx also cannot induce calcium release from the SR (Nabauer et al., 1989). There is supported that ICa activate SR Ca2+ release channel when there is a high concentration of Ca2+ buffer in the cell (Adachi-Akahane et al., 1996). Ca2+ release from SR is most commonly activated by L-type Ca2+ channels and this pathway is called Ca2+ induced Ca2+ release (CICR). There has been little doubt that E-C coupling occurs physiologically but there are other mechanisms which can exit in parallel and give rise to the functional effects. Ca influx via ICa,T In ventricular myocytes, T-type calcium channels is relatively small or absent but it is more prominent in the development and hypertrophy of the heart. Because of T-type calcium current is relatively small and rapidly inactivated, the total amount of calcium influx through T-type calcium current is absolutely small compared to calcium influx via ICa,L (Zhou, 1998). Moreover, T-type calcium current is negligible in most of ventricular myocytes. T-type Ca2+channels are not located at the SR junction, therefore the effectiveness of ICa,T as a trigger for Ca2+ release from SR is not effective as ICa,L. Furthermore, SR Ca2+ release by ICa,T is delayed on onset and slower than ICa,L. However, it can be significant in other cardiac cells such as some atrial cells and Purkinje fibers (Zhou and January, 1998). Since T-type calcium channel is non-functional in most of the myocytes of ventricle, it does not play a major role for ECC although it may function like ICa,L. So, ICa,T only plays a m inor role in triggering Ca2+ release from SR during action potential. Ca influx via Na+/Ca2+ exchange Although L-type Ca2+ current is a major role of CICR in contraction of the heart, some argued that the L-type Ca2+ channels could not be the only way to trigger the calcium release from SR. There is an alternative trigger of calcium release in mammalian cardiac myocytes (Chunlei Han et al., 2002). The result of Ca2+ release by Na+/Ca2+ exchanger has been proved by examination on rats (Wasserstorm and Vites, 1996), rabbit (Litwin et al., 1998) and guinea pig (Sipida et al., 1997). Immunofluorescence labeling shows that the exchanger current is present in the cardiac T-tubules system (Scriven et al, 2000). There are two ways of triggering Ca2+ release from SR by Na+/ Ca2+ exchanger. The first mechanism is Na+ current by increasing local [Na+]sm, increasing Ca2+ entry through Na+/Ca2+ exchanger and causing SR Ca2+ release (Levesque et al.,1994 ). The second one is that depolarization directly stimulates outward INa/Ca and Ca2+ release and contraction when L-type Ca2+ channel become bloc ked or at high positive Em (Levi et al.,1994 and Litwin et al.,1998 ). Increased intracellular sodium stimulate the Na+/Ca+ exchanger (Evans and Cannell, 1997 ) and, if INa is low ([Na+]i=10nM) or lower, the reverse current of the Na+/Ca2+ exchange could trigger Ca2+ release account for 25%. When [Na+]i=30nM, the contribution of Na+/Ca2+ exchanger increase up to 100%. Additionally, the exchanger current is more dependent on the temperature and changes in the intracellular sodium and calcium concentrations than compared to L-type calcium current. Furthermore, these changes are larger in the microdomain or subspace (interaction between RyR receptors and L-type Ca2+ channels occurs) than compared to the rest of the cytoplasm (Vornanen et al., 1994). Although LTCC are faster than the exchanger current in triggering of Ca2+ release from SR, Ca2+ entry through the exchanger into the subspace is faster in beginning than L-type Ca2+ current when there is action potential stimulations becaus e the action potentials upstroke and sodium (inward) current is associated with rapid increase in [Na+]i. Therefore, any physiological stimulation or medication that alters the intracellular sodium becomes the regulator of calcium release from sarcoplasmic reticulum. Stimulation via hormone, such as activation of endothelin-1 (ET-1) receptor (Alvarez et al., 1999), and increasing frequency of action potential (Simor et al., 1997) will increase the intracellular sodium concentration, causing calcium release triggering via the Na+/Ca2+ exchanger by opposing to via the L-type calcium current. Ca2+ release from SR is slower via Ca2+ influx through Na+/Ca2+ exchanger than through L-type calcium channel (Spido et al., 1997) . Ca influx via TTX sensitive-Na channels Aggarwal and co-worker reported voltage-gated, calcium conducting sodium channel, (ICa,TTX), calcium entry via tetrodotoxin-sentive Na+ channels can also mediates CICR. This channel activates at membrane potential of -60mV and has faster kinetics than L-type Ca2+ channels. It can alter selectivity of cardiac Na+ channels triggers by either activation of agonist effects ÃŽÂ ²-adrenergic receptor or cardioactive steroids or cardiac glycosides, resulting Na+ channel prefer Ca2+ than Na channels and it is called slip mode or altered selectivity mode. The tetrodotoxin-sensitive Ca2+ influx can also trigger the SR Ca2+ release. The inotrophic effects of cardiac glycosides and ÃŽÂ ²-adrenergic agonists could be a novel mechanism. These effects could be triggered by SR Ca2+-pump activity and increased ICa or by Na+/K+ ATPase inhibition and also decreased Ca2+ efflux through Na+/Ca2+ exchange for cardiotonic glycosides (Borgatta et al., 1991). Moreover, one study in rat ventricular myoc ytes reported that Na+ current is activated by the phyosphoryation by protein kinase A or by the cardiotonic steroids. (slip mode conductance) (Santana, 1998). In addition, modified Na+currents conduct ICa,TTX which in turn triggers CICR. The relation between slip mode conductance and ICa,TTX is still controversial (Nuss, 1999). On the other hand, another study demonstrarted that Ca2+ current due to ICa,TTX or slip mode conductance is not related and identical. The reason is that the presence of cardiac steroids or activation of PKA is not a requirement for the detection of ICa(TTX). A small fraction of Na + currents can conduct ICa(TTX) even without phosphorylation of PKA (Nuss, 1999). Furthermore, TTX sensitive-Na+ channels cannot be inhibited by the blockers of T-type or L-type Ca2+ channels. Recently, one of studies showed that ICa(TTX) and T-type Ca2+channel coexit in guinea pig venricular myocytes because 10 mM mibefradil could block both ICa(TTX) and T-type Ca2+current (Heuba ch, 2000). Although this current is not the major current for triggering the CICR, its possible functional roles are important in normal heart cells such as promoting the sodium current activation and modulating rhythmicity of the heart. Ca influx via IP3 pathway Inositol (1, 4, 5) triphosphate could trigger Ca2+ release from SR and endoplamic reticulum in different cell types, they are called IP3 receptors. In ventricular myocytes, the major form of InsP3 is isoform 2 (Lipp et al., 2000). There are more InP3 receptors in atrial cells in ventricular myoctyes. Stimulation of IP3 signal transduction pathway can trigger the release of Ca2+ from SR via IP3 receptors which is located on SR. Even high concentration of InP3 in cardiac myocytes could trigger Ca2+ release from the SR, the extent of Ca2+ release from the SR are so much lower than CICR triggered by LTCC. Moreover, action potential cannot stimulate the InP3 production (Kentish et al., 1990). The production of InP3 contractile force is increased by cardiac alpha-adrenergic and muscarinic agonists (Poggioli et al., 1986). In addition, InP3 pathway only plays a very little minor role in cardiac EC coupling. To conclude for triggering Ca2+ release from SR, CICR in cardiac contraction is mai nly through L-type Ca2+channel.Other mechanisms that mentioned above show minor role in SR calcium release. Cardiac relaxation During an action potential, calcium entry into the cell is slow at the end of phase 2 and there is lowering of the cytosolic calcium concentration because calcium is taken back by the SR and removing of calcium from the troponin C and finally initial sarcomere length is restored. For relaxation and cardiac ventricular filling, Ca2+ have be removed from the cytosol to lower [Ca2+]i , causing relaxation. Cardiac relaxation to occur, Ca2+ must be dissociate from troponin C and it requires Ca2+ transport out of the cytosol primarily by four main pathways involving, sarcolemmal Na+/Ca2+ exchange, SR Ca2+-ATPase, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. There are selective inhibition for each transporter during cardiac myocyte relaxation and [Ca2+]i decline (Puglisi et al., 1996). SR Ca2+ uptake can be prevented by either thapsigargin or caffeine, complete removal of extracellular Na+ and Ca2+ can prevent sodium calcium exchange. Either carboxyeosin or elevated [Ca2+]i inhibi t sarcolemmel Ca2+-ATPase, and mitochondrial Ca2+ uptake can be inhibited by rapid dissipation of the electrochemical driving force for SR Ca2+ uptake by using protonophore FCCP. In rabbit ventricular myocytes, 70% of the activated Ca2+ removed by the SR Ca2+-ATPase from the cytosol, whereas 28% was removed by NCX, only 1% for sarcolemmal Ca2+-ATPase as well as mitochondrial Ca2+ uniporter remove 1% of calcium from SR ( the last two pathways are called slow systems). In rat ventricular myocytes, SR Ca2+-ATPase activity is higher due to more pump molecules in unit cell volume (Hove-Madsen Bers, 1993). On the other hand, Ca2+ removal via Na+/Ca2+ exchange is lower, 92% with SR Ca2+-ATPase, 7% with NCX, the slow systems with 1 % respectively. In mouse ventricular myocytes, the uptake mechanism is quite similar to rat, (Li et al., 1998) while the mechanisms of Ca2+ fluxes in human ventricular myocytes, guinea pig and ferret are more similar to rabbit myocytes (Pieske et al., 1999). In contraction and relaxation of myocytes, the amount of calcium removed from the cell during relaxation must be the same as the amount of calcium entry during contraction in each heart beat, if not, the cell may gain or lose the calcium. Defects in Ca2+ removal also can cause impair relaxation Termination of calcium release Although CICR is a positive-feedback mechanism, termination or turning off of the Ca2+is important for diastolic refilling of the heart. There are three major ways for terminations of Ca2+release include local SR depletion, RyR inactivation or adaptation and stochastic attriction (Sham et al.,1998; Lukyanenko Gyorke,1998). Stochastic attriction means L-type Ca2+ channels and all RyRs are closed simultaneously, then local [Ca2+]i will drop quickly to the sub-threshold level and disturbing the release from SR . However, this is only used for 1DHPR and 1-2 RyRs whereas they all will not close at once for other types of channels. In addition, local depletion of SR Ca2+ also may terminate SR Ca2+ but it cannot completely turn-off of release, because very long lasting Ca2+ sparks are found that will not decline with time (Satoh Bers, 1997). However other regions of SR can also limit local SR Ca2+ depletion. During a global Ca2+ transient, the whole SR Ca2+ declines. During a relaxation, SR Ca2+ depletion could lead to the turning -off global SR Ca2+ release. There are two types of RyR inactivation both of which depend on [ Ca2+ ]i .One of them is absorbing inactivation ( for example like Na+ channels), in which the ryanodine receptor cannot reopen until it recovers (Sham et al., 1998; Lukyanenko Gyorke, 1998). The another one is called RyR adaptation in which ryanodine after activation leads to a reduced open probability, but it can be reactivated by higher [Ca2+]i (Valdivia et al.,1995). RyRs inactivation could be important in reducing SR Ca2+ release events between each heart beats. To summarize, Ca2+ release during ECC is terminated mainly by a local RyRs inactivation and partial SR luminal Ca2+ depletion which leads to reduce RyR openings and variant of stochastic attrition also contributes. Role of calcium channels in cardiac hypertrophy, heart failure and arrhythmia Intracellular calcium is the major regulator of cardiac contraction. Therefore, altered cardiomyocyte regulation is important in arrhythmogenesis, cardiac mechanical dysfunction and cardiac hypertrophy associated with heart failure. Alteration in signal transduction pathways can also lead to loss of inotropic effects in heart failure. Defects in ECC have been reported in animal models of cardiomyopathy (Gomez et al., 1997). There is no E-C coupling depression was seen in pressure overload of cardiac hypertrophy with less sign of heart failure. (Rios et al., 1992). Cardiac hypertrophy is the enlargement and thickening of the heart muscle resulting in decreasing size of the chamber of the heart. Cardiac hypertrophy is the main cause of cardiac morbidity and mortality in cardiovascular system. It is associated with heart failure without myocardial infarction. Cardiac hypertrophy is associated with significant changes in myocardial contraction. These contractile dysfunctions are followed by changing in the whole-cell intracellular calcium transient. The pathogenesis and etiology of cardiac hypertrophy and heart failure related with the role of Ca2+ channels still remains controversial. of ÃŽÂ ² subunits of L-type Ca2+ channels (LTCCÃŽÂ ²) enhances the probability of channels opening as well as also favours the trafficking of the Ca2+ channels to the surface membrane leading to increase calcium current (Chen Y.H, 2004). Interestingly, there has been reported upregulation of LTCCÃŽÂ ² in failing human cardiomyocytes (Hullin et al, 2003). In aortic banding, L-type Ca2+ channels concentration is remain unchange in rats myocytes with hypertrophy ( Scamps et al.,1990), cats with pulmonary artery banding (Kleinman, 1988) cardiomyopathy in Syrian hamsters (Sen, 1994) ,and ventricular

The Scarlet Letter, Young Goodman Brown and Hawthorne :: Scarlet Letter essays

The Scarlet Letter, Young Goodman Brown and Hawthorne Writing under the influence of his Puritan background, Hawthorne's attention was on individuals and their relationships within their community. Theocratic Puritans punished sinners as deviants of society and used the punishments to restate the boundaries within the group. The five tenets of Puritanism reveal the curious nature of a religion that promoted goodness as a constant goal of each individual, but provided only negative reward of no punishment for good behavior and actions. The tenet of Unconditional Election made predestination clear. No matter how hard one tried to be good, only those elected were going to heaven. In The Scarlet Letter Hawthorne introduces the community by way of the prison house and the women of the community "being of mature age and church members in good repute." In the conversation that the women have about Hester their jealous hearts and vengeful attitudes are revealed. In this way he shows us that this community, although it was designed to be the perfect Christian community, interprets itself as something else. We can assume that Hawthorne shows us the bitchy ways of the women of the church, the ones who supposedly care for the sick and tend to the elderly, nurturing and comforting in a Christian-like manner, and the prison house to inform us that Puritan society has problems, the same problems that any society might have. We can begin to read Hawthorne from the romantic perspective and see society as the guilty party. Indeed, the author sets us up to see Hester as a heroine, a rose, even though a wild rose. And Young Goodman Brown takes his place as hero in his tale. Although we know that he embarks on an "evil purpose," we also know his intentions are to return to his good Faith. But how can a Puritan return to his good faith when he is a sinner? There is no way to achieve goodness, because Adam sinned, so sinned we all. And if you accept that, even if you reject communion with it, who can be trusted? Not even your self. Young Goodman Brown's happiness could only come from a life with Faith/faith and all he could believe in was the reality of his faith, which was that all were sinners. That means that communion has to be communion with sin. The Scarlet Letter, Young Goodman Brown and Hawthorne :: Scarlet Letter essays The Scarlet Letter, Young Goodman Brown and Hawthorne Writing under the influence of his Puritan background, Hawthorne's attention was on individuals and their relationships within their community. Theocratic Puritans punished sinners as deviants of society and used the punishments to restate the boundaries within the group. The five tenets of Puritanism reveal the curious nature of a religion that promoted goodness as a constant goal of each individual, but provided only negative reward of no punishment for good behavior and actions. The tenet of Unconditional Election made predestination clear. No matter how hard one tried to be good, only those elected were going to heaven. In The Scarlet Letter Hawthorne introduces the community by way of the prison house and the women of the community "being of mature age and church members in good repute." In the conversation that the women have about Hester their jealous hearts and vengeful attitudes are revealed. In this way he shows us that this community, although it was designed to be the perfect Christian community, interprets itself as something else. We can assume that Hawthorne shows us the bitchy ways of the women of the church, the ones who supposedly care for the sick and tend to the elderly, nurturing and comforting in a Christian-like manner, and the prison house to inform us that Puritan society has problems, the same problems that any society might have. We can begin to read Hawthorne from the romantic perspective and see society as the guilty party. Indeed, the author sets us up to see Hester as a heroine, a rose, even though a wild rose. And Young Goodman Brown takes his place as hero in his tale. Although we know that he embarks on an "evil purpose," we also know his intentions are to return to his good Faith. But how can a Puritan return to his good faith when he is a sinner? There is no way to achieve goodness, because Adam sinned, so sinned we all. And if you accept that, even if you reject communion with it, who can be trusted? Not even your self. Young Goodman Brown's happiness could only come from a life with Faith/faith and all he could believe in was the reality of his faith, which was that all were sinners. That means that communion has to be communion with sin.

Effect of Economic Crisis Towards Politics in Malaysia

We have discussed the impact of economic crisis towards economy and social. But there are other consequences due to this subject. One of them is political. Malaysia is practicing the democratic system which all eligible citizens have an equal say in the decisions that affect their lives. Democracy allows people to participate equally either directly or through elected representatives in the proposal, development, and creation of  laws (Roberts, H. Cox. 2012) However, the economic crisis could lead to the destructible of the stable political status in the country.Malaysia now days have lists of political parties that have the same aim which is to rule Malaysia. On the other hand, economic crisis is one of the crimp to these political parties to rule the country or even to the dominant political party such as UMNO. When the Asian financial crisis 1997 hit Malaysia, the impact was traumatic. There was economic and political turmoil. The stock market, the currency and the property mark et nearly collapsed. That in turn affected the overall economy.UMNO, the dominant political party in the ruling alliance, experienced political turbulence when its charismatic deputy president, Anwar Ibrahim, was expelled from the party when he disagreed with the then president, Mahathir Mohamad, over, among other things, Mahathir’s rejection of loans from the International Monetary Fund (IMF). Yet, Malaysia was not that badly affected as compared to some of its neighbors. It did not experience the extent of the socio-political distress as occurred in Indonesia where the rioting that broke out ultimately led to the overthrow of Suharto.Nor was its economic sovereignty that deeply compromised as happened in Indonesia and Thailand when both countries were forced to accept the conditions imposed by the IMF for the acceptance of their loans. Besides, there is a major consideration of questions is the view purported by some quarters that Dr. Mahathir has â€Å"overstayed† h is tenure and that heir apparent Anwar would have been the right successor of a more liberal Malaysia. The questions being around at that time is does it true that Anwar rejection is the consequences of he brings the economic down term in Malaysia and idea in conserving loan from IMF or because Dr.Mahathir is feeling discomfort or unsecure due to the trusts and confident level of the people is falling down? This questions has delivered main elements of events of the recent two years is that possibly what transpired between Mahathir and Anwar climaxed as a second â€Å"battle royale† in Malaysia’s political history. There is more than a hint that underneath it all was a political contestation fought with intense intrigue and complexity; one reflection observes that the â€Å"Anwar group† (some call it the Anwaristas, as opposed to the â€Å"Mahathirists†) had indeed been conspiring to take the mantle of power by contrived means.Accordingly, it was a  "plot† exposed in time by Dr. Mahathir’s forces. But yet, to suggest a real political division between â€Å"Mahathirists† and â€Å"Anwaristas† in the Malaysian political scenario is too neat an explanation of reality, and certainly these inchoate groupings are not mutually exclusive. As may be expected, there are also the â€Å"fence-sitters†. As we noticed, Anwar expels is due to the economic crisis. But if we storming deeper, the existence of opposition of the ruling parties in Malaysia (Barisan Rakyat), namely Parti Keadilan Rakyat.Parti Keadilan Rakyat is formed in 2003 by a merger of the  National Justice Party  and the older  Malaysian People's Party. Keadilan was led by Dr  Wan Azizah Wan Ismail ( Anwar’s wife)  and increased its parliamentary representation from 1 seat to 31 seats in the  Malaysian general election, 2008  until the five-year political ban imposed on former Deputy Prime Minister  Anwar Ibrahim  was lifted on 14 April 2008. Here we can see the existence of one more political party in Malaysia due to economic crisis. Anwar Ibrahim has been expels from the party and he form another party through his wife in the period of he was arrested in jail.Through this brings up another question to Malaysian. Whether Parti Keadilan Rakyat is really stand up on representing the public fate and rights? Or else, is just because of Anwar’s agenda to be the Prime Minister is failed because he was expelled from being Deputy Prime Minister by Dr. Mahathir Mohamad. Then he forms up his own political party? No matter what the question is, we can see that the existence of Parti Keadilan Rakyat giving a huge impact on the political environment in Malaysia. Large portion of society putting their trusts on Keadilan Rakyat and this is the warning and a big challenge to the government Malaysia in uling the country very well. The Malaysia government, Barisan Nasional is doing their best to society be cause they believe that Keadilan Rakyat have their own strength and ability in overcoming the government. In conclusion, economic crisis brings up too many negative impacts towards our politics in Malaysia such as expellation of Anwar Ibrahim, unstable of ruling political party Barisan Nasional, the disunity of public trusts in ruling political party due to lost in trust of the leader on that time.However, the existence of main opposition party Parti Keadilan Rakyat brings a very great impact to government on how they rule the country due to the possibility and ability of Parti Keadilan Rakyat to gain the public trusts. Thus, economic down term really brings a negative impact toward Malaysia in short run, but however the subject brings a cause of positive impact toward Malaysia political environment in long term.

The Burning Giraffe – Salvador Dali

2 â€Å"The Burning Giraffe† is a surrealistic painting by the artist Salvador Dali, done circa 1936. Using a variety of blues, blacks and browns, the piece depicts a bleak, sad, and cold scene. Scenery such as this was very popular amongst modernist painters. The painting, through color choice, showcases the futile, dark, and dreamy feeling epitomized by modern art. Beyond the color scheme, subjects of the painting, also, are clear representations of what modern art is. The two female figures fall in line with the rest of the painting, giving off a sense of loss, despair, and once again, a dream-like quality.The very definition of surreal is â€Å"marked by the intense  irrational  reality of a dream. † There’s no possibility that the images depicted in the painting would ever take place in reality. There’s no clear rational for what’s present in the painting. Both of the figures have unclear oblong objects sticking out of their backs. These ob jects are propped by what look like crutches. The first female figure seems to be missing a layer of flesh on her arms and face, revealing muscle beneath.Farther back into the painting, the second figure is holding something looking similar to meat or muscle tissue. In the distance of the painting is a giraffe on fire. Even the stance and figure of the two females shows the dreaminess. The lines are very fluid and relaxed as in the overall scenery of the painting. There’s a very ominous feeling to it all. Surreal artists and  viewed their work as an expression of the philosophical movement,  inspired by psychologist Sigmund Freud, and placed much emphasize on the unconscious.This particular painting was inspired by this thought process as Dali took much interest in it. The movement was centered on the idea that there were certain thoughts and emotions only accessible though psychotherapy. The drawers protruding from the first female figure’s chest and legs represen t the opening to deeper subconscious thought and feeling. The draws show a literal representation of this. All are characteristics of a surreal piece, found in modernistic art.

Free Essays on Social Conservative

Homosexuality has been a source of constant conflict among many organizations of today’s society. Perhaps the most prominent disputes of this issue exist within the disagreement of same sex relationships from the views of society, homosexuals, the Christian church, and scientist’s biological theories. Society’s view is that homosexuals influence others; therefore, it is a chosen lifestyle. Most homosexuals believe they were born with a homosexual gene and they did not choose this lifestyle for themselves. The Christian church teaches that â€Å"homosexuality† is not God’s design for people, but believes there are ways of changing. It is the Homosexual who don’t want to change themselves. Many Americans thinks that homosexual should not be parents, and they have many biases view about the homosexual couple, thinking that homosexual couple doesn’t make enough money for child to live happy and giving the child wants and needs. According to a survey carried out by Leger Marketing, the level of education and the financial situation of heterosexual and homosexual are practically the same. However, a big group of the population believes that homosexual relationships are unhappy. For example, one study established that heterosexual student from college expected gay and lesbian relationships to be less fulfilling and more frustrating and prone to discord than heterosexual relationships, and they believed homosexual couple making the child to be confused of their sex (Williams & Cohen 53). In a happy family the child should have opposite sex parent. Same-sex couples aren't the most favorable environments in which to raise children. If a child are being rai se up by a family of same sex parent then who will be the mother and who will be the father. There are no such thing that a family have two mom or two dad then the child will be confuse. As the child gets older and at the age of going to school and when the teacher as... Free Essays on Social Conservative Free Essays on Social Conservative Homosexuality has been a source of constant conflict among many organizations of today’s society. Perhaps the most prominent disputes of this issue exist within the disagreement of same sex relationships from the views of society, homosexuals, the Christian church, and scientist’s biological theories. Society’s view is that homosexuals influence others; therefore, it is a chosen lifestyle. Most homosexuals believe they were born with a homosexual gene and they did not choose this lifestyle for themselves. The Christian church teaches that â€Å"homosexuality† is not God’s design for people, but believes there are ways of changing. It is the Homosexual who don’t want to change themselves. Many Americans thinks that homosexual should not be parents, and they have many biases view about the homosexual couple, thinking that homosexual couple doesn’t make enough money for child to live happy and giving the child wants and needs. According to a survey carried out by Leger Marketing, the level of education and the financial situation of heterosexual and homosexual are practically the same. However, a big group of the population believes that homosexual relationships are unhappy. For example, one study established that heterosexual student from college expected gay and lesbian relationships to be less fulfilling and more frustrating and prone to discord than heterosexual relationships, and they believed homosexual couple making the child to be confused of their sex (Williams & Cohen 53). In a happy family the child should have opposite sex parent. Same-sex couples aren't the most favorable environments in which to raise children. If a child are being rai se up by a family of same sex parent then who will be the mother and who will be the father. There are no such thing that a family have two mom or two dad then the child will be confuse. As the child gets older and at the age of going to school and when the teacher as...

Free Essays on The Abolition Of Labor Summary

Marx: The Abolition of Labor Capitalist production has lead to a universal negativity affecting all structural factors related to appropriation by the individual. Marx theorized that a universal revolution of economic forces and structural components will transpose the power of a capitalist society into the hands of the individual. By freeing the individual from the limitations posed upon them through capitalist production, the individual will be able to obtain potentiality for general satisfaction. This new universal order will structure the available productive forces for the power of the individual, and not just for capitalist production. The distribution of labor itself created classes within society. The proletariat is that class in society which lives entirely from the sale of its labor and does not draw profit from any kind of capital; whose sole existence depends on the demand for labor, on the changing state of business, and on the changes of the competition. The classes of the proletarians are the working class of the 19th century. Labor was more and more divided among the individual workers so that the worker who previously had done a complete piece of work now did only a part of that piece. This division of labor made it possible to produce things faster and cheaper. Labor is a commodity, like any other, and its price is therefore determined by exactly the same laws that apply to other commodities. In a regime of big industry or of free competition, the price of a commodity is always equal to its cost of production. The price of labor is also equal to the cost of production of labor. But, the costs of production of labor consist of precisely the quantity of means of subsistence necessary to enable the worker to continue working, and to prevent the working class from dying out. The worker will therefore get no more for his labor than is necessary for this purpose; the price of labor, or the wage, will, in other w... Free Essays on The Abolition Of Labor Summary Free Essays on The Abolition Of Labor Summary Marx: The Abolition of Labor Capitalist production has lead to a universal negativity affecting all structural factors related to appropriation by the individual. Marx theorized that a universal revolution of economic forces and structural components will transpose the power of a capitalist society into the hands of the individual. By freeing the individual from the limitations posed upon them through capitalist production, the individual will be able to obtain potentiality for general satisfaction. This new universal order will structure the available productive forces for the power of the individual, and not just for capitalist production. The distribution of labor itself created classes within society. The proletariat is that class in society which lives entirely from the sale of its labor and does not draw profit from any kind of capital; whose sole existence depends on the demand for labor, on the changing state of business, and on the changes of the competition. The classes of the proletarians are the working class of the 19th century. Labor was more and more divided among the individual workers so that the worker who previously had done a complete piece of work now did only a part of that piece. This division of labor made it possible to produce things faster and cheaper. Labor is a commodity, like any other, and its price is therefore determined by exactly the same laws that apply to other commodities. In a regime of big industry or of free competition, the price of a commodity is always equal to its cost of production. The price of labor is also equal to the cost of production of labor. But, the costs of production of labor consist of precisely the quantity of means of subsistence necessary to enable the worker to continue working, and to prevent the working class from dying out. The worker will therefore get no more for his labor than is necessary for this purpose; the price of labor, or the wage, will, in other w...

Emerald Energy Plc Case Study Example | Topics and Well Written Essays - 2750 words

Emerald Energy Plc - Case Study Example The revenue earnings of Emerald Energy have shown a sharp increase during the year 2008 as compared to the previous year. The increase is significant to the extent of 94% over the sales revenue for the year 2008. The change in the sales revenue during the year 2007 as compared with 2006 is showing a decline of 3.38% over 2006 figures. This trend is depicted in the following graph. The ability of a firm to generate profits can be assessed by working out the profitability ratios for a historical period and by analyzing the sources of income. The gross profit margin, operating profit margin and net income as a percentage of total turnover presents a realistic view of the firm's ability to generate profits. "Profitability ratios offer several different measures of the success of the firm at generating profits." (NetMBA, 2007) The ratios worked out for the Company and the ratio derived for the industry from the published sources are presented below: The above table indicates that the profitability o... The gross margin has increased mainly because of the increase in the sales revenue due to higher prices of petroleum products during early 2008. The increase in gross margin can be traced to the lower cost of sales. The cost of sales for the year 2008 was 29.25% as against 69.92% for the year 2007. This accounts for the steep increase in the gross margin as well as the increase in the operating and net margins. The increase in the profitability can be observed from the following graph. Return on Shareholder's Equity (ROE) The return on shareholder's equity ratio is another important investment valuation ratio used by the investors to evaluate the profitability of the company and its ability to generate earnings by utilizing the capital invested by the equity shareholders. This ratio is considered as more meaningful to the investors. The return on shareholder's equity has increased significantly over the three year period. Presently as per the latest financial information available on the company, the return on shareholder's equity ratio is stated as 28.45% while the ratio for the industry stands at 17.53 (Reuters, 2009). Analysis of Operating Efficiency The working Capital ratios indicate how well the company is able to manage its working capital. "The asset management ratios are also known as working capital ratios or the efficiency ratios. The aim is to measure how effectively the firm is managing its assets." (NetTom, n.d.) The efficiency ratios for Emerald Energy are exhibited below: 2006 2007 2008 Industry Receivables Turnover (Times) 12.06 9.41 5.76 12.26 Total Assets Turnover