In cardiac musculus, exitation-contraction yoke is mediated by the Ca induced Ca released from sarcoplasmic recticulum via ryanodine receptor through L-type Ca channels. Although Ca2+ induced Ca2+ released by L-typed Ca current is the primary tract for triping Ca2+ from sarcoplasmics, there are many mechanism for activation of Ca2 + release from sarcoplasmics reticulum such as CICR mediated by T-typed Ca current, CICR triggered by Ca inflow through Na+/Ca2+ exchange, and CICR triggered by Ca through tetrodotoxin ( TTX ) -sensitive Ca2+ current ( ICa, TTX ) . As Ca is a of import second courier which is indispensable in cardiac electrical activity and besides a chief activator of the myofilament which doing contraction, mishandling of Ca will will take to many pathophysiological conditions.
Introduction
Excitation-contraction yoke ( ECC ) is the procedure in which anA action potentialA triggers a myocyte to contract. In most excitable cells, A musculus fibres respond to the excitement signal with a rapid depolarisation which is coupled with its physiological response and doing contraction. Calcium s the omnipresent second courier which is indispensable in cardiac electrical activity and is the direct activator of the myofilaments, which cause contraction of bosom. ( Bers,2001 ) . In mammalian cardiac myocytes, the procedure of excitation-contraction ( E-C ) yoke is mediated by Ca2+influx from the extracellular infinite triping Ca2+ Calcium- induced Calcium release ( CICR ) from the sarcoplasmic Reticulum ( SR ) ( Bers, 1991 ; Stern & A ; Lakatta, 1992 ) . When action possible range the myocyte, it undergoes depolarisation and Ca ions enter the cell duringA stage 2 which gives rise to the tableland stage of action potency through L type Ca channel which is located on the sarcolemma and so trip the Ca release from the sarcoplasmic recticulum. Intracellular Ca concentration and Ca inflow trigger the contraction of bosom due to the binding of Ca2+ to cardiac musculus fibre protein, troponin C. For activation of SR Ca release, CICR is the widely most recognized mechanism by L-typed Ca current, SR Ca release can be triggered by Ca inflow through sodium-calcium exchange, through tetrodotoxin-sensitive Ca2+urrent, or Inositol ( 1,4,5 ) -triphosphate. Declining of Ca degree in the cells cause the withdrawal of Ca from myofilament and ensuing the relaxation of bosom. There arefour chief tracts for Ca2+ conveyance out of the cytosol including SR Ca2+ ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. Scince CICR is a positive-feedback mechanism, its have to be terminated which is indispensable for diastolic replenishment of the bosom. There are three chief tracts for termaination of Ca release such as local depletion of SR Ca2+ , RyR inactivation ( or version ) , and stochastic abrasion. ( Lukyanenko et al.,1998 ) . The improper contractile map and unnatural bosom rate is due to the mishandling of Ca in bosom musculus
cell. ( Pogwizd et al.,2001 ) .
Calcium handling in contraction of bosom
Ca2+ is indispensable for the organic structure mechanisms. In cardiac musculus, Ca have a function for the ability to do the cardiac cell to contract. L-type Ca channels and T-type Ca channels are two major types of Ca channels in the cells of cardiac tisues. ( Bean,1989 ) . At more positive membrane potency ( Em ) , L-type ( Ica ) can activates and inactivates and easy inactivated and is sensitive to dihydropyridines. ( Tsien et al.,1987 ) . On the other manus, T-type ( Ica ) cause the activation and inactivation at increasing negative membrane potency ( Em ) and dihydropyridines can non barricade efficaciously. ( Nowycky et al.,1985 ) . During development and hypertrophy, T -type Ca current is more outstanding and the T-type current is typically little or absent in ventricular myocytes. The entrance of Ca2+ into
the cell by go throughing thorugh ICa, T is merely responsible for smaller sum of Ca2+ than that go throughing through ICa, L. In most ventricular myocytes. L-type Ca current is about negligible. It shows
that the releasing and replenishment is chiefly provided by Ica, L but it is non take portion in pacemaking really much. The comparative sums of ICa, L and I Ca, T vary among Cardiac myocytes. L-type Ca current and T-type Ca current is variable among cardiac myocytes. T-types Ca current is present in all cardiac myocytes whereas L-type Ca current is have larger constituent in the eyetooth Purkinje i¬?ber. ( Zhou,1998 ) . Depolarization of action possible causes activation of Ca current. During an action potency, the sum of Ca entry is limited by Ca dependent inactivation at the cytosloic side.
In bosom musculus cell, the upstroke of action potency is due to the entrance of Na+ ions via electromotive force gated Na+ channels and it is called fast inward current. The immediate repolarization is non possible due to inactivation of Na+ channel quickly and initial depolarisation allow the entrance of Ca through voltage-grated Ca2+ channels and it is called 2nd inward current. The rate of Na channels inactivation is more rapid than that of Ca channels and so that the entrance of Ca2+ into the cell provide the membrane potency to shut to 0mV for some portion of action potency of bosom musculus. ( Reuter,1984 ) .
Calcium induced calcium release during E-C matching
There have been demonstrated that Calcium bring on SR Ca release in skinned ventrilcular myocytes. ( Fabiato and Fabiato,1975 ) . There are grounds that chief manner of E-C yoke in cardiac myocytes is by Ca influx via L-type Ca channels and can trip SR Ca release. ( Bers,1991 ) . When Ca channel becomes deactivates, before Ca channels near, Ca transient is induced by a big and ephemeral ICa and doing contraction. Furthermore, Ca channel activation without Ca inflow besides could non bring on SR Ca release. ( Nabauer et al.,1989 ) . When there is a high concentration of Ca buffer in the cell, ICa activate SR Ca release channel. ( Adachi-Akahane et al.,1996 ) . Ca2+ release from SR is most normally activated by L-type Ca2+ channels, this mechanism is called Ca2+ induced Ca2+ release ( CICR ) . There have been small uncertainty that E-C yoke occurs physiologically but there are other mechanism which can coexit and give rise to the map effects.
Ca inflow via ICa, T
In ventricular myocytes, T-type Ca current is comparatively little or absent but more outstanding during development and hypertrophy. Because of T-type Ca current is typically little and inactivates really quickly, the entire sum of Ca influx via T-type Ca current is likely little compared to that via ICa, L. ( Zhou,1998 ) . Furthermore, T-type Ca current is negligible in most of ventricular myocytes. So, ICa, T merely plays a minor function in triping SR Ca release during action potency.
Ca inflow via Na+/Ca2+ exchange
Resarch made in guinea hog ventricular myocytes show that T-type Ca2+ current can besides trip Ca2+ release from SR, but it is non every bit efficient as L-type ( Sipido,1998 ) . Since T-type Ca channel is non-functional in most of the myocytes of ventricle, it does non play a major function for exitation-contraction yoke although it may work like Ica, L. Release of Ca2+ from SR in response to Ca2+ inflow through L-type Ca2+ channels is the most common tract, but other mechanism of Ca2+ release from SR by Na+/Ca2+ money changer in status of Ca2+ overload is besides shown ( Berlin et al,1987 ; Bers et al.,1988 ) . The consequence of Ca2+ release by Na+/Ca2+ money changer has been proved by scrutiny on rats ( Wasserstorm and Vites,1996 ) , coney ( Litwin et al. , 1998 ) and guinea hog ( Sipida et al.,1997 ) . There are two ways of triping Ca2+ release from SR by Na+/ Ca2+ money changer. First mechanism is Na+ current by increasing local [ Na+ ] samarium, increasing Ca2+ entry through Na+/Ca2+ money changer and doing SR Ca2+ release ( Levesque et al.,1994 ) . Second one is depolarisation straight stimulate outward INa/Ca and Ca2+ release and contraction when L-type Ca2+ channel become out of use or at high positive Em ( Levi et al.,1994 ; LItwin et al.,1998 ) . Increased intracellular Na stimulate the Na+/Ca+ money changer ( Evans and Cannell, 1997 ) and, if INa is low, the rearward current of the Na+/Ca2+ exchange for Ca2+ release by SR become improbable. Therefore, INa or medicine that alters the intracellular Na become the regulator of Ca release from sarcoplasmic Reticulum. Stimulation via endocrine, such as activation of ET-1 receptor ( Alvarez et al. , 1999 ) , and increasing frequence of action potency ( Simor et al. , 1997 ) . additions INa so that triping Ca2+ release from SR is slower via Ca2+ influx through Na+/Ca2+ money changer than through L-type Ca channel ( Spido et al.,1997 ) .
Ca inflow via TTX sensitive-Na channels
Aggarwa et al.,1997 reported that Ca entry via tetrodotoxin-sentive Na channels.TTX-sensitive Na channels can besides intercede Ca induced Ca release. It can change selectivity of cardiac Na channels triggeres by either activation of b-adrenergic agonist or cardioactive steroids or cardiac gycosides, doing Na channel prefer Ca2+ than Na channels and it is called altered selectivity manner or slipe manner. The tetrodotoxin-sensitive Ca inflow could trip the SR Ca2+ release. This effects could be mediated by increased Ica and SR Ca-pump activity or by Na+/K+ ATPase suppression and reduced Ca outflow via Na+/Ca2+ exchange for glycosides. ( Borgatta et al.,1991 ) .
Ca inflow via IP3 tract
Inositol ( 1,4,5 ) -triphosphate can trip Ca2+ release from SR and endoplamic Reticulum in many cell types, by agencies of IP3 receptors. In ventricular myocytes, ( chiefly isoform 2 ) . ( Lipp et al.,2000 ) . Activation of IP3 signal transduction tract can trip the release of Ca2+ from SR through IP3 receptors located on the SR. Although high concerntration of InP3 can do Ca2+ release in cardiac myocytes, the rate and extent of Ca2+ release are really much lower than CICR.. Furthermore, action potency can non excite 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 ) . InP3 merely has a minor modulatory function in cardiac excitation-contraction yoke.
In drumhead, cardiac SR Ca release is chiefly through CICR by L-type Ca current, Ica is the dominant Ca2+source.Other mechanism that mentioned above show minor function in SR Ca release.
Cardiac relaxation
At the terminal of stage 2, Ca entry into the cell slows and Ca is taken back by the SR ensuing in lowering of the cytosolic Ca concentration and removing of Ca from the troponin C and eventually initial sarcomere length is restored. For relaxation and ventricular filling to happen, the Ca2+ must be removed from the cytosol to take down [ Ca2+ ] I, let the relaxation. Ca2+ have to disassociate from troponin C but require Ca2+ conveyance out of the cytosol by four tracts involing SR Ca2+-ATPase, sarcolemmal Na+/Ca2+ exchange, sarcolemmal Ca2+-ATPase or mitochondrial Ca2+ uniport. There are selective suppression for each transporter during cardiac myocyte relaxation and [ Ca2+ ] i decline.12-15 ( 7 ) . SR Ca2+ consumption was prevented by either thapsigargin or 10mmol/L caffeine, NCX was prevented by complete remotion of extracellular Na+ and Ca2+ , sarcolemmal Ca2+-ATPase was inhibited by either carboxyeosin or elevated [ Ca2+ ] I, and mitochondrial Ca2+ consumption was blocked by rapid dissipation of the electrochemical drive force for Ca2+ uptake utilizing the protonophore FCCP. In coney ventricular myocytes, the SRCa2+-ATPase removes 70 % of the activator Ca2+ from the cytosol, whereas the NCX removes 28 % , with merely ‘1 % each for the sarcolemmal Ca2+-ATPase and mitochondrial Ca2+uniporter ( which are called the slow systems ) . In rat ventricle, the SR Ca2+-ATPase activity is higher due to more pump molecules in unit cell volume ( Hove-Madsen & A ; Bers,1993 ) . Ca2+ remotion through Na+/Ca2+ exchange is lower, 92 % for SR Ca2+ATPase, 7 % for NCX, 1 % for the slow system. In mouse ventricle, the uptake mechanism is rather similar to rat, ( Li et al.,1998 ) whereas the balance of Ca2+ fluxes in guinea hog, Mustela nigripes, and human ventricle are more similar to rabbit. ( Pieske, et al.,1999 ) .
In contraction and relaxation of myocyte, the sum of Ca removed from the cell during relaxation must be the same as the sum of Ca entry for contraction in each round, if non the cell may derive or lose Ca.
Termination of Ca release
Ca2+induced Ca2+release is a positive-feedback mechanism but turning away of the Ca is indispensable for diastolic replenishment of the bosom. Three major wayfs or expiration of Ca release include local SR depletion, RyR inactivation ( or version ) and stochastic attriction. ( Sham et al.,1998 ; Lukyanenko & A ; Gyorke,1998 ) . Stochastic attriction average L-type Ca2+ channels and all Ryanodine receptors are closed at the same time, so local [ Ca2+ ] I will fall bead quickly to the sub-threshold degree and distrubing the release from SR. But this is merely used for 1DHPR and 1-2 RyRs but for other Numberss of channels, they all will non shut at one time. In add-on, local depletion of SR Ca2+ besides may end SR Ca2+ but it can non wholly turn-off of release, because really long enduring Ca2+ flickers are found that will non worsen with clip ( Satoh & A ; Bersi??1997 ) . But there are other part of SR can besides restrict local SR Ca2+ depletion. During a gobal Ca2+ transient, the whole ( Ca2+ ) SR declines. [ Ca2+ ] SR depletion might take to the turning-off planetary SR Ca2+ release during a relaxation. There are two types of RyR inactivation both of which depend on [ Ca2+ ] i One is absorbing inactivation ( like in Na+ channels ) , in which the ryanodine receptor is can non reopening until it recovers. ( Sham et al.,1998 ; Lukyanenko & A ; Gyorke,1998 ) . The another 1 is called version in which ryanodine after activation leads to a lower unfastened chance, but can be reactivated by higher [ Ca2+ ] I ( Valdivia et al.,1995 ) . RyRs inactivation may be of import in cut downing inappropriate SR Ca2+ release events between each bosom beats.
In drumhead Ca2+ release during excitation-contraction yoke is terminated chiefly by a local RyRs inactivation and partial
SR luminal Ca2+ depletion which lead to cut down RyR gaps and discrepancy of stochastic abrasion besides contributes.
Role of Ca channels in cardiac hypertrophy and bosom failure
Cardiac hypertrophy is the chief of import taking cause of cardiac morbidity and mortality in cardiovascular system. It is associated with bosom failure in the absence of a myocardial infarction. Cardiac hypertrophy is associated with important alterations in myocardial contraction. These contractile disfunctions are followed by altering in the whole-cell intracellur Ca transient. The pathogensis of cardiac hypertrophy and bosom failure related with the function of Ca2+ channels remains controversial. L-type Ca2+ current concentration is remain the same in rats myocytes with hypertrophy due to aortal stria. ( Scamps et al.,1990 ) , cats with pneumonic arteria stria. ( Kleinman,1988 ) myocardiopathy in Syrian hamsters, ( Sen,1994 ) , and ventricular myocytes in human from patients with bosom failure, ( Beuckelmann et al.,1992 ) . In contrast, L-type Ca2+ channel concentration is increased in hypertrophic myocytes from guinea hogs with stria of aorta, ( Ryder,1993 ) , and stria of nephritic arteria in rats, ( Keung,1989 ) , while it decreased in ventricular cells from cats with aortal stria, ( Nuss,1993 ) . To further confound the issue, the effects of cardiac hypertrophy on L-type Ca2+ currents seems to depend on the continuance of the disease. There is besides an increased in dihydropyridine binding sites in the myocardium of hamsters with familial myocardiopathy. Then, lessening in adhering sites in rat Black Marias, ( Dixon,1990 ) . No alterations in human bosom depending on the extent of the disease procedure. The release of Ca from the SR seems to depend on a individual channel belongings of the L-type Ca2+ channel that is non reflected in the magnitude of the current i.e. , the average unfastened clip, individual channel current, etc. Therefore, the individual channel belongingss of the L-typeCa2+ channel could be altered in hypertrophy, doing the abnormalcies in contraction noted. This possibility is supported by the observation that L-type Ca2+ current is prolonged in myocytes from virtually all carnal theoretical accounts of cardiac hypertrophy and failure ( Xiao,1994 ) although no addition in continuance was observed in ventricular myocytes from worlds with bosom failure ( Beuckelmann,1991 ) Ca2+ can come in the cell through other ion channels and transporters, which may account for the altered E-Ccoupling with the development of disease. Increases in T-type Ca2+ current have besides been reported in enlarged cells due to growing endocrine releasing tumours ( Xu,1990 ) . There is no information refering the function of the Na/Ca2+ money changer or ICa TTX in E-C matching Ca from hypertrophied or neglecting cardiac myocytes.
Therapeuticss Stragies
In normal excitation-contraction yoke, there are of import function of Ca inflow through the LTCC and the significance of Ca mishandling in bosom disease, have late been reported. ( Bers,2002 ) . Importance of the LTCC as a curative mark for left ventricular hypertrophy has been confirmed in many carnal theoretical accounts that demonstrate decrease in hypertrophy by Ca channel blockers. ( Feron et al,1996 ) . Clinically, Ca channel antagonists cut down blood force per unit area and doing arrested development of LVH, but it is non used for protraction for endurance. Calcium regulated signaling besides plays a cardinal function in the development of LVH. ( Hill,2000 ) . The suppression of calcium-regulated signaling tracts has been shown to cut down force per unit area overload-induced LVH without upseting systolic map. A partial decrease of LTCC look that is sufficient to forestall the activation of Ca regulated signaling tracts and forestall the development of LVH, without impairing normal excitement contraction matching. Modulating the look of LTCC may stand for a specific therapy for LVH and other cardiac iseases associated with Ca botching for illustration, hypertrophic clogging myocardiopathy ( HOCM ) , is conventionally treated with pharmacological Ca channel blockers but in selected instances treated by surgical, and most late Chang et al.,2003 found that nonsurgical septate decrease techniques as a agency of bettering LV escape obstruction.but have side effects, including redness, fibrosis, and arrhythmogenesis. Focal transition of LTCC by a vector capable of inveterate stamp downing cistron look may stand for an attractive
alternate therapy in HOCM. LTCC as a potentially fresh
curative mark for Ca mishandling with associated diverse cardiac disease. The function of RNA intervention in modulating the look of LTCC, modulating Ca inflow and forestalling LVH.
