Exchange, sodium-calcium

Sodium calcium exchanger Na+/Ca2+ exchanger Na+/Ca2+ antiporter NCX NCX1 NCX2 NCX3... 

Philipson KD, Nicoll DA (2000) Sodium-calcium exchange a molecular perspective. Annu Rev Physiol 62 111-133... 

Pignataro G, Gala R, Cuomo O et al (2004) Two sodium/ calcium exchanger gene products, NCX1 andNCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke 35 2566-2570... 

The first inhibitor of NHE, amiloride, was identified in 1982. This drug is a potassium-sparing diuretic that also inhibits the sodium-calcium exchanger and the conductive Na+ channel. Not all the NHE isoforms are inhibited equally by amiloride NHE1 and 2 are responsive, NHE5 is partially responsive and NHE3, 4 and 7 are resistant. Other weak and non-specific inhibitors are clonidine and cimetidine. 

Mode of operation of the sodium calcium exchanger extruding sodium and intruding calcium ions. 

Goldhaber, J.I. and Weiss, J.N. (1993). Hydrogen peroxide increases sodium-calcium exchange in patch-clamped guinea pig ventricular myocytes loaded with Fura-2. Circulation, 88(4), 724, abstract. 

Reeves, J.P., Bailey, C.A. and Hales, C.C. (1986). Redox modification of sodium-calcium exchange activity in cardiac sarcolemmal vesicles. J. Biol. Chem. 561, 4948-4955. 

Fast Inward Sodium Current L Type Calcium Current Transient Outward Current Sodium-Calcium Exchange Current ATP Sensitive Potassium Current Inward Rectifying Potassium Current Delayed Rectifying Potassium Current... 

Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output peripheral vascular resistance may increase. After 6-8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are... 

Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. Na+,K+ ATPase, the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium, calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic...

This antiporter (NCX) uses the sodium gradient to move calcium against its concentration gradient from the cytoplasm to the extracellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic conditions. The sodium-calcium exchanger s ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium. 

Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process first, an increase of intracellular sodium concentration because of Na+,K+ ATPase inhibition and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (NCX in Figure 13-1) caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release. Other mechanisms have been proposed but are not well supported. 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

Benzothiazepines of type 291 were described as antagonists for the mitochondrial sodium-calcium exchanges and thus are potential therapeutics for type II diabetes (Figure 17) <2003JOC92>. 

Yaras, N., and Turan, B. (2005). Interpretation of Relevance of Sodium-Calcium Exchange in Action Potential of Diabetic Rat Heart by Mathematical Model. Mol Cell Biochem 269(1—2) 121-9. 

Blaustein, M. P. and Lederer, W. J., 1999, Sodium/calcium exchange its physiological implications. 

Smith, L. and Smith, J. B., 1994, Regulation of sodium-calcium exchanger by glucocorticoids and growth factors in vascular smooth muscle. J Biol Chem 269, 27527-31. 

Excess of Ca2+ is removed from the cytosol by plasmalemmal Ca2+ pumps and sodium-calcium exchangers. The abnormal function of both systems can result in alteration of basal [Ca2+] and prolongation of evoked Ca2+ signals. Inhibition of PMCA results in pathological Ca2+ homeostasis in several cellular preparations... 

Pogwizd, S.M., Schlotthauer, K., Li, L., et al., 2001, Arrhythmogenesis and contractile dysfunction in heart failure Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res., 88(11), pp 1159—67. 

Moonga BS, Davidson R, Sun L, Adebanjo OA, Moser J, Abedin M, Zaidi N, Huang CL-H, Zaidi M. 2001. Identification and characterization of a sodium/calcium exchanger, NCX-1, in osteoclasts and its role in bone resorption. Biochem Biophys Res Commun283 770-5. 

The SR membrane contains a very efficient calcium uptake transporter, which maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter. This in turn is dependent on the balance of calcium influx (primarily through the voltage-gated membrane calcium channels) and calcium efflux, the amount removed from the cell (primarily via the sodium-calcium exchanger, a transporter in the cell membrane). 

---