Sodium-calcium exchanger action

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...

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. 

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. 

Cardiac glycosides increase the influx of calcium, and decrease the outflow of potassium. Because there is little sequestration of calcium in cardiac cells, intracellular calcium may increase to toxic levels, particularly with high doses of the drug, and may exchange for sodium, via the sodium-calcium exchanger. This results in an overload of intracellular sodium and calcium, which, because of the decreased outflow of potassium, is not counterbalanced. Thus, calcium overload is manifested as an early afterdepolarization of the cardiac action potential, which may result in premature depolarization of Purkinje fibers and the appearance of ventricular arrhythmias, which may result in ventricular tachyarrhythmias and death. 

At the end of the plateau, causes rapid repolarization. The refractory period of the cardiac cell is a function of how rapidly sodium channels recover from inactivation. Recovery from inactivation depends on both the membrane potential (which varies with repolarization time and the extracellular potassium concentration) and the actions of drugs that bind to the sodium channel, ie, sodium channel blockers. The carrier processes (sodium pump and sodium/calcium exchanger) contribute little to the shape of the action potential (but they are critical for the maintenance of the ion gradients on which the sodium, calcium, and potassium currents depend). Antiairhythmic drugs act on one or more of the three major currents (1, Ij, ) or on... 

Noble, D., S.J. Noble, G.C.L. Belt, Y.E. Earm, W.K. Ho, and I.K. So (1991). The role of sodium-calcium exchange during the cardiac action potential. Ann. N.Y. Acad. Sci. 639,334-353 Sodium-Calcium Exchange Proceedings of the 2nd International Conference, April 1991, Baltimore, MD. 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Calcium antagonists (e.g., verapamil, nimodipine) can also block dopamine, 5-HT, and endorphin activity, alter sodium activity via a sodium-calcium counter-exchange, and act as anticonvulsants. Any or all of these actions could be involved in their putative antimanic effects ( 35). 

The studies of Bhatnager et al. (1990) and Beresewicz and Horackova (1991) also report a significant and important increase in the inward movement of Na through the TTX-sensitive Na channel in cells exposed to oxidant stress. It is likely that this increased inward current may play a role in prolonging the action potential and in loading the cell with sodium. Both of these effects would combine to create a situation that would tend to load the cell with calcium through alteration in the activity of the Na/Ca exchange mechanism (Matsuura et al., 1991). 

Mechanism of Action A potassium-sparing diuretic that inhibits sodium, potassium, ATPase. Interferes with sodium and potassium exchange in distal tubule, cortical col-lectingtubule, and collecting duct. Increases sodium and decreases potassium excretion. Also increases magnesium, decreases calcium loss. TAerapeuticEffect Produces diuresis and lowers BP. 

Digitoxin and its derivatives bind to the sodium-potassium pump and prevent it from exchanging sodium and potassium ions. When given in small quantities the result, especially in cardiac tissue, is that calcium ion content will be upset and calcium will be liberated from its stores. The newly available calcium can then interact with cardiac muscle protein to cause contraction. This is a therapeutic effect for those suffering from insufficient heart-pumping action (congestive heart failure or dropsy). The heart is made to contract efficiently and forcefully (inotropic effect). However, you can see that there may be a fine line between a necessary contraction and one which... 

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