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Some cardiac disorders are associated with a reduction in contractility. In these circumstances, enhancing contractility becomes a therapeutic strategy.

How can contractility be enhanced?

Normally, the Ca2+ concentration in the cardiomyocyte cytosol during systole is such that the contractile sites are half activated. Thus the heart has considerable contractile reserve which can be used by increasing the Ca2+ occupancy of the Tn-C binding sites.

Any process that increases the influx of Ca2+ into the cell results in more calcium-induced calcium release from the SR.

Beta-adrenergic stimulation is the common method of increasing cytosolic Ca2+ by increasing the flow of Ca2+ across the L-type Ca2+ channel into the cell. This is mediated by increasing cytosolic cAMP. Dobutamine is a beta-agonist that functions in this way.

Inhibiting the degradation of cAMP (the second messenger of beta stimulation) also increases cytosolic Ca2+. Phosphodiesterase degrades cytosolic cAMP. Phosphodiesterase inhibitors thus increase cAMP. Examples of phosphodiesterase inhibitors include milrinone and pimobendan.

Blocking the Na+/K+-ATPase pump increases cytosolic Ca2+. As Na+ accumulates in the cell in the face of an inhibited Na+/K+ pump, Na+ is extruded from the cell by way of the Na+/Ca2+ exchange mechanism and Ca2+ accumulates in the cell. Digoxin functions by blocking the Na+/K+-ATPase pump.

Independent of increasing cytosolic Ca2+, contractility can be enhanced by increasing the affinity of Tn-C for Ca2+ binding. Calcium sensitizers like pimobendan function this way.