Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure

Figure 2 Milrinone causes inhibition of phosphodiesterase III enzyme which decreases cyclic adenosine monophosphate concentration by converting later into inactive 5’adenosine monophosphate. Increased cyclic adenosine monophosphate (cAMP) activates phosphokinase A (PKA) that inhibits phospholamban (PLB) by phosphorylating it. Inhibition of PLB increases uptake of calcium (Ca²⁺) from cytosol into the SR through sarcoplasmic reticulum calcium ATPase (SERCA). This enhanced Ca²⁺ entry into SR has positive impact on both systolic and diastolic function. During diastole, decreased cytosolic Ca²⁺ causes relaxation. During systole increased release of Ca²⁺ from SR store through ryanodine receptor (RyR) activation increases inotropy. However, unchecked chronic stimulation of beta-adrenoreceptor (βAR) causes inhibition of AC through Gαi protein and increases intracellular Ca²⁺ influx by activation of L-type calcium channel (LTCC). Activated LTCC indirectly increases intracellular Ca²⁺ through activation of RyR mediated release of Ca²⁺ from SR. This increased intracellular influx of Ca²⁺ is associated with increased arrhythmogenicity. ATP: Adenosine triphosphate; Gαi: G inhibitory alpha protein; Gαs: G stimulatory alpha protein; PDE: Phosphodiesterase; SNS: Sympathetic nervous system.