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

Figure 1 Beta-adrenoreceptor mediated signal transduction leads to the activation of both G stimulatory alpha protein and G inhibitory alpha protein. Activated Gαs activates adenylyl cyclase (AC) which converts ATP into cAMP while activated Gαi inhibits AC. Activated Gαs also leads to calcium (Ca²⁺) mobilization into cardiomyocyte by activating L-type calcium channel (LTCC) independent of AC. This increase in intracellular Ca²⁺ concentration leads to activation of ryanodine receptor (RyR) which causes further release of Ca²⁺ from SR, a phenomenon known as calcium-induced calcium release. Elevated cAMP activates phosphokinase A (PKA) that inhibits phospholamban (PLB) by phosphorylating it. Phosphorylation of PLB increases uptake of 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. In diastole, decreased intracellular Ca²⁺ causes relaxation. In systole increased release of Ca²⁺ from SR store through RyR activation increases inotropy. In the failing myocardium, chronic stimulation of βAR results in ineffective activation of AC, persistent activation of L-type calcium channel that increases Ca²⁺ influx, and decreased Ca²⁺ uptake into the SR due to decreased SERCA activity. This translates into systolic and diastolic dysfunction and increased arrhythmogenicity. βAR: Beta-adrenoreceptor; ATP: Adenosine triphosphate; cAMP: Cyclic adenosine monophosphate; Gαi: G inhibitory alpha protein; Gαs: G stimulatory alpha protein; PDE: Phosphodiesterase; SNS: Sympathetic nervous system.