Fig. 1.

Cardiac myocyte signaling coupled to phosphodiesterase (PDE) 5. Cyclic GMP (cGMP) is generated by two mechanisms: a nitric oxide synthase (NOS)-soluble guanylate cyclase (sGC) coupled pathway, and membrane natriuretic receptor-guanylate cyclase (NPR-A/B, rGC) pathway. These two pools of cGMP interact with different effectors – namely other PDEs that regulate both cGMP and cyclic adenosine monophosphate (cAMP), and protein kinase G (PKG). PDE5 is a cGMP-selective PDE that is also activated by cGMP binding to the enzyme as well as PKG phosphorylation of the enzyme. sGC-generated cGMP can both augment and reduce cAMP in the cell by inhibiting PDE3 and activating PDE2, respectively. Inhibiting PDE5 also augments cGMP from this pool, and while this has been proposed to modulate PDE3 in the right ventricle [58], this has not been observed for the left ventricle. PDE5-modulated cGMP pools do not appear to impact cAMP-dependent signaling in normal adult myocytes [23]. Natriuretic peptide receptor (NPR)–coupled cGMP does not normally interact with PDE5; indeed the precise PDE responsible for modulating this pool remains unclear.

Cardiac stress regulation by PDE5 inhibition is primarily controlled by PKG targeting, and PDE5 inhibition enhances PKG signaling to stimulate these pathways. Shown on the left side are sarcomere proteins, sarcoplasmic reticulum (SR) calcium handling proteins (PLB [phospholamban]), mitochondrial signaling involving ATP-sensitive potassium channels (K_ATP), mitogen activated kinases (MAPK), calcineurin (Cn), Rho-activated kinase (ROCK), protein kinase Cα (PKCα) their regulation of nuclear transcription factors (nuclear factor of activated T-cells [NFAT], myocyte enhancer factor-2 [MEF2], SRF, and GATA4). Upstream, these activators are blunted by PKG due to direct inhibition of transient receptor potential channel 6 (TRPC6), and regulator of G-coupled signaling 2 and −4 (RGS2/4) coupled inhibition of Gq-coupled receptors.

At1 angiotensin I; Et1 endothelin 1; a-AR α-adrenergic receptor).