Phosphodiesterases and cardiac cGMP: Evolving roles and controversies

cGMP and its primary target kinase, protein kinase G (PKG), are well recognized modulators of cardiac function and the chronic stress response. Their enhancement appears to serve as a myocardial brake, reducing maladaptive hypertrophy, improving cell survival, signaling and mitochondrial function, protecting against ischemia/reperfusion injury, and blunting the stimulatory effects of catecholamines. Translation of these effects into a chronic treatment for patients with heart failure based on increasing the generation of cGMP has been difficult, however, with tolerance and hypotension effects occurring with nitrates and neutral responses to natriuretic peptides (at least B-type). Inhibition of cGMP-targeted phosphodiesterases (PDEs) such as PDE5A is an alternative approach that appears to have more potent effects. Recent studies in experimental models and patients are revealing benefits in heart failure syndromes, and ongoing multicenter trials are testing the efficacy of PDE5A inhibition. In this review we discuss recent research findings and controversies regarding the PDE/cGMP/PKG signaling pathway, and suggest directions for further research.