Phosphodiesterases and Cardiac cGMP: Evolving Roles and Controversies

摘要

Cyclic guanosine monophosphate (cGMP) and its primary target kinase –protein kinase G (PKG) are well-recognized modulators of cardiac function and chronic stress response. Their enhancement appears to serve as a myocardial brake, reducing maladaptive hypertrophy, enhancing cell survival signaling and mitochondrial function, protecting against ischemia/reperfusion injury, and blunting the stimulatory effects from catecholamines. Translation of these effects into a chronic treatment in patients with heart failure based on enhancing cGMP generation has be difficult however, with tolerance and hypotension effects from nitrates, and neutral responses to natriuretic peptides (at least B-type). Inhibition of cGMP-targeted phosphodiesterases such as PDE5A is an alternative approach, and one 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 specifically testing efficacy of PDE5A inhibition. Here we discuss recent research findings and controversies regarding the PDE/cGMP/PKG signaling pathway, and suggest directions for further research.