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.

Introduction

By the end of each day, the average human heart has beaten more than 100,000 times to fulfill its role of delivering nutrients and oxygen to the peripheral tissues. This requires the ability to respond rapidly to changes in demand and to adapt to chronic stresses ensuing from physiologic or pathologic stimuli. Central to this regulation are the cyclic nucleotide 3′,5′-monophosphates cAMP and cGMP, and their respective effector enzymes, protein kinase A and G (PKA and PKG). cAMP/PKA is a primary regulator of excitation–contraction associated with PKA phosphorylation of voltage-gated calcium channels, ryanodine receptors, phospholamban, and sarcomeric proteins, that increases and accelerates Ca²⁺ cycling through the sarcoplasmic reticulum and stimulates contraction and relaxation. By contrast, cGMP/PKG is considered a myocardial brake, countering cAMP stimulation and independently signaling alternative pathways to blunt contraction and growth, while still enhancing relaxation [1].

The central role of cAMP and cGMP regulation has made these attractive targets for therapeutic intervention in heart failure. To date, activating cAMP has been difficult. Although it acutely enhances cardiac function, chronic stimulation of cAMP can worsen outcome and increase mortality. New approaches based on targeting distal G-protein-coupled receptors such as receptor kinase [2] or sarcoplasmic reticulum calcium ATPase (SERCA) 3, 4 could provide beneficial alternatives, although clinical testing is in its early stages or not yet started.

cGMP has also been targeted, principally by increasing its synthesis through nitric oxide (NO) or natriuretic peptide (NP) stimulation. NO activates soluble guanylate cyclase (sGC), thereby inducing vasodilatation, with the primary cardiac effect being modestly improved diastolic function; however, tachyphylaxis has limited its sustained use. B-type NP was introduced into clinical practice in 2001 for the treatment of acute decompensated heart failure, based on its capacity to lower central vascular pressures rather than its renal or cardiac effects 5, 6. Subsequent studies raised concerns about nephrotoxicity [7], although a recent trial found neutral results, with no toxicity but also no benefits [8]. An alternative approach is to block specific phosphodiesterases (PDEs) that control cGMP hydrolysis. However, by early 2000 little was known about which enzymes accomplished this in the cardiac myocyte. This changed with evidence that PDE5A, the first discovered and still best understood cGMP-selective PDE, might be involved. Over the past decade, experimental and clinical studies have reported on the efficacy of PDE5A inhibition in the treatment of various forms of heart disease. This work led to an ongoing US National Institutes of Health multicenter trial (RELAX: Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure) in patients with heart failure and preserved ejection fraction (EF >50%).

Despite the recent research, many questions and controversies persist. Are the drugs really targeting PDE5A, or are they inhibiting alternative PDEs, such as PDE1, that are more highly expressed in the heart and also hydrolyze cGMP? Is myocyte PDE5A important, or do the cardiac effects seen with PDE5 inhibitors originate from other cell types? Do PDEs selectively partner with specific intracellular cGMP pools, and if so, is this compartment altered by heart disease? How important is myocyte PKG activation to this process? Are the effects of PDE5A inhibition similar in the left ventricle (LV) and the right ventricle (RV)? We discuss these issues and highlight areas for further research.