Trends in Pharmacological Sciences
ReviewPhosphodiesterases and cardiac cGMP: evolving roles and controversies
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.
Section snippets
Identifying the PDEs involved in cardiac function
Five PDEs can hydrolyze cGMP (PDE1, PDE2, PDE3, PDE5, and PDE9), and genes encoding each are expressed in the heart [9]. However, which are most important is debatable. Most studies of PDE activity are based on the use of pharmacologic inhibitors in vitro, but this might not duplicate the complex regulation of PDEs in vivo, particularly for dual-substrate esterases and/or those that are positively or negatively regulated by the cyclic nucleotides themselves. Recent evidence suggests that more
Evidence and controversy regarding myocardial PDE5A regulation
The introduction of sildenafil in 1998 for the treatment of erectile dysfunction was a major ‘fork in the road’ for a drug being tested for hypertension and angina. A decade later, it was approved for pulmonary hypertension, but cardiac indications were still considered unlikely given its modest impact on arterial tone and low expression and activity in resting myocytes. However, in hearts under various forms of stress, the situation appeared different. Initial studies showed that, in intact
Microdomains couple PDEs to specific GCs
Compartmentalization of cAMP is well established and thought to be regulated by anchoring proteins that coordinate the cyclase with the relevant PDE and PKA within a given microdomain. Growing evidence also supports the existence of cGMP compartmentalization, and although equivalent anchoring proteins have not been found, localized PDE regulation appears to be important. In cardiac myocytes, PDE1C1 localizes to Z-disks and M-lines in a striated pattern [10], and has been suggested to provide
Is myocyte PKG important?
PKG is thought to be the primary downstream effector of the cGMP signaling pathway, and has long been thought to play a role in myocardial remodeling. The strongest evidence for this has come from cell culture studies involving selective PKG inhibitors, expression of dominant negative kinase (or gene silencing), or over-expression 33, 55. In vivo evidence has been more a matter of ‘guilt by association’; that is, a given maneuver coupled to cGMP generation improves heart disease and PKG
What about the RV?
One might have presumed that, given the initial focus on PDE5 inhibition in pulmonary disease, studies of its impact on the RV would have been conducted early. However, the concomitant decline in vascular afterload made this difficult to assess. Several experimental studies have since been performed, and the results seem to differ from those for the LV. In two models in which pulmonary arterial banding was used, and contrasted with a model of pulmonary vascular hypertension, sildenafil
Concluding remarks
Almost two decades after the first clinical trials of a novel PDE5 inhibitor, and 12 years after it was turned into a drug for erectile dysfunction, efforts to treat heart disease by this approach have resumed. By the end of 2011, we should have important data on its efficacy in patients with heart failure with preserved ejection fraction. There is movement to develop a large scale trial of sildenafil in dilated cardiomyopathy, and other indications such as muscular dystrophy syndromes may be
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