Hypertrophied Right Hearts Get Two for the Price of One

Phosphodiesterase type 5 (PDE5) was first discovered in the mid 1970s, not as a PDE but rather as a binding protein for cGMP.1 Shortly thereafter, it became clear that this protein also had cGMP-selective PDE activity, and cGMP-binding to domains in the N-terminus (GAF domains) regulated its enzymatic activity.2 PDE5 gained more attention in the mid 1980s when its role in modulating vascular tone was revealed.3 Pharmacologists at Pfizer considered it a potential drug for hypertension or coronary heart disease, which led to the development of UK-92,480 (sildenafil), a selective and potent PDE5 inhibitor. Although the desired cardiovascular responses were unimpressive, the phase I studies revealed a now-famous side effect that was quite popular among the trial participants. This ultimately led to development of PDE5 inhibitors for erectile dysfunction.4 Cardiac data collected to confirm drug safety found little impact of these agents on the heart.5–7 Gene and protein PDE5 expression was low, and even whether the enzyme was in myocytes was controversial.8 Limited functional analysis obtained largely under rest conditions suggested negligible effects.7Article p 238 The plot thickened in the late 1990s when our laboratory reported that PDE5 (or PDE5A) appeared to be present and active in canine myocardium and isolated myocytes and that, in normal animals, selective PDE5 inhibition blunted β-adrenergic stimulation.9 Work subsequently reported by Kukreja and colleagues10 and Das et al11 revealed that PDE5 inhibition preconditioned ischemic hearts and was cytoprotective (antiapoptotic) in isolated myocytes. In mice, PDE5 inhibitors blunt adrenergic stimulation in normal myocytes, an action that depends critically on the synthesis of cGMP by nitric oxide–dependent soluble guanylate cyclase.12 A similar “antiadrenergic” effect was documented in a double-blinded clinical trial in healthy volunteers who showed marked blunting of dobutamine-stimulated contractility when administered sildenafil …