Type 5 Phosphodiesterase Inhibition

Of the molecules that transmit an extracellular message to alter cardiomyocyte physiology, the cyclic nucleotides are among the better understood as regulators of cell function. The relatively recent identification of nitric oxide (NO) as a stimulus of cGMP production by soluble guanyl cyclase,1 as well as of the natriuretic peptides as a stimulating membrane-bound guanylate cyclase,2 has led to increasing interest in the study of the effects of modulating intracellular cGMP, with most interest being in the area of vascular biology. Studies of the myocardial effects of altering intracellular cGMP have been less extensive, perhaps because systemic agents that affect cGMP levels are often vasodilatory, and their administration is accompanied by changes in blood pressure that can limit the ability to observe myocardial effects. Both cAMP, the second messenger of the β-adrenergic signaling system, and cGMP have a rapid intracellular turnover as a result of the balance between their formation by cyclases and their degradation by phosphodiesterases (PDEs). In this issue of Circulation , Borlaug and colleagues use load-independent measures of contractility to assess the myocardial effects of an agent (sildenafil) that increases intracellular cGMP levels by inhibiting its degradation.3Article p 2642 In myocardial cells, cGMP has a several intracellular targets that may alter contractility and diastolic function. cGMP can activate a cGMP-dependent cAMP PDE, decreasing myocardial cAMP levels and thereby leading to a reduction of cAMP-dependent phosphorylation of the L-type calcium channels and of calcium influx.4 cGMP can also depress cAMP production by inhibiting adenylate cyclase.5 Furthermore, a cGMP-dependent protein kinase can also directly decrease the magnitude of calcium influx through the L-type channels.6 In addition, a separate cGMP-dependent protein kinase can phosphorylate troponin I, which results in a decreased sensitivity of the contractile apparatus to calcium.7 The phosphorylation of troponin …