doi: 10.1161/CIRCULATIONAHA.105.577627
(Circulation. 2005;112:2589-2591.)
© 2005 American Heart Association, Inc.
Editorial |
Type 5 Phosphodiesterase Inhibition
The Focus Shifts to the Heart
From the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Marc J. Semigran, MD, Bigelow 800, Massachusetts General Hospital, Fruit St, Boston, MA 02114. E-mail msemigran@partners.org
Key Words: Editorials • heart failure • natriuretic peptides • pulmonary heart disease • nitric oxide
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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 ß-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.3
Article 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
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