Men who regularly take sildenafil and other phosphodiesterase-5 (PDE-5) inhibitors for erectile dysfunction (ED) or lower urinary tract symptoms (LUTS) may also be receiving a hidden heart benefit, according to new research.

Sildenafil is already in clinical trials to prevent heart failure, but researchers have discovered that PDE-5 inhibitors may counter heart failure in an unexpected way. The new findings hold promise for the design of a new drug class for treating heart failure.

Phosphodiesterases break down cyclic guanosine monophosphate (cGMP), the molecular messenger that otherwise puts the brakes on heart muscle cell growth. Drugs that inhibit these enzymes re-apply the brakes.

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“If a man is now being treated with Viagra and he has cardiac remodeling problems then it may be helpful,” said study investigator Chen Yan, PhD, Associate Professor of Cardiovascular Research at the University of Rochester Medical Center in Rochester, N.Y.

Sildenafil shuts down the PDE-5 enzyme, one of 11 PDE families in the body. In a recently published paper in Circulation Research (2009; published online ahead of print), Dr. Yan and her colleagues reported that members of second PDE family, particularly the PDE-1a enzyme, also breaks up cGMP to control hypertrophy.

However, PDE-1a does not work in the same way as PDE-5. Whereas PDE-5 breaks down cyclic nucleotides in response to the vital signaling molecule nitric oxide (NO), PDE-1 affects cyclic nucleotide pathways sensitive to calcium, another major player in cardiac disease.

“Our results suggest that a PDE-1 inhibitor alone can shut down abnormal cardiac growth, and when combined with Viagra or beta blockers, may do so in more than one way,” Dr. Yan said.

Beta blockers reduce hypertrophy, but some patients with heart failure cannot take this class of drugs because they make already weak hearts pump less vigorously. Researchers now believe that combining beta blockers with PDE inhibitors could potentially enable heart failure patients to take lower doses of beta blocker, thus protecting the contractile power of their heart muscle cells while still averting hypertrophy.

An experimental PDE-1 inhibitor known as IC86340 has been found to work in combination with sildenafil to combat hypertrophy to a greater degree than either compound alone in studies of isolated heart muscle cells. Currently, Dr. Yan and her colleagues also are looking at the roles of various PDEs in atherosclerosis and hypertension. 

“Almost every signaling molecule involved in PDE-regulated hypertrophy in the heart, including nitric oxide, calcium and angiotensin II, is at the core of regulating blood pressure and disease-related structural changes in arteries,” Dr. Yan explained. 

“PDE-1a levels appear to influence those pathways in return, which creates the potential for PDE-1 inhibitors that treat both hypertrophy in the heart and vascular diseases like hypertension and atherosclerosis.”