Baltimore, MD - Scientists from Johns Hopkins have shown for the first time that sildenafil (Viagra, Pfizer)—and probably other phosphodiesterase (PDE)-5 inhibitors—have a direct effect on the human heart [1]. In the study, performed in healthy volunteers, the drug exhibited a beta-blocker-like effect, Dr Barry Borlaug and colleagues report in the October 25, 2005 issue of Circulation.

The results indicate that the whole class of PDE-5 inhibitors—which are currently marketed for erectile dysfunction—could have potential as chronic treatments for heart failure, senior author Dr David Kass (Johns Hopkins Medical Institutions, Baltimore, MD) told heartwire. In particular, Kass believes, "They could be of use for patients with heart-failure symptoms who still have preserved systolic function." These people constitute about 40% of heart-failure patients, and there is currently no approved therapy for this group, he adds.

Kass says although this particular experiment was performed with sildenafil, "everything we have seen is indicative of a class effect." His group first started working with a PDE-5 inhibitor from the German company E Merck, he notes, and similar results in animals have been seen with the PDE-5 inhibitor tadalafil (Cialis, Lilly). Another PDE-5 inhibitor, vardenafil (Levitra, Bayer/GlaxoSmithKline), is also available for erectile dysfunction in the US and Europe.

In an accompanying editorial [2], Dr Marc J Semigran (Massachusetts General Hospital, Boston) says: "A picture of the role of PDE 5 in cardiomyocyte function is beginning to emerge from both preclinical studies and the work of Borlaug et al."

In the double-blind, randomized trial in 35 volunteers of both sexes, participants had their cardiac function in response to a dobutamine stress test assessed before and after oral sildenafil 100 mg (n=19) or placebo (n=16).

In subjects who received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32%, 66%, and 63% respectively (each p<0.001 vs the initial response). This contrasted to the placebo group, who displayed similar functional responses with both dobutamine tests.

"This work changes our current thinking about PDE-5 inhibitors," Kass told heartwire. It builds on previous experiments in mice and shows that, in humans, the PDE-5 enzyme becomes much more important when the heart is under stress, he explains.

This work changes our current thinking about PDE 5 inhibitors.

However, he notes that the current study was performed in healthy volunteers in their 30s and it remains to be seen what the effects of PDE-5 inhibitors may be in older people with comorbidities such as diabetes and vascular disease.

"Clearly the real score is if sildenafil [and other PDE-5 inhibitors] can do something chronically to diseases associated with high blood pressure and remodeling of the heart," he notes. "For example, can [these drugs] reverse existing hypertrophy?"

Kass believes that sildenafil and other PDE-5 inhibitors may have a role in more severe heart failure alongside established therapies such as beta blockers. "Viagra doesn't drop the blood pressure, and there may be a role for it as an adjunct to other treatments," he comments. (Although there are warnings on the package inserts to avoid taking Viagra in conjunction with nitrates because of potential drops in blood pressure, Kass told heartwire that this is due to the mechanism of action of nitrates. "We saw very little change in blood pressure, [and this] counterindication is not based on a lot of data either," he notes.)

His team plans to begin a study in patients with preserved systolic function first of all; he told heartwire that both Pfizer and Lilly are very interested in this potential new role for their drugs.