Viagra’s Other Talents: to Help a 'Signaling' Protein Shield the Heart from High Blood Pressur

Johns Hopkins and other researchers report what is believed to be the first direct evidence in lab animals that the erectile dysfunction drug sildenafil amplifies the effects of a heart-protective protein.

The team’s findings, to be published in the Journal of Clinical Investigation online Jan. 5, helps explain why sildenafil, more widely known as Viagra, has already been shown to improve heart function and may one day have value in either treating or preventing heart damage due to chronic high blood pressure.

The key, investigators say, is sildenafil’s effects on a single protein, RGS2, newly identified in the latest study as an essential link in the chain reactions that initially protect the body’s main blood-pumping organ from spiraling into heart failure.

Experimenting in mice, the team of heart experts first established that after a week of induced high blood pressure, the hearts of animals engineered to lack RGS2, or regulator of G-protein signaling 2, quickly expanded in weight by 90 percent. Almost half the mice died of heart failure. In mice with RGS2, by contrast, the dangerous muscle expansion, known as hypertrophy, was delayed, growing only 30 percent, and no mice died.

Subsequent tests treating hypertensive mice that had RGS2 with sildenafil showed enhanced buffering, with less hypertrophy, stronger heart muscle contraction and relaxation, and as much as 10 times lower stress-related enzyme activity compared to their untreated counterparts. In mice lacking RGS2, sildenafil had no effect.

“Sildenafil clearly prolongs the protective effects of RGS2 in mouse hearts,” says study senior investigator and cardiologist David Kass, M.D.

According to Kass, a professor at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute, RGS2 is stimulated by an enzyme, protein kinase G, whose action is, in turn, raised by countering the activity of another enzyme, phosphodiesterase 5 (PDE5A). Sildenafil’s ability to block PDE5A was shown by Kass and his team in 2005 to be responsible for blunting hypertrophy due to high blood pressure in mice and offsetting similar, adrenaline-stimulated heart stress in people.

Kass says RGS2 “acts like a short-term reset mechanism in the heart,” recoupling G proteins that if left alone stimulate the heart’s response to high blood pressure. And without the “reset,” a cascade of reactions known as Gq signaling leads to scar tissue formation, hypertrophy and heart failure.

Currently, physicians use so-called ACE inhibitor and ARB inhibitor drugs to block Gq signaling. These classes of drugs are the most common treatment for heart failure, which afflicts more than 5 million Americans, killing over a quarter million of them each year.

“The evidence is piling up that unbridled Gq signaling is driving a central biological chain reaction in heart failure,” says Kass, “and that by extending the protective effects of RGS2 or by developing a test for its presence, researchers can develop new therapies or improve existing ones, including ACE inhibitors and possibly sildenafil, for people with heart failure who will benefit most.”