Sildenafil, the erectile dysfunction drug more commonly known as Viagra, is currently under consideration as a heart failure treatment. However, new animal studies conducted by John Hopkins University in Baltimore, MD, suggest that this drug may have very different effects on males and females.
Sildenafil works by dilating blood vessels to increase blood flow. In the case of patients with erectile dysfunction, this stimulates blood flow to the penis.
The effect of the drug is similar, in fact, to drugs such as nitrates, which are used to increase blood flow to damaged hearts. Also, recent studies have found beneficial effects from the drug on heart muscles, so researchers are now investigating sildenafil as a treatment for patients with heart failure.
According to heart experts, heart failure is the most common reason for hospital admissions in the US among people accessing health care via Medicare. Drugs such as beta-blockers and ACE inhibitors already help to improve the heart's blood-pumping efficiency for these patients, but experts say they do not fully address the underlying pathology.
Even moderate injury to the muscle cells of the heart can cause widespread changes within heart tissue. Heart attack, hypertension, arteriosclerosis and other problems can cause enlargement of the heart and stiffening of heart chambers. The heart is weakened by these alterations, which then reduces the efficiency of blood circulation.
Lead scientist on the John Hopkins research, Dr. Eiki Takimoto, says that "because cardiac remodeling is an underlying mechanism, we've put more than a decade of research into understanding it enough to stop or reverse it."
Sildenafil versus cardiac remodeling
Central to Dr. Takimoto and team's research is a molecule responsible for "a helpful biochemical cascade" that relieves hypertension and other stressors. A strategic pool of this molecule - called cyclic guanosine monophosphate (cGMP) - is usually maintained within heart cells, but it can become depleted following heart problems.
Sildenafil has a similar action to nitrates, and may have beneficial effects on heart muscles, so researchers are now investigating it as a treatment for patients with heart failure.
Sildenafil, however, has been demonstrated as inhibiting the enzyme - PDE5 - that depletes the reservoirs of cGMP. As such, it is effective at raising levels of cGMP for combating cardiac disease.
A 2005 experiment by Dr. Takimoto's team involved surgically fitting a band around the aorta in mice engineered to have transverse aortic constriction (TAC). The band raised their internal heart pressure, which prompted the cardiac remodeling indicative of classic human heart failure.
The researchers then administered the mice with sildenafil. "By increasing cGMP with sildenafil, we both blocked and reversed remodeling in the animals, ameliorating heart failure," Dr. Takimoto says.
Similar findings were replicated by other researchers in animal studies, paving the way for sildenafil to be considered as a treatment for heart failure in human subjects.
Examining estrogen interaction exposed differences in male-female drug response
Expanding on this research, Dr. Takimoto and team wanted to better understand the benefits of cGMP, such as how it might interact with estrogen, which is known to have naturally protective properties for the heart.
The team repeated the earlier TAC mouse model, except this time they removed the ovaries from half of the female mice, which meant these mice had only minimal estrogen levels. All mice were treated with sildenafil for cardiac remodeling, but this time it was much less effective in the mice with low estrogen.
"This tells us that estrogen critically impacts the response to sildenafil in heart failure treatment," Dr. Takimoto says.
In the male mice, sildenafil generally works well, however. This is because the drug targets a different biological process in males that does not involve estrogen.
This discovery points to an important difference in physiology between males and females. Dr. Takimoto explains:
"In female mice, their normally high estrogen levels insure presence of an ongoing pool of cGMP with its protective effects. In males, however, there's no such pool of cGMP. It's synthesized only in response to stress on the heart."
The team believe the evidence for the differences between the male and female reactions to sildenafil is so strong that they say doctors will need to take gender into consideration when prescribing certain medications. It could also have powerful implications for future clinical trials of new drugs.
"The research is especially significant," Dr. Takimoto concludes, "because it offers a mechanism to explain how estrogen affects sildenafil's efficacy. That's the first time the actual pathway of a hormone's cause and effect on a drug has been mapped out."