Sildenafil improves blood flow after heart attack in an animal model

Dogs treated with sildenafil, a drug most commonly used to treat erectile dysfunction, had better blood flow in coronary arteries than control animals, following an induced artery obstruction and treatment that modeled a heart attack and standard medical care given to people, according to a new study in the Journal of the American College of Cardiology.

“Sildenafil appears to inhibit the mechanism of coronary occlusion in an animal model of acute coronary syndrome mediated by platelet thrombosis. This suggests that its use does not predispose patients to cardiac infarction,” said Marc J. Semigran, M.D. from the Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts.

In a dozen dogs, the researchers created, and then treated, an acute coronary syndrome similar to a heart attack in a person. They created a narrowing in a coronary artery until a clot blocked blood flow. Each dog was then treated with heparin and aspirin, followed by the clot-busting drug tPA, in order to restore some blood flow. For the next hour, all 12 dogs were observed as blood flowed or was obstructed in what is known as cyclic coronary flow reduction. Then six randomly-selected dogs were given a dose of intravenous sildenafil that mimicked the level seen in men being treated with the same drug for erectile dysfunction.

After about 18 minutes, the coronary flow reductions ceased in five of the six animals given sildenafil, but they continued to affect all six control animals. In the treated animals, the portion of time that blood was flowing through the coronary artery increased from an average of 52 percent of the hour before treatment to 83 percent of the hour following treatment. The effect was greater in the dogs that had higher blood levels of sildenafil. In the untreated animals, blood was flowing slightly less than half the time and there was no significant difference between the first and second hours of the observation period.

“This is the first study to demonstrate the effects of sildenafil on platelet function in an animal model that mimics acute myocardial infarction,” said Gregory D. Lewis, M.D., who was the first author of this report.

“There has been concern that sildenafil may cause heart attacks. While epidemiological studies appear to have discounted this, our study demonstrates that sildenafil acts to inhibit the mechanism by which heart attacks or acute coronary syndromes occur: platelet-mediated thrombosis,” Dr. Semigran said.

Although the results may ease concerns about sildenafil possibly triggering a heart attack, Dr. Semigran said the drug probably won’t be added to heart attack treatments for now, because it can dangerously interact with another heart drug, nitroglycerin.

“The combination of sildenafil and nitroglycerin can have a potent blood pressure lowering effect.  As long as nitroglycerin is given to patients with heart attacks, sildenafil cannot be given. I would note that nitroglycerin has never been shown to improve mortality in patients having acute coronary syndromes or a heart attack,” he said.

Dr. Semigran pointed out that sildenafil was first developed to treat angina, but that use was dropped because of the interaction with nitrate-based heart medicines, such as nitroglycerin. The effect on heart artery blow flow is produced by the same mechanism that treats erectile dysfunction. By inhibiting a substance in the body called phosphodiesterase 5 (PDE5), sildenafil enhances the effect of nitric oxide (NO), thus helping relax blood vessels in order to maintain an erection. Sildenafil’s inhibition of PDE 5 also affects platelets, and thus reduces clot formation.

Dr. Semigran said further work to refine dosing should be done in animals. He said human trials with patients who are suffering from unstable angina, but are not taking any nitrates that could interact with sildenafil, could also provide useful information.

Jay Mehta, M.D., Ph.D. from the University of Arkansas for Medical Sciences and the VAMC in Little Rock, Arkansas, who was not connected with this study, said the results suggest the active ingredient of sildenafil may help counteract artery blockages, at least in an animal model.

“This model is akin to what happens in humans with acute coronary syndromes. Although the study was done in a small number of animals, the results are impressive. If the results can be translated to humans, then one can at least say that sildenafil does not promote thrombus formation and hence lead to heart attacks,” Dr. Mehta said.