Antiarrhythmic Tikosyn May be Repurposed to Treat PAH, Study Suggests

Tikosyn (dofetilide), a medicine approved by the U.S. Food and Drug Administration (FDA) to treat heart arrhythmias, may be used to treat pulmonary arterial hypertension (PAH), a recent study suggests.

The findings warrant further investigation into the therapy’s potential positive effects for patients with PAH, the researchers stated.

The study, titled “Increased Smooth Muscle Kv11.1 Channel Expression in Pulmonary Hypertension and Protective Role of Kv11.1 Channel Blocker Dofetilide,” was published in The American Journal of Pathology.

Kv11.1 potassium selective channels are especially known for their important role in the heart, as they help maintain a normal beating rhythm. These channels also play important functions in other organs, such as the brain, where they are responsible for controlling neurons’ excitability (their ability to send signals).

Moreover, “Potassium channels are essential for proper lung function, and defects in ion channels have been linked to various respiratory diseases. However, surprisingly little is known about Kv11.1 channel expression and function in normal lung tissue,” the researchers said.

In two lung diseases in particular — PAH and chronic obstructive pulmonary disease (COPD) — different types of potassium channels have been implicated in the process of vascular remodeling that causes the narrowing of blood vessels in the lungs.

“Despite the importance of Kv11.1 channels for many physiologic processes, their expression and function in the pulmonary vasculature [blood vessels] and their potential role in PAH- and COPD-associated vascular remodeling have not been investigated,” the researchers said.

In this study, researchers from Georgetown University Medical Center discovered that the lungs of patients with COPD associated with PAH and rats with experimentally-induced PAH had significantly more Kv11.1 channels, compared to lungs of healthy humans and rats.

Importantly, when they examined lung tissues from healthy volunteers and animals, they found that Kv11.1 channels were present only in large pulmonary arteries (PAs) — the arteries that connect the heart to the lungs.

However, when they analyzed samples from patients with COPD associated with PAH and rats with PAH, they discovered these channels were present not only in large PAs, but also in blood vessels of small caliber (those that are less than 100 μm in diameter).

Moreover, they discovered the increase in the levels of Kv11.1 channels in lung tissues of sick rats accompanied the process of vascular remodeling as PAH progressed.

When they treated animals with Tikosyn — a pharmacological inhibitor of Kv11.1 channels that’s marketed by Pfizer — they managed to halt the process of vascular remodeling.

In these animals, Tikosyn increased the diameter of the lumen (inside) and reduced the thickness of PA walls to values identical to those seen in healthy rats.

“Our study suggests that Kv11.1 channel blockers may have therapeutic potential for treatment of PAH. Specifically, we have shown that dofetilide, which is already FDA-approved as an antiarrhythmic and therefore has passed all of the drug safety requirements, can be considered for repurposing for treatment of patients with PAH,” Tinatin I. Brelidze, PhD, assistant professor of pharmacology in the department of pharmacology and physiology at Georgetown University Medical Center, and senior author of the study, said in a press release.

Drug repurposing refers to the process of testing a medication with established safety in conditions other than those for which it was originally approved. This strategy offers many advantages over developing a new therapy, namely financial and time-saving gains.