An FDA-approved antiarrhythmic drug known as dofetilide could be repurposed to treat pulmonary arterial hypertension (PAH), researchers have found.
Dofetilide, sold commercially as Tikosyn, is a federally cleared Kv11.1 channel blocker that’s commonly used to treat cardiac arrhythmias, Tinatin I. Brelidze, PhD, and colleagues wrote in the American Journal of Pathology on Dec. 12. Kv11.1 potassium channels are voltage-activated channels that are expressed in many tissues and organs, but in the heart they help to repolarize cardiac action potentials to maintain proper heart rhythm.
Brelidze and colleagues examined lung tissue from patients with chronic obstructive pulmonary disease (COPD) and rats with experimentally induced PAH in an effort to determine whether dofetilide could have any bearing on PAH- and COPD-associated vascular remodeling. They found that in control rats, Kv11.1 channels were expressed in the smooth muscle cell layer of large-diameter pulmonary arteries (PAs), but not in the smooth muscle cells of small-diameter PAs of less than 100 micrometers. In rats with experimentally induced PAH, Kv11.1 channel expression increased, and the channels were found in both small and large PAs.
When rats with PAH were treated with dofetilide, there wasn’t any evidence of the pathological changes in vasculature that are typically associated with the disease. Dofetilide seemed to increase lumen diameter and decrease PA wall thickness to the levels observed in control rats.
In healthy humans, Brelidze et al. reported that Kv11.1 channels were present only in the walls of large-diameter PAs. Lung tissue from COPD patients showed collapse of alveoli, mild edema of arterial walls, and fibrosis and thickening of PA walls, and Kv11.1 channels were found in the walls of both large and small PAs, similar to rats with lab-induced PAH.
The researchers said that since Kv11.1 potassium selective channels were expressed in lungs, blocking those channels with dofetilide inhibits PAH associated with vascular remodeling.
“Our study suggests that Kv11.1 channel blockers may have therapeutic potential for treatment of PAH,” Brelidze said in a release. “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.”