Pulmonary Circulation Under Pressure: Pathophysiological and Therapeutic Implications of BK Channel.

Abstract

The large-conductance Ca²⁺-activated K⁺ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca⁺² concentration, and chronic hypoxia, resulting in massive K⁺ efflux, membrane hyperpolarization, decreased L-type Ca⁺² channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.