Genetic deficit of KCa3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation

Background and Purpose The intermediate conductance calcium/calmodulin‐regulated K + channel K Ca 3.1 produces hyperpolarizing K + currents that counteract depolarizing currents carried by transient receptor potential ( TRP ) channels, and provide the electrochemical driving force for C l − and fluid movements. We investigated whether a deficiency in K Ca 3.1 ( K Ca 3.1 −/− ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium‐permeable TRP subfamily vanilloid type 4 ( TRPV 4) channels. Experimental Approach An opener of TRPV 4 channels, GSK 1016790 A , was infused in wild‐type (wt) and K Ca 3.1 −/− mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells ( PAEC ). Key Results In wt mice, GSK 1016790 A decreased right ventricular and systemic pressure leading to a fatal circulatory collapse that was accompanied by increased protein permeability, lung haemorrhage and fluid extravasation. In contrast, K Ca 3.1 −/− mice exhibited a significantly smaller drop in pressure to GSK 1016790 A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK 1016790 A‐induced relaxation of pulmonary arteries of K Ca 3.1 −/− mice was significantly less than that of wt mice. GSK 1016790 A induced TRPV 4 currents in PAEC from wt and K Ca 3.1 −/− mice, which co‐activated K Ca 3.1 and disrupted membrane resistance in wt PAEC , but not in K Ca 3.1 −/− PAEC . Conclusions and Implications Our findings show that a genetic deficiency of K Ca 3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium‐permeable TRPV4 channels. Therefore, inhibition of K Ca 3.1 channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.