| Popis: |
Background and Purpose The intermediate conductance calcium/calmodulin-regulated K+ channel KCa3.1 produces hyperpolarizing K+ currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl− and fluid movements. We investigated whether a deficiency in KCa3.1 (KCa3.1−/−) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. Experimental Approach An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and KCa3.1−/− 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, GSK1016790A 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, KCa3.1−/− mice exhibited a significantly smaller drop in pressure to GSK1016790A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK1016790A-induced relaxation of pulmonary arteries of KCa3.1−/− mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and KCa3.1−/− mice, which co-activated KCa3.1 and disrupted membrane resistance in wt PAEC, but not in KCa3.1−/− PAEC. Conclusions and Implications Our findings show that a genetic deficiency of KCa3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4 channels. Therefore, inhibition of KCa3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse. |
