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

• Published in: British journal of pharmacology 2015-09, Vol.172 (18), p.4493-4505
• Main Authors: Wandall‐Frostholm, Christine, Dalsgaard, Thomas, Bajoriūnas, Vytis, Oliván‐Viguera, Aida, Sadda, Veeruanjaneyulu, Beck, Lilliana, Mogensen, Susie, Stankevicius, Edgaras, Simonsen, Ulf, Köhler, Ralf
• Format: Article
• Language: English
• Subjects: Pulmonary arteries; Research Papers; Rodents
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13234

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.