Genetic deficit of K_Ca3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation

Background and Purpose

The intermediate conductance calcium/calmodulin‐regulated K⁺ channel K_Ca3.1 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 K_Ca3.1 (K_Ca3.1^−/−) 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 K_Ca3.1^−/− 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, K_Ca3.1^−/− 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 K_Ca3.1^−/− mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and K_Ca3.1^−/− mice, which co‐activated K_Ca3.1 and disrupted membrane resistance in wt PAEC, but not in K_Ca3.1^−/− PAEC.

Conclusions and Implications

Our findings show that a genetic deficiency of K_Ca3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium‐permeable TRPV4 channels. Therefore, inhibition of K_Ca3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.

DOI: 10.1111/bph.13234

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