Genetic deficit of K_Ca 3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation.

ABSTRACT:

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 Cl^- 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 (TRPV4) channels.

Experimental approach

An opener of TRPV4 channels, GSK1016790A, 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, 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_Ca 3.1^-/- 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_Ca 3.1^-/- mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 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 3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.

SUBMITTER: Wandall-Frostholm C 

PROVIDER: S-EPMC4562510 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature