Activation of endothelial and epithelial KCa2.3 calcium-activated potassium channels by NS309 relaxes human small pulmonary arteries and bronchioles.

Background and purpose: Small (KCa2) and intermediate (KCa3.1) conductance calcium-activated potassium channels (KCa) have been proposed to contribute to both epithelium- and endothelium-dependent relaxations, but this has not been established in human pulmonary arteries and bronchioles. Therefore, we investigated the expression of KCa2.3 and KCa3.1 channels, and hypothesised that activation of these channels produce relaxation of human bronchioles and pulmonary arteries. Experimental approach: Channel expression and functional studies were conducted in isolated human small pulmonary arteries and bronchioles, and KCa2 and KCa3.1 currents were examined in human small airways epithelial (HSAEpi) cells by whole-cell patch-clamp. Results: While KCa2.3expression was similar, KCa3.1 protein was highest expressed in pulmonary arteries compared to bronchioles. Immunoreaction to KCa2.3 and KCa3.1 were found both in the endothelium and epithelium. KCa-currents were present in HSAEpi cells and sensitive to the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34. In pulmonary arteries contracted by U46619 and in bronchioles contracted by histamine, the KCa2.3/KCa3.1 activator, NS309, induced concentration-dependent relaxations. NS309 was equally potent in pulmonary arteries, but less potent in bronchioles if compared to relaxation induced by salbutamol. NS309 relaxation was sensitive to the KCa2 blocker apamin, while the KCa3.1 blocker, charybdotoxin failed to reduce relaxation to 0.01-1 µM NS309. Conclusions and implications: Thus, KCa2.3 and KCa3.1 are expressed in the endothelium of human pulmonary arteries and epithelium of bronchioles. KCa2.3 channels contribute to endo- and epithelium-dependent relaxations suggesting that these channels are potential targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.