Activation of endothelial and epithelial K(Ca) 2.3 calcium-activated potassium channels by NS309 relaxes human small pulmonary arteries and bronchioles

• Published in: British journal of pharmacology 2012-09, Vol.167 (1), p.37-47
• Main Authors: Kroigaard, Christel, Dalsgaard, Thomas, Nielsen, Gorm, Laursen, Britt E, Pilegaard, Hans, Köhler, Ralf, Simonsen, Ulf
• Format: Article
• Language: English
• Subjects: Aged; Bronchioles - drug effects; Bronchioles - physiology; Cells, Cultured; Endothelium - drug effects; Endothelium - physiology; Epithelial Cells - drug effects; Epithelial Cells - physiology; Humans; In Vitro Techniques; Indoles - pharmacology; Intermediate-Conductance Calcium-Activated Potassium Channels - agonists; Intermediate-Conductance Calcium-Activated Potassium Channels - physiology; Middle Aged; Oximes - pharmacology; Pulmonary Artery - drug effects; Pulmonary Artery - physiology; Respiratory Mucosa - cytology; RNA, Messenger - metabolism; Small-Conductance Calcium-Activated Potassium Channels - agonists; Small-Conductance Calcium-Activated Potassium Channels - physiology
• ISSN: 1476-5381
• DOI: 10.1111/j.1476-5381.2012.01986.x

Small (K(Ca) 2) and intermediate (K(Ca) 3.1) conductance calcium-activated potassium channels (K(Ca) ) may 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 K(Ca) 2.3 and K(Ca) 3.1 channels, and hypothesized that activation of these channels would produce relaxation of human bronchioles and pulmonary arteries. Channel expression and functional studies were conducted in human isolated small pulmonary arteries and bronchioles. K(Ca) 2 and K(Ca) 3.1 currents were examined in human small airways epithelial (HSAEpi) cells by whole-cell patch clamp techniques. While K(Ca) 2.3 expression was similar, K(Ca) 3.1 protein was more highly expressed in pulmonary arteries than bronchioles. Immunoreactive K(Ca) 2.3 and K(Ca) 3.1 proteins were found in both endothelium and epithelium. K(Ca) currents were present in HSAEpi cells and sensitive to the K(Ca) 2.3 blocker UCL1684 and the K(Ca) 3.1 blocker TRAM-34. In pulmonary arteries contracted by U46619 and in bronchioles contracted by histamine, the K(Ca) 2.3/ K(Ca) 3.1 activator, NS309, induced concentration-dependent relaxations. NS309 was equally potent in relaxing pulmonary arteries, but less potent in bronchioles, than salbutamol. NS309 relaxations were blocked by the K(Ca) 2 channel blocker apamin, while the K(Ca) 3.1 channel blocker, charybdotoxin failed to reduce relaxation to NS309 (0.01-1 µM). K(Ca) 2.3 and K(Ca) 3.1 channels are expressed in the endothelium of human pulmonary arteries and epithelium of bronchioles. K(Ca) 2.3 channels contributed to endo- and epithelium-dependent relaxations suggesting that these channels are potential targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease.