Properties of the high‐conductance Ca2+‐activated K+ (BK) channel in pulmonary arterial smooth muscle cells

Abstract

Pulmonary hypertension (PH) is associated with a loss of vasodilator influences in the pulmonary circulation, which results in pathogenic vasoconstriction. However, we observed an over‐expression of high‐conductance, Ca2+‐activated K+ (BK) channels in pulmonary arteries (PA) during chronic hypoxia (CH)‐induced PH, providing a potential vasodilator target. Here, we report that BK channels of PA smooth muscle cells (PASMCs) from CH rats retain high Ca2+‐sensitivity, α‐β1 subunit coupling that confers sensitivity to BK channel openers, and hypoxia‐insensitivity as compared to normal (N) rats (n=4‐11). Importantly, these properties may permit pharmacological activation of the BK channel even in a hypoxic environment. In inside‐out membrane patches used to record unitary BK currents in PASMCs from CH rats (n= 4‐7), the BK channel log(Ca2+ EC50(mol/L)) was ‐5.9 in both N and CH rats. Lithocholate (LCA), a BKβ1 subunit‐dependent opener, caused a 26‐fold and 19‐fold increase in BK channel open‐state probability in PASMC from CH and N rats, respectively. Using lung samples from organ donors without diagnosed PH, we also defined BK channel properties in human PASMCs. Similar to rat, the hBK channel exhibited high Ca2+‐sensitivity (log(Ca2+ EC50(mol/L)) = ‐6.1), was activated by LCA, and was not inhibited by acute hypoxia (n=4‐7). Thus, PASMCs from N and CH rats and humans without diagnosed lung disease express a β1 subunit‐coupled, hypoxia‐insensitive BK channel, which is responsive to BK channel openers.Supported by AHA 13PRE17240055 (NDD), NIH UL1RR029884 (NDD), and the UAMS College of Medicine Dean's Society.