Functional expression of inwardly rectifying and ATP‐sensitive potassium channels in human pulmonary artery smooth muscle and endothelial cells

Abstract The resting membrane potential (V M ) of vascular cells is a key determinant of arterial tone, integrating multiple ionic conductances to control smooth muscle contractility and endothelial signalling. In the human pulmonary circulation, the specific K + channels responsible for setting the V M of smooth muscle cells (SMCs) and endothelial cells (ECs) remain incompletely defined. This study investigated whether inwardly rectifying (Kir2) and ATP‐sensitive (K ATP ) K + channels are functionally expressed in native human pulmonary artery (PA) SMCs and ECs and assessed their contribution to vascular tone. Combining patch‐clamp electrophysiology, immunofluorescence and wire myography, we evaluated channel expression and function in freshly isolated PASMCs and PAECs, and intact PAs. Kir2 channels were identified by Ba 2+ ‐sensitive inward currents with a characteristic rectification profile, supported by immunolabelling of Kir2.1 and Kir2.2 subunits. Functionally, BaCl 2 induced concentration‐dependent contractions of PA rings and significantly attenuated acetylcholine‐evoked, endothelium‐dependent relaxation, revealing a tonic vasodilatory role for Kir2 channels. K ATP currents, activated by pinacidil and blocked by glibenclamide and PNU‐37883A, were also observed in PASMCs and PAECs, consistent with immunodetection of Kir6.1 and SUR2 subunits. In isolated PAs, pinacidil elicited concentration‐dependent vasodilatation, which was significantly reduced by K ATP channel blockade. Collectively, these findings demonstrate for the first time the functional presence of Kir2 and K ATP channels in native human pulmonary vascular cells, and their modulatory role on V M and arterial tone. These channels emerge as key electro‐metabolic regulators of pulmonary vascular function and promising therapeutic targets in diseases characterized by V M dysregulation, such as pulmonary arterial hypertension. image Key points Inwardly rectifying (Kir2) K + channels are key regulators of the resting membrane potential (V M ) in different vascular cell types across multiple vascular beds, whereas ATP‐sensitive (K ATP ) K + channels detect changes in the metabolic state of vascular cells and translate these changes into V M modulation. Despite their well‐established physiological relevance, a comprehensive characterization of Kir2 and K ATP channels in freshly isolated human pulmonary vascular cells – particularly within the endothelium – remains lacking. Our study provides compelling evidence for the functional expression of Kir2 and K ATP channels in native human pulmonary arterial smooth muscle and endothelial cells, demonstrating their contribution to V M regulation and pulmonary vascular tone at rest and in response to specific stimuli.