Salidroside ameliorates monocrotaline-induced pulmonary arterial hypertension in rats by modulating BKCa channels

Salidroside (Sal) is a natural active ingredient extracted from Crassulaceae plants, which has pharmacological effects such as anti-tumor, anti-oxidation, and cardiovascular protection. Potassium channel function in pulmonary artery smooth muscle cells (PASMCs) is crucial in the development of pulmonary arterial hypertension (PAH). This study explored the effects of Sal on large-conductance calcium-activated potassium channels (BKCa) in these cells, focusing on the mechanisms underlying its protective effect in PAH. A rat model of PAH was established using monocrotaline (MCT) alongside an in vitro model of primary PASMCs stimulated by platelet-derived growth factor-BB. This study thoroughly assesses Salidroside's impact on PAH across tissue function, molecular mechanisms, and electrophysiological characteristics. Our results show that Sal treatment reduced right ventricular pressure in MCT-induced PAH rats, ameliorated pulmonary vascular remodeling and right ventricular reconstruction, and enhanced pulmonary vasoconstriction and relaxation activity. It increased the expression of BKCa channel proteins on the membrane of PASMCs, inhibited the proliferation of PASMCs, promoted their apoptosis, and improved the electrophysiological remodeling of PASMCs and pulmonary vascular remodeling caused by PAH. Activation and excessive expression of PKC α markedly suppressed BKCa channel function. Sal was able to activate BKCa channels by inhibiting PKC α, leading to enhanced K⁺ efflux, cellular hyperpolarization, and vasodilation. In conclusion,by reinstating BKCa channel activity in PASMCs, Sal rectified the dysregulation between cell proliferation and apoptosis within the pulmonary vasculature. This mechanism, potentially mediated indirectly by Sal's modulation of PKC α, offers a novel therapeutic approach for PAH.