High K⁺-induced membrane depolarization attenuates endothelium- dependent pulmonary vasodilation

Impairment of endothelium-dependent pulmonary vasodilation has been implicated in the development of pulmonary hypertension. Pulmonary vascular smooth muscle cells and endothelial cells communicate electrically through gap junctions; thus, membrane depolarization in smooth muscle cells would depolarize endothelial cells. In this study, we examined the effect of prolonged membrane depolarization induced by high K⁺ on the endothelium- dependent pulmonary vasodilation. Isometric tension was measured in isolated pulmonary arteries (PA) from Sprague-Dawley rats, and membrane potential was measured in single PA smooth muscle cells. Increase in extracellular K⁺ concentration from 4.7 to 25 mM significantly depolarized PA smooth muscle cells. The 25 mM K⁺-mediated depolarization was characterized by an initial transient depolarization (5-15 s) followed by a sustained depolarization that could last for up to 3 h. In endothelium-intact PA rings, ACh (2 μM), levcromakalim (10 μM), and nitroprusside (10 μM) reversibly inhibited the 25 mM K⁺mediated contraction. Functional removal of endothelium abolished the ACh-mediated relaxation but had no effect on the levcromakalim- or the nitroprusside-mediated pulmonary vasodilation. Prolonged (~3 h) membrane depolarization by 25 mM K⁺ significantly inhibited the ACh-mediated PA relaxation (-55 ± 4 vs. -29 ± 2%, P < 0.001), negligibly affected the levcromakalim-mediated pulmonary vasodilation (-92 ± 4 vs. -95 ± 5%), and slightly but significantly increased the nitroprusside-mediated PA relaxation (- 80 ± 2 vs. 90 ± 3%, P < 0.05). These data indicate that membrane depolarization by prolonged exposure to high K⁺ concentration selectively inhibited endothelium-dependent pulmonary vasodilation, suggesting that membrane depolarization plays a role in the impairment of pulmonary endothelial function in pulmonary hypertension.