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

Impairment of endothelium-dependent pulmonary vasodilation has been implica ted in the development of pulmonary hypertension. Pulmonary vascular smooth muscle cells and endothelial cells communicate electrically through gap ju nctions; thus, membrane depolarization in smooth muscle cells would depolar ize endothelial cells. In this study, we examined the effect of prolonged m embrane depolarization induced by high K+ on the endothelium-dependent pulm onary vasodilation. Isometric tension was measured in isolated pulmonary ar teries (PA) from Sprague-Dawley rats, and membrane potential was measured i n 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 de polarization (5-15 s) followed by a sustained depolarization that could las t for up to 3 h. In endothelium-intact PA rings, ACh (2 mu M), levcromakali m (10 mu M), and nitroprusside (10 mu M) reversibly inhibited the 25 mM K+- mediated contraction. Functional removal of endothelium abolished the ACh-m ediated relaxation but had no effect on the levcromakalim- or the nitroprus side-mediated pulmonary vasodilation. Prolonged (similar to 3 h) membrane d epolarization by 25 mM K+ significantly inhibited the ACh-mediated PA relax ation (-55 +/- 4 vs. -29 +/- 2%, P < 0.001), negligibly affected the levcro makalim-mediated pulmonary vasodilation (-92 +/- 4 vs. -95 +/- 5%), and sli ghtly but significantly increased the nitroprusside-mediated PA relaxation (-80 +/- 2 vs. 90 +/- 3%, P < 0.05). These data indicate that membrane depo larization by prolonged exposure to high K+ concentration selectively inhib ited endothelium-dependent pulmonary vasodilation, suggesting that membrane depolarization plays a role in the impairment of pulmonary endothelial fun ction in pulmonary hypertension.