Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California School of Medicine, San Diego, California 92103-8382 Nitric oxide (NO) is an endogenous endothelium-derived relaxing factor that regulates vascular smooth muscle cell proliferation and apoptosis. This study investigated underlying mechanisms involved in NO-induced apoptosis in human and rat pulmonary artery smooth muscle cells (PASMC). Exposure of PASMC to NO, which was derived from the NO donor S -nitroso- N -acetyl-penicillamine, increased the percentage of cells undergoing apoptosis. Increasing extracellular K + concentration to 40 mM or blocking K + channels with 1 mM tetraethylammonia (TEA), 100 nM iberiotoxin (IBTX), and 5 mM 4-aminopyridine (4-AP) significantly inhibited the NO-induced apoptosis. In single PASMC, NO reversibly increased K + currents through the large-conductance Ca 2+ -activated K + (K Ca ) channels, whereas TEA and IBTX markedly decreased the K Ca currents. In the presence of TEA, NO also increased K + currents through voltage-gated K + (K v ) channels, whereas 4-AP significantly decreased the K v currents. Opening of K Ca channels with 0.3 mM dehydroepiandrosterone increased K Ca currents, induced apoptosis, and further enhanced the NO-mediated apoptosis. Furthermore, NO depolarized the mitochondrial membrane potential. These observations indicate that NO induces PASMC apoptosis by activating K Ca and K v channels in the plasma membrane. The resulting increase in K + efflux leads to cytosolic K + loss and eventual apoptosis volume decrease and apoptosis. NO-induced apoptosis may also be related to mitochondrial membrane depolarization in PASMC. mitochondrial membrane potential; calcium; artery; potassium current