A proper balance between apoptosis and proliferation is necessary for the normal functioning and development of tissue. Disturbing this equilibrium can lead to disease states, such as hypertension. K⁺ channels play a major role in regulating pulmonary vascular tone by controlling the contractility of pulmonary artery smooth muscle cells (PASMC). K⁺ channels are also fundamental to sustaining normal pulmonary vascular tissue homeostasis in this cell population, as they play a role in both apoptosis and cell proliferation. There are two apoptotic pathways: the death receptor (extrinsic) and mitochondrial (intrinsic) pathways. In the intrinsic pathway, cytochrome c, released from mitochondria, is an essential component of the apoptosome which activates effector caspases in the cytoplasm. In the extrinsic pathway, activated death receptors trigger the initiation caspase activity. Effector caspases, which serve as proteases and nuclease activators, are the final mediators of apoptosis. The Na⁺/K⁺ pump maintains a high level of intracellular K⁺ ([K⁺]_i). Because ionic movements into and out of the cell largely determine cell volume, and because K⁺ permeability is high at rest, K⁺ currents are important determinants of cell volume. Water is passively transported across the cell membrane in response to the ionic flux to maintain hydrostatic pressure gradients. Apoptotic volume decrease (AVD) is an early hallmark and prerequisite of programmed cell death. Its earliest phase is marked by efflux of K⁺ and Cl^–, and outward transportation of water. As K⁺ efflux increases through opened K⁺ channels in early stages of AVD, Cl^– ions follow, moving down their electrochemical gradient. Water exits the cell through aquaporins to maintain the osmotic pressure balance between the intracellular and extracellular compartments, thus achieving cell shrinkage. Various subfamilies of K⁺ channels have been implicated in AVD, including voltage-gated (KV) and Ca²⁺-activated (KCa) K⁺ channels, while other subfamilies, including two-pore domain (K2P), inward-rectifier (KIR) and ATP-sensitive (KATP) K⁺ channels have been found to play a role in early apoptotic K⁺ efflux or AVD in apoptosis. It has also been shown that increased extracellular K⁺, which leads to maintaining high [K⁺]_i by decreasing the driving force for K⁺ efflux, or pharmacological block of K⁺ channels can inhibit apoptosis prior to cytochrome c release, can inhibit caspase activation, and can inhibit cytochrome c release. This supports an important role for K⁺ efflux during the early stages of apoptosis. Physiological levels of intracellular K⁺ have also been found to play a protective role against apoptosis in that it inhibits caspase and nuclease activity. Both K⁺ channel blockers and high extracellular [K⁺] have been shown to attenuate apoptosis. Therefore, K⁺ loss or efflux, in addition to leading to AVD, creates a permissible environment for caspase and nuclease activity by relieving the inhibition on these apoptotic mediators. Overall, K⁺ efflux contributes to apoptosis in two ways: by causing AVD and by releasing inhibition on endogenous caspases and nucleases. In addition to its role in apoptosis, K⁺ channels also play an important role in cell proliferation, mainly through their regulation of resting membrane potential (E_m) which in turn regulates intracellular Ca²⁺ levels. At rest, cells have a negative E_m, which is established by the electrogenic Na⁺/K⁺ ATPase that extrudes 3 K⁺ for every 2 Na+ ions brought into the cell. Furthermore, K⁺ permeability is relatively high at rest, so K⁺ flows out of the cell down its electrochemical gradient. Decrease of K⁺ channel activity (due to downregulated K⁺ channel expression and/or to decreased K⁺ channel conductance or open probability) causes membrane depolarization. This in turn would lead to an opening of L- and T-type voltage-dependent Ca²⁺ channels (VDCC) and an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt). The increased [Ca²⁺]_cyt causes smooth muscle cell contraction through Ca²⁺/calmodulin-mediated activation of myosin light chain kinase. Intracellular Ca²⁺ is also an important second messenger for cell migration and proliferation; Ca²⁺ influx through VDCCs triggers various transcriptional factors (e.g. CREB, NF-AT, NF-kB, c-Jun, c-Fos) that are involved in cell proliferation and protein synthesis. In addition, Ca²⁺ is also required for cell cycle progression, including the G0 to G1 transition, DNA synthesis and mitosis. Recently, another role of K⁺ in promoting cell survival has been found. In response to membrane permeabilization by bacterial toxins, a decrease in cytoplasmic K⁺ promotes membrane biogenesis which promotes cell survival by facilitating membrane repair.