Graded response of K⁺ current, membrane potential, and [Ca²⁺]_i to hypoxia in pulmonary arterial smooth muscle

Many studies indicate that hypoxic inhibition of some K⁺ channels in the membrane of the pulmonary arterial smooth muscle cells (PASMCs) plays a part in initiating hypoxic pulmonary vasoconstriction. The sensitivity of the K⁺ current (I_k), resting membrane potential (E_m), and intracellular Ca²⁺ concentration ([Ca²⁺]_i) of PASMCs to different levels of hypoxia in these cells has not been explored fully. Reducing PO₂ levels gradually inhibited steady-state I_k of rat resistance PASMCs and depolarized the cell membrane. The block of I_k by hypoxia was voltage dependent in that low O₂ tensions (3 and 0% O₂) inhibited I_k more at 0 and -20 mV than at 50 mV. As expected, the hypoxia-sensitive I_k was also 4-aminopyridine sensitive. Fura 2-loaded PASMCs showed a graded increase in [Ca²⁺]_i as PO₂ levels declined. This increase was reduced markedly by nifedipine and removal of extracellular Ca²⁺. We conclude that, as in the carotid body type I cells, PC-12 pheochromocytoma cells, and cortical neurons, increasing severity of hypoxia causes a proportional decrease in I_k and E_m and an increase of [Ca²⁺]_i.