Chronic hypoxia decreases K-V channel expression and function in pulmonaryartery myocytes

Activity of voltage-gated K+ (KV) channels regulates membrane potential (E- m) and cytosolic free Ca2+ concentration ([Ca2+](cyt)). A rise in [Ca2+](cy t) in pulmonary artery (PA) smooth muscle cells (SMCs) triggers pulmonary v asoconstriction and stimulates PASMC proliferation. Chronic hypoxia (PO2 30 -35 mmHg for 60-72 h) decreased mRNA expression of K-V channel alpha -subun its (Kv1.1, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) in PASMCs but not in mesenteric artery (MA) SMCs. Consistently, chronic hypoxia attenuated protein express ion of Kv1.1, Kv1.5, and Kv2.1; reduced K-V current [I-K(V)]; caused E-m de polarization; and increased [Ca2+](cyt) in PASMCs but negligibly affected K -V channel expression, increased I-K(V), and induced hyperpolarization in M ASMCs. These results demonstrate that chronic hypoxia selectively downregul ates K-V channel expression, reduces I-K(V), and induces Em depolarization in PASMCs. The subsequent rise in [Ca2+](cyt) plays a critical role in the development of pulmonary vasoconstriction and medial hypertrophy. The diver gent effects of hypoxia on K-V channel alpha -subunit mRNA expression in PA SMCs and MASMCs may result from different mechanisms involved in the regula tion of K-V channel gene expression.