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Heterogeneity of hypoxia-mediated decrease in I_K(V) and increase in [Ca²⁺]_cyt in pulmonary artery smooth muscle cells

Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California

Submitted 3 October 2006 ; accepted in final form 23 May 2007

Hypoxic pulmonary vasoconstriction is caused by a rise in cytosolic Ca²⁺ ([Ca²⁺]_cyt) in pulmonary artery smooth muscle cells (PASMC) via multiple mechanisms. PASMC consist of heterogeneous phenotypes defined by contractility, proliferation, and apoptosis as well as by differences in expression and function of various genes. In rat PASMC, hypoxia-mediated decrease in voltage-gated K⁺ (Kv) currents (I_K(V)) and increase in [Ca²⁺]_cyt were not uniformly distributed in all PASMC tested. Acute hypoxia decreased I_K(V) and increased [Ca²⁺]_cyt in 46% and 53% of PASMC, respectively. Using combined techniques of single-cell RT-PCR and patch clamp, we show here that mRNA expression level of Kv1.5 in hypoxia-sensitive PASMC (in which hypoxia reduced I_K(V)) was much greater than in hypoxia-insensitive cells (in which hypoxia negligibly affected I_K(V)). These results demonstrate that 1) different PASMC express different Kv channel - and -subunits, and 2) the sensitivity of a PASMC to acute hypoxia partially depends on the expression level of Kv1.5 channels; hypoxia reduces whole-cell I_K(V) only in PASMC that express high level of Kv1.5. In addition, the acute hypoxia-mediated changes in [Ca²⁺]_cyt also vary in different PASMC. Hypoxia increases [Ca²⁺]_cyt only in 34% of cells tested, and the different sensitivity of [Ca²⁺]_cyt to hypoxia was not related to the resting [Ca²⁺]_cyt. An intrinsic mechanism within each individual cell may be involved in the heterogeneity of hypoxia-mediated effect on [Ca²⁺]_cyt in PASMC. These data suggest that the heterogeneity of PASMC may partially be related to different expression levels and functional sensitivity of Kv channels to hypoxia and to differences in intrinsic mechanisms involved in regulating [Ca²⁺]_cyt.

voltage-gated K⁺ channel; Kv1.5; membrane potential; vascular smooth muscle cells