Deficiency in the Functional Activity of BK Channels Leads to Systemic, But Not Pulmonary, Hypertension

Abstract

Big-conductance, Ca2+-activated K+ (BK) channels are important for the control of vascular tone in systemic arteries (SAs). Pulmonary arteries (PAs) are very different in many aspects from SAs. Thus, this study was designed to determine whether BK channels may show functional differences in these two distinct circulation systems. Our data reveal that deficiency in BK channels by targeted gene deletion of the channel β1 subunits leads to the significantly elevated systemic, but not pulmonary, blood pressure. Using patch clamp recordings, we have found that the activity of whole-cell and single BK channels are significantly higher in systemic (cerebral) artery smooth muscle cells (SASMCs) than in PASMCs. Similarly, the voltage and Ca2+ sensitivity of BK channels are higher in SASMCs than in PASMCs. Real-time RT-PCR and Western blotting experiments revealed that BK channel α subunit mRNA and protein expression were comparable in CASMCs and PASMCs; β1 subunit protein, but not its mRNA, expression is higher in SASMCs than in PASMCs. Pharmacological inhibition of BK channels diminished norepinephrine-induced increase in [Ca2+]i in SASMCs, but not in PASMCs. In summary, these findings provide the first evidence that the activity of BK channels is higher in systemic (cerebral) than in pulmonary artery SMCs. This heterogeneity is primarily determined by the differential functions and molecular expression of β1 subunits. Moreover, pharmacological and genetic data further verify the importance of heterogeneous functions of β1 subunits in the regulation of cellular responses and blood pressure in systemic and pulmonary circulation systems.