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Protein Kinase C Inhibits Cyclic Adenosine Monophosphate-Induced Calcium-Activated and Voltage-Activated Potassium Channel Activity in Fawn-Hooded Rat Pulmonary Arterial Smooth Muscle Via Phosphodiesterases*

Scott. A. Barman, PhD; Shu Zhu, MD; Mary L. Meadows, BA; Richard. E. White, PhD
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*From the Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA.

Correspondence to: Scott A. Barman, PhD, Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912; e-mail: sbarman@mail.mcg.edu



Chest. 2005;128(6_suppl):576S. doi:10.1378/chest.128.6_suppl.576S
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Signaling mechanisms that elevate cyclic adenosine monophosphate (cAMP) activate large-conductance, calcium-activated and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle and cause pulmonary vasodilatation. BKCa channel modulation is important in the regulation of pulmonary arterial pressure, and the inhibition (closing) of the BKCa channel has been implicated in the development of pulmonary vasoconstriction. Protein kinase C (PKC) causes pulmonary vasoconstriction, but little is known about the effect of PKC on BKCa channel activity in pulmonary arterial smooth muscle. Accordingly, studies were performed to determine the effect of PKC activation on cAMP-induced BKCa channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMCs) of the fawn-hooded rat, which is a recognized animal model of pulmonary hypertension. Forskolin (10 μmol/L), which is a stimulator of adenylate cyclase and an activator of cAMP, opened BKCa channels in single fawn-hooded rat PASMCs that was blocked by a specific PKC isozyme (ie, α, β, δ, γ, or ε) activator thymeleatoxin (100 nmol/L). The inhibitory effect of thymeleatoxin on forskolin-induced BKCa channel activity was blocked by 100 μmol/L IBMX (nonspecific-cAMP and cyclic guanidine monophosphate [cGMP] phosphodiesterase), 10 μmol/L milrinone (type III cGMP phosphodiesterase), and 10 μmol/L zaprinast (type V cGMP phosphodiesterase). Collectively, these results indicate that specific PKC isozymes inhibit cAMP-induced activation of the BKCa channel in PASMCs via phosphodiesterase activity, which suggests a unique signaling pathway to modulate BKCa channels and, subsequently, cAMP-induced pulmonary vasodilation.

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