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Open Access item Thromboxane A2-Induced Inhibition of Voltage-Gated K+ Channels and Pulmonary Vasoconstriction

Authors:Cogolludo, Angel
Moreno, Laura
Boscá, Lisardo
Tamargo, Juan
Perez-Vizcaino, Francisco
Keywords:K channels, Pulmonary artery, Protein kinase C, Thromboxane A2
Issue Date:3-Oct-2003
Publisher:American Heart Association
Citation:Circulation Research 93(7): 656-663 (2003)
Abstract:Voltage-gated K+ channels (KV) and thromboxane A2 (TXA2) play critical roles in controlling pulmonary arterial tone under physiological and pathological conditions. We hypothesized that TXA2 might inhibit KV channels, thereby establishing a link between these two major pathogenic pathways in pulmonary hypertension. The TXA2 analogue U46619 inhibited IK(V) (Emax=56.1±3.9%, EC50=0.054±0.019 µmol/L) and depolarized pulmonary artery smooth muscle cells via activation of TP receptors. In isolated pulmonary arteries, U46619 simultaneously increased intracellular Ca2+ concentration and contractile force, and these effects were inhibited by nifedipine or KCl (60 mmol/L). U46619-induced contractions were not altered by the inhibitors of tyrosine kinase genistein or Rho kinase Y-27632 but were prevented by the nonselective protein kinase C (PKC) inhibitors staurosporine and calphostin C. Furthermore, these responses were sensitive to Gö-6983 but insensitive to bisindolylmaleimide I and Gö-6976. Based on the specificity of these drugs, we suggested a role for an atypical PKC in U46619-induced effects. Thus, treatment with a PKC{zeta} pseudosubstrate inhibitor markedly prevented the vasoconstriction, the inhibition of IK(V), and the depolarization induced by U46619. Western blots showed a transient translocation of PKC{zeta} from the cytosolic to the particulate fraction on stimulation with U46619. These results indicate that TXA2 inhibits IK(V), leading to depolarization, activation of L-type Ca2+ channels, and vasoconstriction of rat pulmonary arteries. We propose PKC{zeta} as a link between TP receptor activation and KV channel inhibition.
Description:8 pages, 6 figures.
Publisher version (URL):http://dx.doi.org/10.1161/01.RES.0000095245.97945.FE
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