Published online before print September 11, 2003, doi: 10.1161/01.RES.0000095245.97945.FE
© 2003 American Heart Association, Inc.
Cellular Biology |
Thromboxane A2-Induced Inhibition of Voltage-Gated K+ Channels and Pulmonary Vasoconstriction
Role of Protein Kinase C
From the Institutes of Pharmacology and Toxicology and Biochemistry (L.B.), School of Medicine, Universidad Complutense, Madrid, Spain.
Correspondence to Angel Cogolludo, PhD, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail acogolludo{at}ift.csic.es
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 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 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 as a link between TP receptor activation and KV channel inhibition.
Key Words: K+ channels • pulmonary artery • protein kinase C • thromboxane A2
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