Published online before print September 11, 2003, doi: 10.1161/01.RES.0000095245.97945.FE
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 13, 2003
Revised on September 2, 2003
Accepted on September 3, 2003
Thromboxane A2-Induced Inhibition of Voltage-Gated K+ Channels and Pulmonary Vasoconstriction. Role of Protein Kinase C
Angel Cogolludo *;
From the Institutes of Pharmacology and Toxicology and Biochemistry (L.B.), School of Medicine, Universidad Complutense, Madrid, Spain.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  M. Xu, O. Platoshyn, A. Makino, W. H. Dillmann, K. Akassoglou, C. V. Remillard, and J. X.-J. Yuan Characterization of agonist-induced vasoconstriction in mouse pulmonary artery Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H220 - H228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moreno, G. Frazziano, A. Cogolludo, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Role of Protein Kinase C{zeta} and Its Adaptor Protein p62 in Voltage-Gated Potassium Channel Modulation in Pulmonary Arteries Mol. Pharmacol., November 1, 2007; 72(5): 1301 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Sampson, L. M. Davies, R. Barrett-Jolley, N. B. Standen, and C. Dart Angiotensin II-activated protein kinase C targets caveolae to inhibit aortic ATP-sensitive potassium channels Cardiovasc Res, October 1, 2007; 76(1): 61 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cogolludo, G. Frazziano, A. M. Briones, L. Cobeno, L. Moreno, F. Lodi, M. Salaices, J. Tamargo, and F. Perez-Vizcaino The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation Cardiovasc Res, January 15, 2007; 73(2): 424 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Blanco-Rivero, A. Sagredo, G. Balfagon, and M. Ferrer Protein kinase C activation increases endothelial nitric oxide release in mesenteric arteries from orchidectomized rats J. Endocrinol., January 1, 2007; 192(1): 189 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wareing, S. L. Greenwood, G. K. Fyfe, and P. N. Baker Reactivity of Human Placental Chorionic Plate Vessels from Pregnancies Complicated by Intrauterine Growth Restriction (IUGR) Biol Reprod, October 1, 2006; 75(4): 518 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Budzyn, M. Paull, P. D. Marley, and C. G. Sobey Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 791 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Snetkov, G. A Knock, L. Baxter, G. D. Thomas, J. P. T. Ward, and P. I. Aaronson Mechanisms of the prostaglandin F2{alpha}-induced rise in [Ca2+]i in rat intrapulmonary arteries J. Physiol., February 15, 2006; 571(1): 147 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hinton, L. Mellow, A. J. Halayko, A. Gutsol, and S. Dakshinamurti Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L375 - L384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ding and P. A. Murray Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L825 - L833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Song, J. E. Jones, H. Beppu, J. F. Keaney Jr, J. Loscalzo, and Y.-Y. Zhang Increased Susceptibility to Pulmonary Hypertension in Heterozygous BMPR2-Mutant Mice Circulation, July 26, 2005; 112(4): 553 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cogolludo, L. Moreno, F. Lodi, J. Tamargo, and F. Perez-Vizcaino Postnatal maturational shift from PKC{zeta} and voltage-gated K+ channels to RhoA/Rho kinase in pulmonary vasoconstriction Cardiovasc Res, April 1, 2005; 66(1): 84 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Kurjiaka, S. B. Bender, D. D. Nye, W. B. Wiehler, and D. G. Welsh Hypertension attenuates cell-to-cell communication in hamster retractor muscle feed arteries Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H861 - H870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. W. Hopf, W. S. Mailliard, G. F. Gonzalez, I. Diamond, and A. Bonci Atypical Protein Kinase C Is a Novel Mediator of Dopamine-Enhanced Firing in Nucleus Accumbens Neurons J. Neurosci., January 26, 2005; 25(4): 985 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moreno, G. Gonzalez-Luis, A. Cogolludo, F. Lodi, A. Lopez-Farre, J. Tamargo, E. Villamor, and F. Perez-Vizcaino Soluble guanylyl cyclase during postnatal porcine pulmonary maturation Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L125 - L130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ding and P. A. Murray Regulation of pulmonary venous tone in response to muscarinic receptor activation Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L131 - L140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Luykenaar, S. E. Brett, B. N. Wu, W. B. Wiehler, and D. G. Welsh Pyrimidine nucleotides suppress KDR currents and depolarize rat cerebral arteries by activating Rho kinase Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1088 - H1100. [Abstract] [Full Text] [PDF]
|
|