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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/H348    most recent 00512.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Wang, Y.-X. Articles by Zhu, Y.-C. Search for Related Content PubMed PubMed Citation Articles by Wang, Y.-X. Articles by Zhu, Y.-C.

Role of PKC in the novel synergistic action of urotensin II and angiotensin II and in urotensin II-induced vasoconstriction

¹Department of Physiology and Pathophysiology, Shanghai Medical College, and ²Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, People's Republic of China; and ³Department of Pharmacology, National University of Singapore, Singapore

Submitted 19 May 2006 ; accepted in final form 25 August 2006

The intracellular signaling of human urotensin II (hU-II) and its interaction with other vasoconstrictors such as ANG II are poorly understood. In endothelium-denuded rat aorta, coadministration of hU-II (1 nM) and ANG II (2 nM) exerted a significant contractile effect that was associated with increased protein kinase C (PKC) activity and phosphorylation of PKC-/II and myosin light chain, whereas either hU-II or ANG II administered alone at these concentrations had no statistically significant effect. This synergistic effect was abrogated by the PKC inhibitor chelerythrine (10 and 30 µM), the selective PKC-/II inhibitor Gö-6976 (0.1 and 1 µM), the hU-II receptor ligand urantide (30 nM and 1 µM), or the ANG II antagonist losartan (1 µM). Moreover, in endothelium-intact rat aorta, the synergistic effect of hU-II and ANG II was not exerted any longer, and this synergistic effect was unmasked by pretreatment of the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester. hU-II (10 nM) alone caused a long-lasting increase in phospho-PKC-, phospho-myosin light chain, and PKC activity, which was associated with long-lasting vasoconstriction. These changes were prevented by chelerythrine. Methoxyverapamil-thapsigargin treatment reduced the hU-II-induced vasoconstriction by 50%. The methoxyverapamil-thapsigargin-resistant component of hU-II-induced vasoconstriction was dose-dependently inhibited by chelerythrine. In conclusion, hU-II induces a novel PKC-dependent synergistic action with ANG II in inducing vasoconstriction. PKC-/II is probably the PKC isoform involved in this synergistic action. Nitric oxide produced in the endothelium probably masks this synergistic action. The long-lasting vasoconstriction induced by hU-II alone is PKC dependent and associated with PKC- phosphorylation.

protein kinase C; vascular smooth muscle cells

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