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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/L1039    most recent 00094.2005v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Knock, G. A. Articles by Aaronson, P. I. Search for Related Content PubMed PubMed Citation Articles by Knock, G. A. Articles by Aaronson, P. I.

Modulation of PGF₂- and hypoxia-induced contraction of rat intrapulmonary artery by p38 MAPK inhibition: a nitric oxide-dependent mechanism

¹Department of Asthma, Allergy and Respiratory Science and ²Cardiovascular Division, School of Medicine, King’s College London, London SE1 9RT, United Kingdom; and King’s College London, ³Smooth Muscle Research Group and Department of Biochemistry & Molecular Biology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada

Submitted 1 March 2005 ; accepted in final form 26 July 2005

The mechanisms through which p38 mitogen-activated protein kinase (p38 MAPK) is involved in smooth muscle contraction remain largely unresolved. We examined the role of p38 MAPK in prostaglandin F₂ (PGF₂)-induced vasoconstriction and in hypoxic pulmonary vasoconstriction (HPV) of rat small intrapulmonary arteries (IPA). The p38 MAPK inhibitors SB-203580 and SB-202190 strongly inhibited PGF₂-induced vasoconstriction, with IC₅₀s of 1.6 and 1.2 µM, whereas the inactive analog SB-202474 was 30-fold less potent. Both transient and sustained phases of HPV were suppressed by SB-203580, but not by SB-202474 (both 2 µM). Western blot analysis revealed that PGF₂ (20 µM) increased phosphorylation of p38 MAPK and of heat shock protein 27 (HSP27), and this was abolished by SB-203580 but not by SB-202474 (both 2 µM). Endothelial denudation or blockade of endothelial nitric oxide (NO) synthase with N-nitro-L-arginine methyl ester (L-NAME) significantly suppressed the relaxation of PGF₂-constricted IPA by SB-203580, but not by SB-202474. Similarly, the inhibition of HPV by SB-203580 was prevented by prior treatment with L-NAME. SB-203580 (2 µM), but not SB-202474, enhanced relaxation-induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP) in endothelium-denuded IPA constricted with PGF₂. In -toxin-permeabilized IPA, SB-203580-induced relaxation occurred in the presence but not the absence of the NO donor sodium nitroprusside (SNP); SB-202474 was without effect even in the presence of SNP. In intact IPA, neither PGF₂- nor SNAP-mediated changes in cytosolic free Ca²⁺ were affected by SB-203580. We conclude that p38 MAPK contributes to PGF₂- and hypoxia-induced constriction of rat IPA primarily by antagonizing the underlying Ca²⁺-desensitizing actions of NO.

p38 mitogen-activated protein kinase; pulmonary artery; prostaglandin F₂; intracellular calcium; calcium sensitization; heat shock protein 27