Modulation of PGF(2 alpha)- and hypoxia-induced contraction of rat intrapulmonary artery by p38 MAPK inhibition: a nitric oxide-dependent mechanism

TY - JOUR

T1 - Modulation of PGF(2 alpha)- and hypoxia-induced contraction of rat intrapulmonary artery by p38 MAPK inhibition: a nitric oxide-dependent mechanism

AU - Knock, G A

AU - De Silva, A S

AU - Snetkov, V A

AU - Siow, R

AU - Thomas, G D

AU - Shiraishi, M

AU - Walsh, M P

AU - Ward, J P T

AU - Aaronson, P I

PY - 2005/12

Y1 - 2005/12

N2 - 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 F-2 alpha (PGF(2 alpha))-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 PGF(2 alpha)-induced vasoconstriction, with IC(50)s of 1.6 and 1.2 mu M, whereas the inactive analog SB-202474 was similar to 30- fold less potent. Both transient and sustained phases of HPV were suppressed by SB-203580, but not by SB-202474 (both 2 mu M). Western blot analysis revealed that PGF(2 alpha) (20 mu M) 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 mu M). Endothelial denudation or blockade of endothelial nitric oxide (NO) synthase with N-omega-nitro-L-arginine methyl ester (L-NAME) significantly suppressed the relaxation of PGF(2 alpha)-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 mu M), but not SB-202474, enhanced relaxation-induced by the NO donor S-nitroso-N- acetylpenicillamine (SNAP) in endothelium-denuded IPA constricted with PGF(2 alpha). In alpha-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 PGF(2 alpha)- nor SNAP-mediated changes in cytosolic free Ca2+ were affected by SB-203580. We conclude that p38 MAPK contributes to PGF(2 alpha)- and hypoxia-induced constriction of rat IPA primarily by antagonizing the underlying Ca2+-desensitizing actions of NO

AB - 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 F-2 alpha (PGF(2 alpha))-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 PGF(2 alpha)-induced vasoconstriction, with IC(50)s of 1.6 and 1.2 mu M, whereas the inactive analog SB-202474 was similar to 30- fold less potent. Both transient and sustained phases of HPV were suppressed by SB-203580, but not by SB-202474 (both 2 mu M). Western blot analysis revealed that PGF(2 alpha) (20 mu M) 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 mu M). Endothelial denudation or blockade of endothelial nitric oxide (NO) synthase with N-omega-nitro-L-arginine methyl ester (L-NAME) significantly suppressed the relaxation of PGF(2 alpha)-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 mu M), but not SB-202474, enhanced relaxation-induced by the NO donor S-nitroso-N- acetylpenicillamine (SNAP) in endothelium-denuded IPA constricted with PGF(2 alpha). In alpha-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 PGF(2 alpha)- nor SNAP-mediated changes in cytosolic free Ca2+ were affected by SB-203580. We conclude that p38 MAPK contributes to PGF(2 alpha)- and hypoxia-induced constriction of rat IPA primarily by antagonizing the underlying Ca2+-desensitizing actions of NO

U2 - 10.1152/ajplung.00094.2005

DO - 10.1152/ajplung.00094.2005

M3 - Article

VL - 289

SP - L1039 - L1048

JO - AMERICAN JOURNAL OF PHYSIOLOGY: LUNG CELLULAR AND MOLECULAR PHYSIOLOGY

JF - AMERICAN JOURNAL OF PHYSIOLOGY: LUNG CELLULAR AND MOLECULAR PHYSIOLOGY

IS - 6

ER -