Cyclooxygenase,p38 Mitogen-Activated Protein Kinase (MAPK),Extracellular Signal-Regulated Kinase MAPK,Rho Kinase,and Src Mediate Hydrogen Peroxide-Induced Contraction of Rat Thoracic Aorta and Vena Cava

摘要

In hypertension,blood vessels exhibit increased reactive oxygen species production that may alter vascular tone.We previously observed that H_2O_2 contracted rat thoracic vena cava under resting tone and aorta contracted with KCI.In arteries but not veins,H_2O_2-induced contraction required extracellular Ca~(2+) influx.Because of this difference in Ca~(2+) utilization,we hypothesized that signaling pathways mediating H_2O_2-induced contraction in vena cava under resting tone differed from those mediating H_2O_2-induced contraction in aorta contracted with KCI.Inhibitors of cyclooxygenase (COX) 1 and 2 (indomethacin,10 mu M),thromboxane A_2 (TXA_2) receptors [ICI185282 (2RS,4RS,5SR-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-diox-an-5-yl heptenoic acid),10 mu M],p38 mitogen-activated protein kinase (MAPK) [SB203580 (4-[5-(4-fluorophenyl)-2-[4-(methyl-sulfonyl)phenyl]-1H-imidazol-4-yl]pyridine),10 mu M],extracellular signal-regulated kinase (Erk) [PD98059 (2'-amino-3'-me-thoxyflavone),10 mu M],src [PP1 (4-amino-5-(4-methylphenyl)-7-(f-butyl)pyrazolo[3,4-d]pyrimidine,10 mu M),and rho kinase [Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohex-anecarboxamide dihydrochloride),10 mu M],significantly reduced H_2O_2-induced contraction in vena cava under resting tone and aorta after KCI (30 mM) contraction.In contrast,the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one,20 mu M] did not reduce aortic or venous H_2O_2-induced contraction.p38 MAPK,Erk MAPK,and src inhibition did not reduce aortic or venous contraction to the TXA_2 receptor agonist U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy PGF_(2 alpha),1 mu M),whereas rho kinase inhibition significantly reduced aortic and venous contraction to U46619,and PI3-K inhibition reduced venous contraction to U46619.Our data suggest that,in rat thoracic aorta and vena cava,a COX-derived metabolite is one important mediator of H_2O_2 contraction,possibly via rho kinase activation,and that H_2O_2-induced contraction via p38 and Erk MAPK probably occurs independently of TXA_2 receptor activation.