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.
In hypertension, blood vessels exhibit increased reactive oxygen species production that may alter vascular tone. We previously observed that H2O2 contracted rat thoracic vena cava under resting tone and aorta contracted with KCl. In arteries but not veins, H2O2-induced contraction required extracellular Ca2+ influx. Because of this difference in Ca2+ utilization, we hypothesized that signaling pathways mediating H2O2-induced contraction in vena cava under resting tone differed from those mediating H2O2-induced contraction in aorta contracted with KCl. Inhibitors of cyclooxygenase (COX) 1 and 2 (indomethacin, 10 microM), thromboxane A2 (TXA2) receptors [ICI185282 (2RS,4RS,5SR-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl heptenoic acid), 10 microM], p38 mitogen-activated protein kinase (MAPK) [SB203580 (4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine), 10 microM], extracellular signal-regulated kinase (Erk) [PD98059 (2'-amino-3'-methoxyflavone), 10 microM], src [PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, 10 microM], and rho kinase [Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride), 10 microM], significantly reduced H2O2-induced contraction in vena cava under resting tone and aorta after KCl (30 mM) contraction. In contrast, the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, 20 microM] did not reduce aortic or venous H2O2-induced contraction. p38 MAPK, Erk MAPK, and src inhibition did not reduce aortic or venous contraction to the TXA2 receptor agonist U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy PGF(2alpha), 1 microM), 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 H2O2 contraction, possibly via rho kinase activation, and that H2O2-induced contraction via p38 and Erk MAPK probably occurs independently of TXA2 receptor activation.
Thakali
Keshari
K
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. thakalik@msu.edu
Davenport
Lauren
L
Fink
Gregory D
GD
Watts
Stephanie W
SW
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013928:Thromboxane A2 / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*; D014684:Venae Cavae / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D054460:rho-Associated Kinases; D019061:src-Family Kinases / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013928:Thromboxane A2; D006861:Hydrogen Peroxide; D011451:Prostaglandin-Endoperoxide Synthases; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases