Involvement of p44/42 mitogen-activated protein kinases in regulating angiotensin II- and endothelin-1-induced contraction of rat thoracic aorta.
In order to elucidate the signal transduction pathway of vascular smooth muscle contraction induced by the activation of receptors for angiotensin II and endothelin-1, we examined whether tyrosine kinases and mitogen-activated protein (MAP) kinases are involved in the development of force of contraction in the rat aorta. Isolated aortic smooth muscles without endothelium were incubated in a modified Krebs-Henseleit solution and stimulated with angiotensin II (100 nM) or endothelin-1 (10 nM). A tyrosine kinase inhibitor genistein (10 microM) reduced the angiotensin II- and endothelin-1-induced aortic contraction, while 10 microM of daidzein (an inactive analogue of genistein) did not. The K(+) depolarization-induced contraction was not attenuated by 10 microM of genistein. Selective inhibitors of MAP kinase/extracellular signal-regulated kinase (Erk) kinase (MEK) such as PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] inhibited the angiotensin II- and endothelin-1-induced vasocontraction. The p44/42 MAP kinases were phosphorylated in cultured aortic smooth muscle cells and in physiologically contracted aortic vessels stimulated with angiotensin II and endothelin-1 for 5 min. The angiotensin II- and endothelin-1-induced phosphorylations of p44/42 MAP kinases were inhibited by PD98059 as well as U0126 in the intact aorta. These results suggest that the activation of genistein-sensitive tyrosine kinases and p44/42 MAP kinases is involved in the angiotensin II- and endothelin-1-induced rat aortic contraction.
Ishihata
Akira
A
Department of Physiology I, Yamagata University School of Medicine, 2-2-2, Iida-Nishi, Japan. ishihata@med.id.yamagata-u.ac.jp
Tasaki
Katsunari
K
Katano
Yumi
Y
D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases