p38 mitogen-activated protein kinase contributes to the diminished aortic contraction by endothelin-1 in DOCA-salt hypertensive rats.
We investigated whether the diminished contractile responsiveness to endothelin-1 (ET-1) is associated with the altered activation of mitogen-activated protein kinase (MAPK) in aortic smooth muscles from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. ET-1 dose-dependently increased contractions in aortic smooth muscle strips, and the contractions were significantly attenuated in tissues from DOCA-salt hypertensive rats compared with those from sham-operated rats. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was elevated by ET-1, with the magnitude and time-course being similar between strips. Although ET-1 also increased the phosphorylation of p38 MAPK in both strips, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. 5-hydroxytryptamine (5-HT) increased vascular contraction and phosphorylation of both MAPK isoforms; these were greater in DOCA-salt hypertensive rats than in sham-operated rats. ET-1 also increased the phosphorylation of caldesmon, an actin-binding protein, in sham-operated and DOCA-salt hypertensive rats. However, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. The phosphorylation of MAPK isoforms and caldesmon elevated by ET-1 was inhibited by PD098059, an inhibitor of ERK1/2 kinase, and SB203580, an inhibitor of p38 MAPK, respectively. These results suggest that ET-1 and 5-HT induce contraction by activating the MAPK pathway in rat aortic smooth muscle and that the diminished responsiveness to ET-1 in the DOCA-salt hypertensive rat may be, in part, mediated by the decrease of caldesmon phosphorylation after the decreased activation of p38 MAPK.
Kim
Bokyung
B
Department of Physiology, College of Medicine, Konkuk University, Choongju, Korea.
Kim
Junghwan
J
Bae
Young M
YM
Cho
Sung I
SI
Kwon
Seong C
SC
Jung
Jin Y
JY
Park
Jung-C
JC
Ahn
Hee Y
HY
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D003900:Desoxycorticosterone / Q000633:toxicity; D019332:Endothelin-1 / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014661:Vasoconstriction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D002148:Calmodulin-Binding Proteins; D019332:Endothelin-1; D005419:Flavonoids; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D017673:Sodium Chloride, Dietary; D012701:Serotonin; D003900:Desoxycorticosterone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one