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Abstract-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. 3,4 Previous reports have shown that ET-1 induces a sustained contraction, which results from the increase of [Ca 2ϩ ] i in isolated vascular smooth muscle. 5,6 In addition to the [Ca 2ϩ ] i -MLC kinase pathway, a number of intracellular signal molecules, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol 3 kinase (PI3K), and Rho kinase, play important roles in the regulation of smooth muscle contraction. 4,7-10 ET-1 can also stimulate these kinases.MAPK is a family of serine/threonine-specific protein kinase, consisting of three isoforms: extracellular signalregulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). 11,12 MAPK plays a central role in intracellular signal transduction initiated by extracellular stimuli, including growth factors, neurotransmitters, and hormones. 13,14 ERK1/2 is activated by receptor agonists, including angiotensin II and phenylephrine, which induce smooth muscle contraction. 15,16 ET-1 also increases the activity of ERK1/2 in vascular smooth muscle. [17][18][19] There is accumulating evidence that the MAPK pathway is closely linked to modulating the intensity of contraction in vascular smooth muscle. 15,20 -23 Moreover, the inhibition of p...