The biological activity of endothelins (ETs) in non-innervated Synbranchus marmoratus melanophores was demonstrated. These peptides induced a dose-dependent pigment aggregation (lightening skin) in these cells. However, they presented EC50's (effective concentration required to produce 50% of response) 26, 106 and 35 times higher than, respectively, the melanin concentrating hormone (MCH) EC50, and exhibited a characteristic temporal and dose-dependent autodessensibilization of the aggregative effect on the melanophores of this fish. The receptor characterization suggested the presence of the ET(B) subtype, since BQ-788 (selective antagonist of ET(B)) but not BQ-485 (selective antagonist of ET(A)) blocked the aggregative effect of the hormones. Confirming these data, sarafotoxin (SRTX) S6c, a toxin selective for ET(B), induced maximal aggregation of pigment granules. S6c presented an EC50 6.8 times higher than the MCH EC50, and 3.9, 15.6 and 5.1 times lower than the EC50's ETs, respectively. The melanotropic effect of SRTX S6b and vasoactive intestinal contractor (VIC) were demonstrated for the first time in this work. SRTX S6b induced a dose-dependent pigment aggregation and presented an EC50 2.54 and 17.2 times higher than the S6c and MCH EC50's, respectively. Compared to the ETs it was 1.53, 6.19 and 2.03 times lower, respectively.

2005-01-01·Journal of Biomedical Science2区 · 医学

Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy

2区 · 医学

ArticleOA

作者: J. J. Chen ; Neng Lang Shih ; Jer Young Liou ; Yen Ling Chen ; Yee Shiuan Chen ; Hsing Wen Tsai ; Cheng-Hsien Chen ; Heng Lin ; Ju-Chi Liu ; Ching Feng Cheng ; Hung Hsing Chao ; Tzu-Hurng Cheng

Endothelin-1 (ET-1) has been found to increase cardiac beta-myosin heavy chain (beta-MyHC) gene expression and induce hypertrophy in cardiomyocytes. ET-1 has been demonstrated to increase intracellular reactive oxygen species (ROS) in cardiomyocytes. The exact molecular mechanism by which ROS regulate ET-1-induced beta-MyHC gene expression and hypertrophy in cardiomyocytes, however, has not yet been fully described. We aim to elucidate the molecular regulatory mechanism of ROS on ET-1-induced beta-MyHC gene expression and hypertrophic signaling in neonatal rat cardiomyocytes. Following stimulation with ET-1, cultured neonatal rat cardiomyocytes were examined for 3H-leucine incorporation and beta-MyHC promoter activities. The effects of antioxidant pretreatment on ET-1-induced cardiac hypertrophy and mitogen-activated protein kinase (MAPKs) phosphorylation were studied to elucidate the redox-sensitive pathway in cardiomyocyte hypertrophy and beta-MyHC gene expression. ET-1 increased 3H-leucine incorporation and beta-MyHC promoter activities, which were blocked by the specific ET(A) receptor antagonist BQ-485. Antioxidants significantly reduced ET-1-induced 3H-leucine incorporation, beta-MyHC gene promoter activities and MAPK (extracellular signal-regulated kinase, p38, and c-Jun NH2 -terminal kinase) phosphorylation. Both PD98059 and SB203580 inhibited ET-1-increased 3H-leucine incorporation and beta-MyHC promoter activities. Co-transfection of the dominant negative mutant of Ras, Raf, and MEK1 decreased the ET-1-induced beta-MyHC promoter activities, suggesting that the Ras-Raf-MAPK pathway is required for ET-1 action. Truncation analysis of the beta-MyHC gene promoter showed that the activator protein-2 (AP-2)/specificity protein-1 (SP-1) binding site(s) were(was) important cis-element(s) in ET-1-induced beta-MyHC gene expression. Moreover, ET-1-induced AP-2 and SP-1 binding activities were also inhibited by antioxidant. These data demonstrate the involvement of ROS in ET-1-induced hypertrophic responses and beta-MyHC expression. ROS mediate ET-1-induced activation of MAPK pathways, which culminates in hypertrophic responses and beta-MyHC expression.

2004-07-01·Journal of Trauma: Injury, Infection & Critical Care

Hemostasis in the Absence of Clotting Factors

Article

作者: Hechtman, Herbert B. ; Favuzza, Joanne

BACKGROUNDThis study tests whether the hemostatic action of poly-N-acetyl glucosamine (p-GlcNAc) fiber material involves vasoconstrictor release leading to closure of an aortic laceration.METHODSA 22-gauge cannula was inserted into an infrarenal aortic segment of a rat. Surrounding ligatures were tied, and the aorta was flushed with 60 mL of saline from a reservoir held at 80 cm. A 23-gauge aortic puncture was made. The time taken to empty the reservoir was recorded.RESULTSControl patches led to an emptying time of 295 seconds, whereas p-GlcNAc patches increased this time to greater than 600 seconds. Ten minutes after patch removal, the emptying time decreased to 330 seconds. The rats were treated intravenously with endothelin receptor antagonists BQ-485 or JKC-301. The emptying time shortened to control values, despite the use of the p-GlcNAc fiber-based patch.CONCLUSIONThe mechanism of hemostasis by poly-N-acetyl glucosamine involves endothelin release independent of formed elements of blood.

100 项与 BQ-485 相关的药物交易

登录后查看更多信息