Suppression of hyperglycemia-induced superoxide formation and endothelin-1 gene expression by carvedilol.
Carvedilol (CV) is a beta-blocker with favorable effects on cardiovascular disease. To determine whether CV can prevent increases in superoxide (SO) production due to hyperglycemia, human umbilical vein endothelial cells (HUVEC) were treated with either 100 or 500 mg/dL dextrose in the presence or absence of 0.1, 1.0, and 10 micromol/L CV. Superoxide levels were measured using the hydroethidine (HE) fluorescence method. Generation of SO was linear from time 0 to 60 minutes. At 60 minutes, the HE fluorescence in cells treated with 500 mg/dL dextrose (123.3+/-4.9 units) was significantly higher than that in control cells treated with 100 mg/dL dextrose (84.0+/-3.5 units) (P<0.002). Addition of 0.1, 1.0, and 10 micromol/L CV to cells treated with 500 mg/dL dextrose decreased SO generated to 113.3+/-1.8, 98.7+/-8.3, and 70.0+/-1.0 units, respectively (P<0.13, P<0.05, and P<0.004, respectively). Cellular endothelin-1 mRNA and endothelin-1 protein secreted in culture media were significantly increased in the presence of 500 mg/dL dextrose. The addition of 10 micromol/L CV significantly decreased both endothelin-1 (1-21) mRNA and protein levels. Measurements of media lactate dehydrogenase activity indicated that CV inhibited cytotoxicity caused by 500 mg/dL dextrose. These findings suggest that CV not only prevents dextrose-induced SO generation in endothelial cells but may also have favorable effects on gene expression and cell survival.
Horani
Mohamad H
MH
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
Haas
Michael J
MJ
Mooradian
Arshag D
AD
D000959:Antihypertensive Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology; D005947:Glucose; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism*
D000959:Antihypertensive Agents; D002227:Carbazoles; D019332:Endothelin-1; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D013481:Superoxides; D005947:Glucose