Carvedilol, a new vasodilating beta-adrenoceptor blocker, inhibits oxidation of low-density lipoproteins by vascular smooth muscle cells and prevents leukocyte adhesion to smooth muscle cells.
The present study was undertaken to assess the effect of carvedilol, a new vasodilating beta-adrenoceptor blocker with antioxidant activity, on the oxidation of low-density lipoproteins (LDL) by rat aortic smooth muscle cells (RASMC). LDL oxidation was assessed as thiobarbituric acid reactive substances (TBARS) formation and increase in electrophoretic mobility. Oxidized (ox) LDL-induced cytotoxicity was assessed as lactate dehydrogenase release (LDH) from cells and ox-LDL-enhanced adhesiveness of the RASMC for leukocytes was also determined. Carvedilol inhibited TBARS formation and LDH release from RASMC with IC50 values of 1.74 and 1.62 microM, respectively. Under the same conditions, the IC50 values of probucol and nicardipine were 2.33 and 5.60 microM, respectively, for inhibition of TBARS and 5.16 and 12.10 microM, respectively, for inhibition of LDH release; propranolol, atenolol, pindolol and labetalol, at concentrations up to 100 microM, had virtually no effect on either variable. RASMC-dependent ox-LDL stimulated the adhesive properties of RASMC for both monocytes and neutrophils in a concentration- and time-dependent manner, which were prevented when the RASMC were treated with carvedilol (IC50 2.07 microM for monocytes and 1.12 microM for neutrophils), whereas other beta blockers, at concentrations up to 30 microM, had only mild effects. The monoclonal antirat intercellular adhesion molecule-1 antibody partially inhibited ox-LDL-induced adhesion of RASMC for monocytes and neutrophils. Northern analysis demonstrated that ox-LDL induced intracellular adhesion molecule-1 messenger RNA expression on RASMC, which was inhibited by carvedilol and probucol via inhibition of LDL oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Yue
T L
TL
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Wang
X
X
Gu
J L
JL
Ruffolo
R R
RR
Feuerstein
G Z
GZ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000319:Adrenergic beta-Antagonists; D000911:Antibodies, Monoclonal; D002227:Carbazoles; D008077:Lipoproteins, LDL; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D018799:Intercellular Adhesion Molecule-1