Comparative effect of ursodeoxycholic acid and calcium antagonists on the binding, uptake and degradation of LDL in isolated hamster hepatocytes.
We have shown that ursodeoxycholic acid (UDCA) stimulates low density lipoprotein (LDL) metabolism (Biochem. J. 280 (1991) 589), as well as calcium mobilization (Am. J. Physiol. 264 (1993) G243) in isolated hepatocytes. Therefore, the effect of UDCA and that of different calcium antagonists on hepatic LDL metabolism was compared. Isolated hamster hepatocytes were incubated at 37 degrees C for 60 min in the presence of 125I-labelled hamster LDL, increasing concentrations (25-100 microM) of verapamil, nifedipine, and diltiazem, respectively, and with or without 700 microM ursodeoxycholic acid (UDCA). At concentrations up to 100 microM, neither verapamil nor nifedipine significantly affected cell associated LDL, but both agents decreased LDL degradation in a dose-dependent manner, with almost total inhibition with 100 microM of either agent. In contrast, 25 microM diltiazem stimulated LDL binding and uptake, with a maximum increase of 15-20% of control, while 50 and 100 microM diltiazem stimulated LDL degradation by 50 and 100%, respectively. UDCA increased native LDL binding and uptake by 20%, and degradation by 50%. None of the agents tested had any effect on the binding, uptake and degradation of methylated LDL. The increased hepatic LDL uptake induced by UDCA was not altered in the presence of calcium antagonists, while the increased degradation of LDL by UDCA was abolished by the addition of 50 microM of either verapamil or nifedipine. However, 100 microM diltiazem and 700 microM UDCA stimulated LDL degradation without any additive effect. These studies show that different calcium antagonists have differential effects on hepatic LDL metabolism. The similarities between the effect of diltiazem and UDCA on LDL metabolism and the absence of any additive effect, suggest that these two agents have a similar mechanism of action, which may involve the integration of both agents into the plasma membrane lipid bilayer.
Bouscarel
B
B
Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
Ceryak
S
S
Fromm
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006224:Cricetinae; D004110:Diltiazem / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008745:Methylation; D009543:Nifedipine / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D014580:Ursodeoxycholic Acid; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine