Effects of the selective alpha 1-antagonist, doxazosin, on hepatic lipid levels and metabolism in the golden hamster.
The effect of the selective alpha 1-antagonist, doxazosin, on lipid metabolism was studied in cholesterol-fed golden hamsters. The hamsters were studied after short-term (1 week) and long-term (6-8 weeks) treatment. Doxazosin was added to the food (0.05-0.1%). Doxazosin lowered, within 1 week, plasma cholesterol and triglyceride concentrations by 12 and 19%, respectively. These effects were slightly larger during long-term treatment (cholesterol by 15% and triglycerides by 27%). Lipoprotein lipase (LPL) activity in postheparin plasma or in adipose tissue or heart was affected by doxazosin. The hepatic triglyceride secretion rate was lowered by 40%. Doxazosin treatment partially prevented the accumulation of cholesterol and triglycerides in the liver. Hepatic cholesterol synthesis was decreased by 25-40%. When determined under optimal conditions, i.e., after prior dephosphorylation, the hepatic microsomal HMG-CoA reductase activity was lowered by 10-25% in the doxazosin-treated animals. However, if HMG-CoA reductase was determined under conditions to prevent phosphorylation and dephosphorylation of the enzyme, representing the in situ expressed activity, the activity in the doxazosin-treated animals was 40% lower than in the controls. These results indicate that the plasma lipid-lowering effect of doxazosin is largely due to its interference with hepatic lipid metabolism and that one of the effects is a lowering of hepatic cholesterol synthesis, probably due to an increase in the phosphorylation grade of HMG-CoA reductase.
Jansen
H
H
Department of Biochemistry, Medical Faculty, Erasmus University Rotterdam, The Netherlands.
Birkenhäger
J C
JC
D000317:Adrenergic alpha-Antagonists / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D006224:Cricetinae; D017292:Doxazosin; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008049:Lipase / Q000097:blood; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011224:Prazosin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D014280:Triglycerides; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008049:Lipase; D008071:Lipoprotein Lipase; D017292:Doxazosin; D011224:Prazosin