Effects of pravastatin on cholesterol metabolism of cholesterol-fed heterozygous WHHL rabbits.
1. We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg(-1) body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2. After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quantified by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3. The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no significant differences between the groups. Total plasma levels of lathosterol and campesterol also revealed no significant differences between the groups, if expressed relative to plasma cholesterol. 4. The findings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering effect of pravastatin in this animal model. We propose a reduced cholesterol absorption efficiency compatible with similar campesterol levels between both groups observed in our study.
Harsch
M
M
Institute of Pathology, University of Hamburg, Germany.
Gebhardt
A
A
Reymann
A
A
Lang
G
G
Schliack
M
M
Löser
R
R
Braesen
J H
JH
Niendorf
A
A
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D006579:Heterozygote; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy*; D007150:Immunohistochemistry; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010840:Phytosterols; D016133:Polymerase Chain Reaction; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010840:Phytosterols; D012333:RNA, Messenger; D011973:Receptors, LDL; C021273:campesterol; C001521:lathosterol; D002784:Cholesterol; D017035:Pravastatin