Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.
Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.
Osborne
J A
JA
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Lento
P H
PH
Siegfried
M R
MR
Stahl
G L
GL
Fusman
B
B
Lefer
A M
AM
D000818:Animals; D002319:Cardiovascular System / Q000503:physiopathology*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003327:Coronary Disease / Q000150:complications / Q000503:physiopathology; D003402:Creatine Kinase / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000503:physiopathology*; D007527:Isoenzymes; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D011817:Rabbits
D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D008148:Lovastatin; D003402:Creatine Kinase