Chronic hydroxymethylglutaryl coenzyme a reductase inhibition and endothelial function of the normocholesterolemic rat: comparison with angiotensin-converting enzyme inhibition.
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors seem to have clinical benefits beyond those predicted by their lipid-lowering action. The objective was to evaluate the vascular effect of long-term treatment with statins on isolated rat aorta and their ability to prevent the acute toxicity of oxidized low-density lipoproteins (oxLDLs) compared with angiotensin-converting enzyme (ACE) inhibitors. Four groups of Wistar rats were treated for 5 weeks. Group 1 received pravastatin 20 mg/kg/d orally; group 2 received atorvastatin 10 mg/kg/d; group 3 received ciprofibrate 25 mg/kg/d; and group 4 served as control. Total cholesterol and triglyceride plasma levels were not altered, except in group 3, in which both parameters were decreased. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in group 1. A significant leftward shift of the concentration-response curves to acetylcholine (1 nM-0.1 mM) was observed in group 1 but the maximal relaxation to acetylcholine was similar in the four groups. In contrast, in the presence of human Cu2+-oxLDL (300 microg/ml, 30 min of preincubation), the maximal relaxation to acetylcholine was markedly decreased (p < 0.02) in groups 3 and 4 versus that of groups 1 and 2. No difference in superoxide accumulation was observed by the chemiluminescence technique. Cyclic guanosine monophosphate (cGMP), measured by enzyme immunoassay in aortic tissues, was increased in group 1 in the presence of superoxide dismutase. Endothelial nitric oxide synthase (eNOS) expression was not altered (Western blot and enzyme-linked immunosorbent assay). In aortas isolated from a fifth group of rats treated with an ACE inhibitor (ramipril 10 mg/kg/d for 6 weeks), similar results to those of group 1 were observed except that the eNOS abundance was significantly enhanced. Thus, long-term statin treatment upregulates the eNOS pathway and attenuates the acute toxicity of human oxLDL. In contrast to chronic ACE inhibition, the eNOS abundance is not increased.
Laboratory of Basic Physiology and Pharmacology, ULB/Free University of Brussels, Boulevard du Triomphe CP205/7, B-1050 Brussels, Belgium. David.Fontaine@ulb.ac.be
David
D
Fontaine
Jeanine
J
Fontaine
Isabelle
I
Dupont
Chantal
C
Dessy
Alina
A
Piech
Yvon
Y
Carpentier
Guy
G
Berkenboom
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D017035:Pravastatin / Q000633:toxicity*; D017257:Ramipril / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D017035:Pravastatin; D017257:Ramipril