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.
Fontaine
David
D
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
Fontaine
Jeanine
J
Dupont
Isabelle
I
Dessy
Chantal
C
Piech
Alina
A
Carpentier
Yvon
Y
Berkenboom
Guy
G
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