title: Simvastatin inhibits cardiac hypertrophy and angiotensin-converting enzyme activity in rats with aortic stenosis.
abstract: 1. In the present study, we tested the hypothesis that long-term administration of the hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may regress hypertrophy and the possible effect of simvastatin on angiotensin-converting enzyme (ACE) activity in rats with pressure-overload cardiac hypertrophy. 2. Pressure-overload left ventricular hypertrophy (LVH) of rats was induced by part coarctation of the abdominal aorta; a sham-operated group served as the control. Six weeks after operation, animals were divided into three groups and an 8 week treatment period was insitgated as follows: (i) the simvastatin treatment group received simvastatin at 3.6 mg/kg per day, p.o.; (ii) the ACE inhibitor group received captopril at 50 mg/kg per day, p.o.; and (iii) the LVH control group received no drug treatment. 3. At the end of the treatment period, left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were monitored in vivo. Diastolic pressure-volume relationships were evaluated in a Langendorff preparation with a balloon-in-left ventricle (LV) heart. Myocyte cell width was measured. Angiotensin-converting enzyme activity and angiotensin (Ang)II and hydroxyproline contents of the LV were determined. 4. At the end of the experiments, LVH was established in the LVH control group by increases in LV weight, LV weight/body-weight ratio, LV weight/right ventricle weight ratio, LV myocyte cell width, LVSP and LVEDP by 40, 26, 19, 61, 56 and 59%, respectively (all P < 0.01), compared with the sham-operated group. In the simvastatin-treated and ACE inhibitor groups all these parameters were significantly reduced compared with sham-operated controls. In the LVH control group, ACE activity and AngII and hydroxyproline contents of LV tissue increased by 180, 123 and 70, respectively (all P < 0.01), compared with the sham-operated group. Compared with the LVH group, in the simvastatin-treated and ACE inhibitor groups ACE activity was reduced by 36 (P < 0.05) and 48% (P < 0.01), respectively, AngII content was reduced by 11 (P < 0.05) and 43% (P < 0.01), respectively, and hydroxyproline content was reduced by 23 (P < 0.01) and 10% (P < 0.05), respectively. 5. For the first time, the results of the present study demonstrate that simvastatin significantly reduces LVH, cardiac tissue ACE activity and improves LV performance in pressure-overloaded rats. Because, compared with captopril, simvastatin is more potent in its reduction of LVH and less potent in its inhibition of ACE activity, the mechanism of its antihypertrophic action, in addition to ACE inhibition, may involve inhibition of the mevalonic acid pathway, the main target of action of statins. Thus, HMG-CoA reductase inhibitors may be beneficial for the clinical treatment of cardiac hypertrophy.
authors.affiliation: Department of Pharmacology, Guangzhou Medical College, China. joluoa@public.guangzhou.gd.cn
authors.forename: J D
authors.initials: JD
authors.lastname: Luo
authors.forename: W W
authors.initials: WW
authors.lastname: Zhang
authors.forename: G P
authors.initials: GP
authors.lastname: Zhang
authors.forename: J X
authors.initials: JX
authors.lastname: Guan
authors.forename: X
authors.initials: X
authors.lastname: Chen
mesh_terms: D000804:Angiotensin II / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006909:Hydroxyproline / Q000032:analysis; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000804:Angiotensin II; D002216:Captopril; D019821:Simvastatin; D007703:Peptidyl-Dipeptidase A; D006909:Hydroxyproline