Simvastatin restores endothelial NO-mediated vasorelaxation in large arteries after myocardial infarction.
Congestive heart failure (CHF) after myocardial infarction is associated with diminished endothelial nitric oxide (NO)-mediated vasorelaxation. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors have been shown to modulate vascular tone independent of the effects on lipid lowering. We hypothesized that simvastatin restores NO-dependent vasorelaxation with CHF. We found that incubation of the normal rat aorta with 0.1 mM simvastatin for 24 h enhanced ACh-mediated vasorelaxation (P < 0.05). Moreover, simvastatin increased (P < 0.05) endothelial NO synthase (eNOS) protein content by >200% (82.0 +/- 14.0 vs. 21.6 +/- 7.9% II/microg). In cultured endothelial cells, simvastatin (10 and 20 microM) increased eNOS levels by 114.7 +/- 39.9 and 212.0 +/- 75.0% II/microg protein, respectively (both P < 0.05; n = 8). In the rat coronary artery ligation model, oral gavage with 20 mg. kg(-1). day(-1) simvastatin for 3 wk decreased (P < 0.05) mean arterial pressure (121 +/- 20 vs. 96.5 +/- 10.8 mmHg) and left ventricular change in pressure with time (4,500 +/- 700 vs. 4,091 +/- 1,064 mmHg/s, n = 6). Simvastatin reduced (P < 0.05) basal vasoconstriction and improved ACh-mediated vasorelaxation in CHF arterial rings. Inhibition of NO generation by N(G)-nitro-L-arginine methyl ester (100 microM) abolished the ACh-induced vasorelaxation in all rats. In conclusion, chronic treatment of CHF with simvastatin restores endothelial NO-dependent dysfunction and upregulates eNOS protein content in arterial tissue.
Cardiology Section, Southern Arizona Veterans Administration Health Care System, Tucson, AZ 85723, USA.
Kathryn
K
Bates
Charles E
CE
Ruggeroli
Steven
S
Goldman
Mohamed A
MA
Gaballa
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology*; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000150:complications*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation; D014666:Vasomotor System / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat