title: Combined effects of an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and angiotensin II receptor antagonist on nitric oxide bioavailability and atherosclerotic change in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.
abstract: We investigated the effects of co-administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and angiotensin II type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. A total of 36 myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits equally derived (n=6 per group) were treated with 1) vehicle (control), 2) hydralazine (15 mg/kg/d), 3) the HMG-CoA reductase inhibitor pitavastatin (P: 0.5 mg/kg/d), 4) the ARB valsartan (V: 5 mg/kg/d), and 5) pitavastatin+valsartan (P+V) together without or 6) with N(G)-nitro-L-arginine methyl ester (L-NAME) for 8 weeks. After treatment, acetylcholine (ACh)-induced NO production was measured as a surrogate for endothelium protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured for assessing dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology as well as optical coherence tomography (OCT). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all drug treatments than with the control. P+V increased ACh-induced NO by 4.1 nmol/L significantly more than either P or V singly. The vascular peroxynitrite concentration was 1.6 pmol/mg protein in the control group and significantly less than those in the P- and V-monotherapy-groups. The lowest peroxynitrite concentration was observed in the P+V group (0.4 pmol/mg protein), which was significantly lower than those in the P- and the V-monotherapy-groups. OCT and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy. In conclusion, the combined treatment with an HMG-CoA reductase inhibitor and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.
authors: Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. t-imani@wakayama-med.ac.jp
authors: Toshio
authors: T
authors: Imanishi
authors: Hideyuki
authors: H
authors: Ikejima
authors: Hiroto
authors: H
authors: Tsujioka
authors: Atsushi
authors: A
authors: Tsujioka
authors: Akio
authors: A
authors: Kuroi
authors: Katsunobu
authors: K
authors: Kobayashi
authors: Masashi
authors: M
authors: Shiomi
authors: Yasuteru
authors: Y
authors: Muragaki
authors: Seiichi
authors: S
authors: Mochizuki
authors: Masami
authors: M
authors: Goto
authors: Kiyoshi
authors: K
authors: Yoshida
authors: Takashi
authors: T
authors: Akasaka
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D001682:Biological Availability; D004359:Drug Therapy, Combination; D004452:Echocardiography; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006949:Hyperlipidemias / Q000150:complications*; D009203:Myocardial Infarction / Q000209:etiology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D011804:Quinolines / Q000008:administration & dosage*; D011817:Rabbits; D017382:Reactive Oxygen Species; D013777:Tetrazoles / Q000008:administration & dosage*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D000068756:Valsartan; D014633:Valine; C108475:pitavastatin; D000109:Acetylcholine