title: Effects of angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist combination on nitric oxide bioavailability and atherosclerotic change in Watanabe heritable hyperlipidemic rabbits.
abstract: We investigated the effects of co-administration of an angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. Plasma NO was measured using the new NO sensor in the abdominal aorta of anesthetized Watanabe heritable hyperlipidemic (WHHL) rabbits. Acetylcholine (ACh)-stimulated (20 microg in 5 min into the aortic arch) NO production was recorded after an 8 week per os pretreatment with 1) vehicle (control), 2) the ACEI enalapril (E: 3 mg/kg/day), 3) the ARB losartan (L: 30 mg/kg/day) and 4) enalapril (1.5 mg/kg/day)+losartan (15 mg/kg/day) (E+L). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all the drug treatments than with the control. E increased ACh-induced NO significantly more than L (by 6.9 nmol/L, and 4.7 nmol/L, respectively). E+L increased ACh-induced NO by 9.5 nmol/L, significantly more than either E or L. Plasma peroxynitrite concentration was 1.2 pmol/mg protein in the control group and significantly less than in the E- and L-group. The lowest peroxynitrite concentration was observed in the E+L group (0.5 pmol/mg protein), which was significantly lower than in the E-group and the L-group. Optical coherence tomography and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy (p<0.01). In conclusion, the combined treatment with an ACEI and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.
authors.affiliation: Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. t-imani@wakayama-med.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Imanishi
authors.forename: Akio
authors.initials: A
authors.lastname: Kuroi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikejima
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Masami
authors.initials: M
authors.lastname: Goto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasaka
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006949:Hyperlipidemias / Q000235:genetics* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000097:blood; D011817:Rabbits; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D014665:Vasodilator Agents; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D004656:Enalapril; D019808:Losartan; D000109:Acetylcholine