Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes.
We investigated whether aliskiren, a direct renin inhibitor, improves NO bioavailability and protects against spontaneous atherosclerotic changes. We also examined the effects of cotreatment with aliskiren and valsartan, an angiotensin II receptor blocker, on the above-mentioned outcomes. Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), aliskiren, valsartan, or aliskiren plus valsartan for 8 weeks. Then, acetylcholine-induced NO production was measured as a surrogate index of endothelium protective function, and both superoxide and vascular peroxynitrite were measured. Tetrahydrobiopterin in aortic segments was assessed by high-performance liquid chromatography with fluorescence detection. Plaque area was quantified by histology. Increase in plasma NO concentration in response to intra-aortic acetylcholine infusion was significantly greater in all of the test groups than in controls. Aliskiren+valsartan cotreatment increased acetylcholine-induced NO by 6.2 nmol/L, which was significantly higher than that with either aliskiren or valsartan alone. Vascular superoxide and peroxynitrite levels were both significantly higher in controls and significantly lower in the aliskiren+valsartan group than in the aliskiren or valsartan group. The highest tetrahydrobiopterin levels were observed after aliskiren+valsartan cotreatment. Histology of the thoracic aorta revealed that the plaque area was significantly decreased with combination therapy compared with monotherapy. Treatment with a direct renin inhibitor has protective effects on endothelial function and atherosclerotic changes. Furthermore, cotreatment with a direct renin inhibitor and an angiotensin II receptor blocker has additive protective effects on both.
Imanishi
Toshio
T
Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama City, Wakayama, Japan. t-imani@wakayama-med.ac.jp
Tsujioka
Hiroto
H
Ikejima
Hideyuki
H
Kuroi
Akio
A
Takarada
Shigeho
S
Kitabata
Hironori
H
Tanimoto
Takashi
T
Muragaki
Yasuteru
Y
Mochizuki
Seiichi
S
Goto
Masami
M
Yoshida
Kiyoshi
K
Akasaka
Takashi
T
D000109:Acetylcholine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000092502:Renin Inhibitors
D000109:Acetylcholine; D000577:Amides; D000959:Antihypertensive Agents; D001708:Biopterins; D005650:Fumarates; D018841:HSP90 Heat-Shock Proteins; D018836:Inflammation Mediators; D008055:Lipids; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin; D013777:Tetrazoles; D014443:Tyrosine; D014633:Valine; D000068756:Valsartan; D014665:Vasodilator Agents; D000092502:Renin Inhibitors; C002744:3-nitrotyrosine; C446481:aliskiren; C003402:sapropterin