Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury.
To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
Chen
Rui
R
Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan.
Iwai
Masaru
M
Wu
Lan
L
Suzuki
Jun
J
Min
Li-Juan
LJ
Shiuchi
Tetsuya
T
Sugaya
Takashi
T
Liu
Hong-Wei
HW
Cui
Tai-Xing
TX
Horiuchi
Masatsugu
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D065168:Bradykinin Receptor Antagonists; D002455:Cell Division; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003250:Constriction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C065166:imidapril; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester