Participation of kinins in the captopril-induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

被引:15
作者
Emanueli, C
Salis, MB
Figueroa, C
Chao, J
Chao, L
Gaspa, L
Capogrossi, MC
Madeddu, P [1 ]
机构
[1] Natl Inst Biostruct & Biosyst, Natl Lab, Gene Therapy Sect, Sassari, Italy
[2] IRCCS, IDI, Lab Patol Vasc, Rome, Italy
[3] Univ Sassari, Sch Med, Inst Internal Med, I-07100 Sassari, Italy
[4] Univ Austral Chile, Ist Histol & Patol, Valdivia, Chile
[5] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
关键词
intimal hyperplasia; angiotensin converting enzyme inhibitors; kinins; receptor antagonists; nitric oxide; knockout mice;
D O I
10.1038/sj.bjp.0703388
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 In the rat balloon injury model, angiotensin-converting enzyme (ACE) inhibitors prevent vascular remodelling by inhibiting angiotensin II generation and kinin breakdown. We investigated if ACE inhibition also prevents the structural vascular responses to disruption of carotid artery blood flow and if kinin potentiation plays a role in such a protection. 2 Morphometric analysis of the structural alterations caused by ligation of the left carotid artery was performed 14 days after surgery in J129Sv wild-type mice (B-2(+/+)) drinking normal tap water or water containing captopril (120 mg kg(-1) per day). In addition, the effect of captopril on vascular remodelling was tested in B-2(+/+) given the bradykinin (BK) BI receptor antagonist des-Arg(9)-[Leu(8)]BK (DALBK. 50 nmol kg(-1) per day, intraperitoneally) or the BK B-2 receptor antagonist D-Arg,[Hyp(3),Thi(5)D-Tic(7),Oic(8)]-BK (icatibant, 1 mu mol kg(-1) per day, intraperitoneally), and in Bz receptor gene knockout mice (B2(-/-)) 3 Interruption of blood flow resulted in carotid artery intimal hyperplasia and media thickening in untreated B-2(+/+), these responses being partially suppressed by captopril. The inhibition of intimal thickening exerted by captopril was reduced in B-2(+/+) given DALBK or icatibant (P<0.05 for both comparisons) as well as in B-2(-/-) (P < 0.05). Neither antagonism of kinin receptors nor disruption of the B-2 receptor gene altered the suppressive effect of captopril on media thickening. The protection of vascular wall structure was independent of the reduction in blood pressure by captopril. 4 These results demonstrate that kinins participate in the inhibitory effect of captopril on intimal hyperplasia via B-1 and B-2 receptor signalling. Our findings may have important implications in treating vascular remodelling evoked by altered sheer stress conditions.
引用
收藏
页码:1076 / 1082
页数:7
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