Sigusch H H, Campbell S E, Weber K T
Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia 65212, USA.
Cardiovasc Res. 1996 Apr;31(4):546-54.
Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain.
We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.).
When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII-treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls.
The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII.
血浆血管紧张素II（AngII）长期升高与血浆大分子外流至血管周围及相邻间质间隙有关。随后出现巨噬细胞以及产生I型胶原蛋白的成纤维样细胞，这些细胞先于这些部位纤维组织的积累出现。血管周围和间质纤维化是AngII对这些细胞胶原蛋白周转的直接作用，还是由一氧化氮、前列腺素和/或因AngII释放的缓激肽介导的间接反应，尚不确定。
我们在雄性Sprague-Dawley大鼠中测量了对14天输注AngII（150 ng/kg/分钟，皮下注射）的血管周围和间质纤维化（苦味酸天狼星染色组织）。将治疗动物与未治疗对照以及接受AngII同时联合一氧化氮合酶抑制剂[NG-硝基-L-精氨酸甲酯（L-NAME），饮用水中10 mg/kg/天]、环氧化酶抑制剂（吲哚美辛，饮用水中2 mg/kg/天）或缓激肽B2受体拮抗剂（Hoe140，115 ng/kg/分钟，皮下注射）的组进行比较。
将治疗大鼠的左心室和右心室与未治疗对照相比，AngII导致血管周围胶原容积分数（PCVF）分别增加68%和48%，间质胶原容积分数（ICVF）分别增加54%和22%。联合给予AngII + L-NAME并未减弱PCVF或ICVF，而吲哚美辛分别使左心室和右心室的PCVF显著减弱37%和33%，但与AngII治疗动物相比，未改变任一心室的ICVF。联合给予AngII + Hoe140完全阻止了血管周围和间质胶原积累，血管周围纤维化程度与未治疗对照相当。
外源性给予AngII时观察到的大鼠左心室和右心室血管周围和间质纤维化是由缓激肽和前列腺素的释放介导的，因此是对循环中AngII升高的间接反应。
