Lack of a centrally-mediated antihypertensive effect following acute or chronic central treatment with AT(1)-receptor antagonists in spontaneously hypertensive rats

被引:21
作者
Bunting, MW [1 ]
Widdop, RE [1 ]
机构
[1] MONASH UNIV, DEPT PHARMACOL, CLAYTON, VIC 3168, AUSTRALIA
关键词
CV-11974; losartan; brain renin-angiotensin system; hypertension; spontaneously hypertensive rats;
D O I
10.1111/j.1476-5381.1995.tb15122.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The role of the central renin-angiotensin system in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR) was examined following acute and chronic intracerebroventricular (i.c.v.) infusions of angiotensin(1) (AT(1)) receptor antagonists. 2 Groups of SHR were chronically instrumented for acute i.c.v. administration of the ATI receptor antagonists, losartan and CV-11974, on mean arterial blood pressure (MAP) and heart rate (HR). Other groups of SHR also had mini-osmotic pumps implanted for chronic i.c.v. infusion of CV-11974. 3 Initially both young (15-18 weeks, n=8) and old (25-29 weeks, n=9) SHR received acute i.c.v. injections of losartan (10 mu g) while a third group of young SHR received CV-11974 (1 mu g, n=6). In all three groups of SHR, MAP and HR did not change up to 24 h after antagonist injection. However, changes in MAP and HR in response to i.c.v. angiotensin II (AII, 100 ng) were abolished 15 min after administration of the AT(1) receptor antagonists. These responses had returned to control levels after 3 h in both groups given losartan but were still significantly depressed at 24 h in the CV-11974-treated group. By contrast, responses to i.v. AII (25 ng) before and 1 h after administration of AT(1) receptor antagonists were not significantly different. 4 For chronic studies, four groups of SHR received chronic i.c.v. infusion of either vehicle (n=9) or CV-11974 (1, 5 and 100 mu g kg(-1) day(-1)) (n=4, 7 and 8 respectively) for 4 days. Baseline cardiovascular parameters were monitored daily together with changes in MAP and HR in response to both i.c.v. and i.v. AII (100 ng and 50 ng respectively) and i.v. phenylephrine (3 mu g). Responses to i.c.v. carbachol (5 mu g) were also recorded on day 4 while baroreflex function was assessed between days 1-3. In SHR treated chronically with i.c.v. vehicle or CV-11974, at 1 or 5 mu g kg(-1) day(-1), resting MAP and HR did not vary over the four day infusion period. However, SHR treated with 100 mu g kg(-1) day(-1) CV-11974 had significantly lower MAP compared to vehicle-treated SHR. While there was some variation in resting HR, there were no differences between the drug-treated and vehicle-treated groups. Presser responses following i.c.v. AII administration were slightly, but significantly, inhibited on days 3 and 4 in the low dose CV-11974-treated (1 mu g kg(-1) day(-1)) SHR. However, these responses were abolished on all 4 days in the 5 and 100 mu g kg(-1) day(-1) CV-11974-treated groups. By contrast, changes in MAP and HR following i.v. AII injection did not vary over the 4 day infusion between SHR treated with the 2 lowest doses of CV-11974 and the vehicle-treated group. However, in the high dose CV-11974-treated SHR (100 mu g kg(-1) day(-1)), the cardiovascular effects of AII were abolished. In addition, phenylephrine (i.v.) and carbachol (i.c.v.) induced changes in MAP and HR were not significantly different in all four treatment groups. Similarly, baroreflex function was unaffected by i.c.v. infusion of 100 mu g kg(-1) day(-1) CV-11974, except for a significant fall in BPS, which paralleled the fall in resting MAP. 5 Collectively, these results indicate that acute and chronic central AT(1) receptor antagonism does not lower MAP in conscious SHR in doses which only block central AII-induced presser activity. Chronic central infusion of CV-11974 at sufficiently high doses will lower MAP, as has been reported by others, but not without the abolition of the peripheral effects of AII. Therefore it is most likely that peripheral AT(1) receptor blockade contributes to the hypotensive action of CV-11974 under these conditions.
引用
收藏
页码:3181 / 3190
页数:10
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