LACK OF A CENTRALLY-MEDIATED ANTIHYPERTENSIVE EFFECT FOLLOWING ACUTE OR CHRONIC CENTRAL TREATMENT WITH AT(1)-RECEPTOR ANTAGONISTS IN SPONTANEOUSLY HYPERTENSIVE RATS

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.) infusion s of angiotensin(1) (AT(1)) receptor antagonists. 2 Groups of SHR were chronically instrumented for acute i.c.v. administration of the ATI r eceptor antagonists, losartan and CV-11974, on mean arterial blood pre ssure (MAP) and heart rate (HR). Other groups of SHR also had mini-osm otic pumps implanted for chronic i.c.v. infusion of CV-11974. 3 Initia lly both young (15-18 weeks, n=8) and old (25-29 weeks, n=9) SHR recei ved 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 S HR, MAP and HR did not change up to 24 h after antagonist injection. H owever, changes in MAP and HR in response to i.c.v. angiotensin II (AI I, 100 ng) were abolished 15 min after administration of the AT(1) rec eptor antagonists. These responses had returned to control levels afte r 3 h in both groups given losartan but were still significantly depre ssed 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 res pectively) for 4 days. Baseline cardiovascular parameters were monitor ed 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 k g(-1) day(-1), resting MAP and HR did not vary over the four day infus ion period. However, SHR treated with 100 mu g kg(-1) day(-1) CV-11974 had significantly lower MAP compared to vehicle-treated SHR. While th ere was some variation in resting HR, there were no differences betwee n the drug-treated and vehicle-treated groups. Presser responses follo wing i.c.v. AII administration were slightly, but significantly, inhib ited on days 3 and 4 in the low dose CV-11974-treated (1 mu g kg(-1) d ay(-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-1197 4-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 unaf fected 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 MA P. 5 Collectively, these results indicate that acute and chronic centr al AT(1) receptor antagonism does not lower MAP in conscious SHR in do ses which only block central AII-induced presser activity. Chronic cen tral infusion of CV-11974 at sufficiently high doses will lower MAP, a s has been reported by others, but not without the abolition of the pe ripheral effects of AII. Therefore it is most likely that peripheral A T(1) receptor blockade contributes to the hypotensive action of CV-119 74 under these conditions.