Blocking Hypothalamic Al\ Receptors Lowers Blood Pressure in Salt-Sensitive Rats

Previous studies from our laboratory have shown that microinjection of DuP 753 (2-n-butyl-4-chloro-5(hydroxymethyl)-l-[[2'-(lH-tetrazol-5-yl)biphenyi-4-yi]methyl]Imidazole, potassium salt), a highly selective nonpeptide antagonist of type 1 angiotensin II receptors, into the anterior hypothalamic area produces a dose-related depressor response in salt-sensitive spontaneously hypertensive rats fed a basal (1%) salt diet. The current study tested the hypothesis that the depressor response to anterior hypothalamic type 1 angiotensin II receptor blockade with DuP 753 or its metabolite EXP 3174 is enhanced by high (8%) salt feeding in this model. DuP 753 or EXP 3174 (40 /tg in 100 nl artificial cerebrospinal fluid vehicle) or vehicle alone was microinjected into the anterior hypothalamic area of conscious salt-sensitive spontaneously hypertensive and Wistar-Kyoto rats that had been fed 1% or 8% salt diets for 3 weeks. Both DuP 753 and EXP 3174 caused significant decreases in mean arterial pressure in spontaneously hypertensive but not in Wistar-Kyoto rats fed either diet. The magnitude and duration of the depressor responses to DuP 753 and EXP 3174 were significantly greater in the 8% salt-fed spontaneously hypertensive rats than in 1% salt-fed rats. Vehicle injections had no effect on blood pressure in either strain-diet group. Microinjection of angiotensin n (2 /tg in 100 nl artificial cerebrospinal fluid vehicle) into the anterior hypothalamic area caused significant pressor and bradycardic responses in all strain-diet groups; dietary salt supplementation enhanced these effects in salt-sensitive spontaneously hypertensive rats but not in Wistar-Kyoto rats. These responses were blocked by pretreatment with EXP 3174. These findings suggest that endogenous angiotensin II and type 1 angiotensin II receptors in the anterior hypothalamic area may be involved in the pathogenesis of salt-sensitive hypertension in this model. (Hypertension 1992^20:755-762)