Blocking hypothalamic AT1 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)-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]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 micrograms 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 II (2 micrograms in 100 nl artificial cerebrospinal fluid vehicle) into the anterior hypothalamic area caused significant pressor and bradycardiac 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Yang
R H
RH
Department of Medicine, University of Alabama, Birmingham 35294.
Jin
H
H
Chen
S J
SJ
Wyss
J M
JM
Oparil
S
S
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000378:metabolism* / Q000502:physiology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004032:Diet; D006339:Heart Rate / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008845:Microinjections; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D012965:Sodium Chloride; C066026:losartan carboxylic acid; D019808:Losartan