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  • Title: EXP3174, a metabolite of losartan (MK 954, DuP 753) is more potent than losartan in blocking the angiotensin II-induced responses in vascular smooth muscle cells.
    Author: Sachinidis A, Ko Y, Weisser P, Meyer zu Brickwedde MK, Düsing R, Christian R, Wieczorek AJ, Vetter H.
    Journal: J Hypertens; 1993 Feb; 11(2):155-62. PubMed ID: 8385175.
    Abstract:
    OBJECTIVE: EXP3174 is a metabolite of losartan (previous name DuP753), which is a non-peptide angiotensin II receptor antagonist. DESIGN: The inhibitory potency of these two antagonists on the angiotensin II-induced responses in vascular smooth muscle cells (VSMC) was investigated. METHODS: The effect of angiotensin II on cell growth was determined by [3H]-thymidine incorporation into cell DNA and by cellular protein measurements. Intracellular cytosolic Ca2+ concentration was measured by the fura-2 method. Inositolphosphates were determined by high-performance liquid chromatography after cell labelling with myo-[2-3H]-inositol. The early growth response gene-1 (Egr-1) messenger RNA (mRNA) expression was determined by the Northern blotting method. Binding and displacement studies of the antagonists were performed using [125I]-angiotensin II. RESULTS: An apparent dissociation constant (Kd) of 5.9 nmol/l for [125I]-angiotensin II (maximal binding coefficient 69 fmol/10(6) cells) was found. The specific binding of [125I]-angiotensin II to VSMC was inhibited by losartan, EXP3174 and saralasin with a half-maximal inhibitory concentration (IC50) of 1.0 X 10(-8), 1.1 X 10(-9) and 1.8 X 10(-9) mol/l, respectively. EXP3174 and losartan abolished the angiotensin II-induced formation of inositolphosphates in VSMC. EXP3174 and losartan inhibited the angiotensin II-induced elevation of intracellular cytosolic Ca2+ concentration with an IC50 of 5 X 10(-9) and 5 X 10(-8) mol/l, respectively. EXP3174 was more effective than losartan in blocking the angiotensin II-induced increase in Egr-1 mRNA. EXP3174 and losartan inhibited the angiotensin II-induced cell protein synthesis with an IC50 of 3 X 10(-9) and 4 X 10(-8) mol/l, respectively. CONCLUSIONS: These results indicate that EXP3174 is significantly more potent than losartan in blocking angiotensin II-induced cellular responses.
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