EXP3174, a metabolite of losartan (MK954, DuP753) is more potent than losartan in blocking the angiotensin ll-induced responses in vascular smooth muscle cells


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Abstract

ObjectiveEXP3174 is a metabolite of losartan (previous name DuP753), which is a non-peptide angiotensin II receptor antagonist.DesignThe inhibitory potency of these two antagonists on the angiotensin ll-induced responses in vascular smooth muscle cells (VSMC) was investigated.MethodsThe effect of angiotensin II on cell growth was determined by PHHhymidine 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 P25l]-angiotensin II.ResultsAn apparent dissociation constant (Kj) of 5.9nmol/l for P25l]-angiotensin II (maximal binding coefficient 69fmol/106 cells) was found. The specific binding of [125l]-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 ll-induced formation of inositolphosphates in VSMC. EXP3174 and losartan inhibited the angiotensin ll-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 ll-induced increase in fgr-1 mRNA. EXP3174 and losartan inhibited the angiotensin ll-induced cell protein synthesis with an IC50 of 3 x 1O˜9 and 4 x 10˜8mol/l, respectively.ConclusionsThese results indicate that EXP3174 is significantly more potent than losartan in blocking angiotensin II–induced cellular responses.

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