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.
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.
Authors: Michael D Kim; Nathalie Baumlin; Makoto Yoshida; Deepika Polineni; Sebastian F Salathe; Joseph K David; Charles A Peloquin; Adam Wanner; John S Dennis; Juliette Sailland; Philip Whitney; Frank T Horrigan; Juan R Sabater; William M Abraham; Matthias Salathe Journal: Am J Respir Crit Care Med Date: 2020-02-01 Impact factor: 21.405
Authors: Sara Maslanka Figueroa; Daniel Fleischmann; Sebastian Beck; Philipp Tauber; Ralph Witzgall; Frank Schweda; Achim Goepferich Journal: Adv Sci (Weinh) Date: 2020-04-22 Impact factor: 16.806