ABSTRACT
Objective To investigate the dual pharmacology characteristics of a new structural telmisartan derivative Tek- 1 based on angiotensin II (ANGII) receptor I (AT1) and peroxisome proliferator-activated receptor-γ (PPARγ) and the influence of Tek- 1 on blood pressure in spontaneously hypertensive rats (SHR). Methods The AT1 receptor affinity of Tek- 1 was explored through radioligand binding assay on rat primary vascular smooth muscle cells; the PPARγ agonistic activity of Tek-1 was explored using PPARγ-responsive element-luciferase report assay; the antagonistic effect of Tek-1 on AT1receptor activation induced by ANGII was explored using intracellular calcium mobilization detection assay; the effect of Tek-1 on the regulation of systolic blood pressure (SBP) was evaluated in SHR in vivo. Results Tek-1 and telmisartan had high affinity to AT1 receptor, their Ki values for AT1 receptor were 1.1×10-9 and 2.3×10-10mol/L, respectively. Tek-1 and telmisartan could activate PPARγ ranging from 0.1 to 10 μmol/L in a concentration-dependent manner. The relative lucifarase activity induced by Tek-1 and telmisartan were 1.56±0.08 and 1.39±0.14 fold at 10 μmol/L. Compared with solvent group, the effect of AT1 agonist ANGII were inhibited by Tek-1 in a concentration-dependent manner with IC50 value of 1.02±0.1 nmol/L ranging from 0.0128 to 1 μmol/L. SHR were randomly administered telmisartan (5 or 10 mg/kg) and Tek-1 (1 mg/kg, 5 mg/kg or 10 mg/kg) orally each day for one week every day. After 1-week treatment, compared with the baseline SBP and DBP in the pretreatment of SHR, telmisartan in the dose of 5 and 10 mg/kg both showed significantly decreased SBP (P < 0.01) and DBP (P < 0.05). Tek-1 in the dose of 1, 5 and 10 mg/kg also significantly decreased SBP (P < 0.05); however, only the high dose of 10 mg/kg Tek-1 showed a significant decrease in DBP (P < 0.05). Conclusion Tek-1 Behaveds as an ATI blocker with partial PPARγ agonist activity in vitro and attenuates the blood pressure in SHR in vivo.