Takanobu Takezako1,2, Hamiyet Unal3, Sadashiva S Karnik3, Koichi Node4. 1. Department of Advanced Heart Research, Saga University, Saga, Japan. 2. Department of Internal Medicine, Nadeshiko Lady's Hospital, Kobe, Japan. 3. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. 4. Department of Cardiovascular Medicine, Saga University, Saga, Japan.
Abstract
BACKGROUND AND PURPOSE: Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT1 receptors is necessary. EXPERIMENTAL APPROACH: To identify the robust inverse agonist for active state of AT1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT1 receptors and active-state N111G mutant AT1 receptors. KEY RESULTS: Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT1 receptors compared with the ground-state WT-AT1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT1 receptors. In contrast, interactions between eprosartan and N111G-AT1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. CONCLUSIONS AND IMPLICATIONS: Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT1 receptor activation are warranted.
BACKGROUND AND PURPOSE: Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT1 receptors is necessary. EXPERIMENTAL APPROACH: To identify the robust inverse agonist for active state of AT1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT1 receptors and active-state N111G mutant AT1 receptors. KEY RESULTS: Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT1 receptors compared with the ground-state WT-AT1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT1 receptors. In contrast, interactions between eprosartan and N111G-AT1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. CONCLUSIONS AND IMPLICATIONS: Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT1 receptor activation are warranted.
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