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Pharmacological Evaluation on Antihypertensive Activity of a Novel AT1 Angiotensin II Receptor Antagonist


Affiliations
1 The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
2 Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
 

Hypertension is a major risk factor for human cardiovascular health, which can damage heart, brain, kidneys, etc. In this study we aimed to develop novel angiotensin II receptor blockers (ARBs) that prevent the increase of blood pressure for treatment of hypertension. (2-(4-((2-Amyl-5-nitro-1H-benzo[d]-imidazol-1-yl) methyl)-1H-indol-1-yl) tetrazole; compound 1a) was one of the ARBs designed and synthesized. It was prepared and orally administered to spontaneous hypertensive rats to study the antihypertensive effects. The maximum reduction in blood pressure reached 50 mmHg after dosing compound 1a for 5 h. Acute toxicity test was carried out on healthy 4 week old 30 male and 30 female ICR mice and LD50 for 1a was found to be 2864.03 mg/kg. High performance liquid chromatography was employed to determine the level of 1a plasma concentration at various time points after administration. The plasma concentration of 1a increased after 2 h, declined gradually and was still detectable in the plasma after 72 h. The drug distribution analysis of 1a was performed on healthy Wistar rats. It was present in the liver with the highest concentration, in kidney with a lower concentration, and in the spleen, lung, heart and brain with the lowest concentration. It displayed high affinity to AT1 receptor, and had an efficient and long-lasting effect in reducing blood pressure, which lasted for more than 12 h. Due to its biological safety, 1a could be absorbed quickly, metabolized smoothly, and can be distributed in important organs. Therefore, 1a could be considered as a suitable ARB candidate for further studies.

Keywords

Angiotensin II Receptor Blockers, Antagonistic Activity, Antihypertension, Pharmacological Evaluation.
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  • Pharmacological Evaluation on Antihypertensive Activity of a Novel AT1 Angiotensin II Receptor Antagonist

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Authors

Bei Tang
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Helin Li
Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
Ze Zhong
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Huiping Wu
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Hongwei Shen
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Jiayuan Hu
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Jianping Ma
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Jinting Wu
The First People's Hospital of Jiande City, The Second Affiliated Hospital, Zhejiang University School of Medicine, 311600, China
Yuehui Wang
Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany

Abstract


Hypertension is a major risk factor for human cardiovascular health, which can damage heart, brain, kidneys, etc. In this study we aimed to develop novel angiotensin II receptor blockers (ARBs) that prevent the increase of blood pressure for treatment of hypertension. (2-(4-((2-Amyl-5-nitro-1H-benzo[d]-imidazol-1-yl) methyl)-1H-indol-1-yl) tetrazole; compound 1a) was one of the ARBs designed and synthesized. It was prepared and orally administered to spontaneous hypertensive rats to study the antihypertensive effects. The maximum reduction in blood pressure reached 50 mmHg after dosing compound 1a for 5 h. Acute toxicity test was carried out on healthy 4 week old 30 male and 30 female ICR mice and LD50 for 1a was found to be 2864.03 mg/kg. High performance liquid chromatography was employed to determine the level of 1a plasma concentration at various time points after administration. The plasma concentration of 1a increased after 2 h, declined gradually and was still detectable in the plasma after 72 h. The drug distribution analysis of 1a was performed on healthy Wistar rats. It was present in the liver with the highest concentration, in kidney with a lower concentration, and in the spleen, lung, heart and brain with the lowest concentration. It displayed high affinity to AT1 receptor, and had an efficient and long-lasting effect in reducing blood pressure, which lasted for more than 12 h. Due to its biological safety, 1a could be absorbed quickly, metabolized smoothly, and can be distributed in important organs. Therefore, 1a could be considered as a suitable ARB candidate for further studies.

Keywords


Angiotensin II Receptor Blockers, Antagonistic Activity, Antihypertension, Pharmacological Evaluation.

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DOI: https://doi.org/10.18520/cs%2Fv116%2Fi12%2F1987-1992