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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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  • Ferrario, C. M., The remin–angiotensin system - importance in physiology and pathology. J. Cardiovasc. Pharmacol., 1990, 15, S1–S5.

  • Hallberg, I., Ranerup, A. and Kjellgren, K., Supporting the self-management of hypertension: patients' experiences of using a mobile phone-based system. J. Hum. Hypertens, 2016, 30, 141-146.

  • Li, X. et al., An rgd-modified hollow silica@au core/shell nanoplatform for tumor combination therapy. Acta Biomater., 2017, 62, 273–283.

  • Munoz-Durango, N. et al., Role of the rennin–angiotensin-aldosterone system beyond blood pressure regulation: molecular and cellular mechanisms involved in end-organ damage during arterial hypertension. Int. J. Mol. Sci., 2016, 17(7), 797.

  • Li, X., Yang, M., Shi, X., Chu, X., Chen, L., Wu, Q. and Wang, Y., Effect of the intramolecular hydrogen bond on the spectral and optical properties in chitosan oligosaccharide. Physica E, 2015, 69, 237–242.

  • Williamson, J. D. et al., Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years a randomized clinical trial. J. Am. Med. Assoc., 2016, 315, 2673-2682.

  • Storch, U., Blodow, S., Gudermann, T. and Schnitzler, M. M. Y., Cysteinyl leukotriene 1 receptors as novel mechanosensors mediating myogenic tone together with angiotensin ii type 1 receptors-brief report. Arterioscler, Thromb, Vasc. Biol., 2015, 35, 121–126.

  • Lyseng W., Olmesartan medoxomil/amlodipine/hydrochlorothiazide 20 mg/5 mg/12.5 mg fixed-dose combination in hypertension: a profile of its use. Drugs Ther. Perspect., 2018, 34, 1–7.

  • Ji, Y. H., Di, W. Y., Yang, Q. H., Lu, Z. H., Cai, W. M. and Wu, J. Q., Inhibition of autophagy increases proliferation inhibition and apoptosis induced by the pi3k/mtor inhibitor NVP-BEZ235 in breast cancer cells. Clin. Lab., 2015, 61, 1043–1051.

  • Santos, R. A. S. et al., The ACE2/angiotensin-(1-7)/MAS axis of the rennin–angiotensin system: focus on angiotensin-(1-7). Physiol. Rev., 2018, 98, 505–553.

  • Nie, Y. Y. et al., Synthesis and biological evaluation of novel potent angiotensin ii receptor antagonists with anti-hypertension effect. Bioorg. Med. Chem., 2012, 20, 2747–2761.

  • Uemura, H. et al., Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol. Cancer Ther., 2003, 2, 1139–1147.

  • Li, X., Xing, L., Zheng, K., Wei, P., Du, L., Shen, M. and Shi, X., Formation of gold nanostar-coated hollow mesoporous silica for tumor multimodality imaging and photothermal therapy. ACS Appl. Mater Interf., 2017, 9, 5817–5827.

  • Wang, S. et al., Bottom-up synthesis of WS2 nanosheets with synchronous surface modification for imaging guided tumor regression. Acta Biomater., 2017, 58, 442–454.

  • Salvetti, G. et al., Chronic renin–angiotensin system (RAS) blockade may not induce hypotension during anaesthesia for bariatric surgery. Obes. Surg., 2016, 26, 1303–1307.

  • Yang, H., Zhao, J., Wu, C., Ye, C., Zou, D. and Wang, S., Facile synthesis of colloidal stable MOS2 nanoparticles for combined tumor therapy. Chem. Eng. J., 2018, 351, 548–558.

  • Ettehad, D. et al., Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Eur. Heart J., 2016, 37, 639–639.

  • Li, X., Yang, M., Ye, Z., Chen, L., Xu, C. and Chu, X., DFT research on the IR spectrum of glycine–tryptophan oligopeptides chain. Acta Phys. Sin., 2013, 62, 156103.

  • Zhao, J. et al., Outside-in synthesis of mesoporous silica/ molybdenum disulfide nanoparticles for antitumor application. Chem. Eng. J., 2018, 351, 157–168.

  • Han, X. et al., Synthesis and biological evaluation of novel 2,3dihydrochromeno 3,4-d imidazol-4(1h)-one derivatives as potent anticancer cell proliferation and migration agents. Eur. J. Med. Chem., 2016, 114, 232–243.

  • Li, X., Yu, S., Yang, M., Xu, C., Wang, Y. and Chen, L., Electronic structure analysis of glycine oligopeptides and glycinetryptophan oligopeptides. Phys. E, 2014, 57, 63–68.

  • Bavishi, C., Bangalore, S. and Messerli, F. H., Outcomes of intensive blood pressure lowering in older hypertensive patients. J. Am. Coll. Cardiol., 2017, 69, 486–493.

  • Raimondi, S., Botteri, E., Munzone, E., Cipolla, C., Rotmensz, N., DeCensi, A. and Gandini, S., Use of beta-blockers, angiotensinconverting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: systematic review and meta-analysis. Int. J. Cancer, 2016, 139, 212–219.

  • Melville, J. M. and Hultstrom, M., Losartan may reduce the effect of fluid resuscitation following faemorrhage in rats. FASEB J., 2016, 30, 1217.12.

  • Corry, D. B., Eslami, P., Yamamoto, K., Nyby, M. D., Makino, H. and Tuck, M. L., Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J. Hypertens, 2008, 26, 269–275.

  • Li, X., Xiong, Z., Xu, X., Luo, Y., Peng, C., Shen, M. and Shi, X., 99mTc-labeled multifunctional low-generation dendrimer-entrapped gold nanoparticles for targeted SPECT/CT dual-mode imaging of tumors. ACS Appl. Mater. Interf., 2016, 8, 19883–19891.


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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