Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model
Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was...
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MDPI AG
2023-02-01
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/295 |
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| author | Wael A. Alanazi Abdulrahman S. Alanazi Doaa M. El-Nagar Abdullah M. Aljuraybah Sary Alsanea Metab Alharbi |
| author_facet | Wael A. Alanazi Abdulrahman S. Alanazi Doaa M. El-Nagar Abdullah M. Aljuraybah Sary Alsanea Metab Alharbi |
| author_sort | Wael A. Alanazi |
| collection | DOAJ |
| description | Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib. |
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| format | Article |
| id | doaj.art-72f2a0d0d629430c97dc3402f82597f8 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:17:57Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-72f2a0d0d629430c97dc3402f82597f82023-11-16T22:37:40ZengMDPI AGPharmaceuticals1424-82472023-02-0116229510.3390/ph16020295Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice ModelWael A. Alanazi0Abdulrahman S. Alanazi1Doaa M. El-Nagar2Abdullah M. Aljuraybah3Sary Alsanea4Metab Alharbi5Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaTivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib.https://www.mdpi.com/1424-8247/16/2/295tivozanibVEGFRangiotensin-II (AngII)endothelin-1 (ET-1)oxidative stressnitric oxide (NO) |
| spellingShingle | Wael A. Alanazi Abdulrahman S. Alanazi Doaa M. El-Nagar Abdullah M. Aljuraybah Sary Alsanea Metab Alharbi Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model Pharmaceuticals tivozanib VEGFR angiotensin-II (AngII) endothelin-1 (ET-1) oxidative stress nitric oxide (NO) |
| title | Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model |
| title_full | Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model |
| title_fullStr | Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model |
| title_full_unstemmed | Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model |
| title_short | Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model |
| title_sort | mechanism underlying triple vegfr inhibitor tivozanib induced hypertension in mice model |
| topic | tivozanib VEGFR angiotensin-II (AngII) endothelin-1 (ET-1) oxidative stress nitric oxide (NO) |
| url | https://www.mdpi.com/1424-8247/16/2/295 |
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