Selective ETA vs. dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria inWKY rats
| Autor: | Augusto C. Montezano, Jorie Versmissen, Karla B Neves, Estrellita Uijl, Anton H. van den Meiracker, Hans J. Baelde, Katrina M Mirabito Colafella, A.H. Jan Danser, René de Vries, Richard van Veghel, Ingrid M. Garrelds, Rhian M. Touyz |
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| Přispěvatelé: | Internal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Endothelin A Receptor Antagonists Physiology Thromboxane medicine.drug_class Blood Pressure Prostacyclin Thiophenes Pharmacology Kidney urologic and male genital diseases Rats Inbred WKY chemistry.chemical_compound Physiology (medical) Sitaxentan Sunitinib medicine Albuminuria Animals Renal injury Antihypertensive Agents Macitentan Sulfonamides Endothelin-1 business.industry Arteries Isoxazoles Receptor Endothelin A Receptor antagonist Epoprostenol Receptor Endothelin B female genital diseases and pregnancy complications Endothelin B Receptor Antagonists Angiogenesis inhibition Disease Models Animal Endothelin receptor antagonists Pyrimidines chemistry Oxidative stress Hypertension cardiovascular system medicine.symptom Cardiology and Cardiovascular Medicine Endothelin receptor business Signal Transduction medicine.drug |
| Zdroj: | Cardiovascular Research, 116(10), 1779-1790. Oxford University Press Cardiovascular Research, 116(10), 1779-1790. OXFORD UNIV PRESS |
| ISSN: | 0008-6363 |
| Popis: | AimsAlthough effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria.Methods and resultsMale Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan.ConclusionsOur results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury. |
| Databáze: | OpenAIRE |
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