Selective ETA vs. dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats.

Abstract

AIMS:

Although 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 RESULTS:

Male 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.

CONCLUSIONS:

Our 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.

• Authors: Katrina M Mirabito Colafella, Karla B Neves, Augusto C Montezano, Ingrid M Garrelds, Richard van Veghel, René de Vries, Estrellita Uijl, Hans J Baelde, Anton H van den Meiracker, Rhian M Touyz, A H Jan Danser, Jorie Versmissen
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 116 Issue 10 Pg. 1779-1790 (08 01 2020) ISSN: 1755-3245 [Electronic] England
• PMID: 31593221 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• Antihypertensive Agents
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Isoxazoles
• Pyrimidines
• Receptor, Endothelin A
• Receptor, Endothelin B
• Sulfonamides
• Thiophenes
• ednrb protein, rat
• Epoprostenol
• sitaxsentan
• Sunitinib
• macitentan

Topics

• Albuminuria (chemically induced, metabolism, pathology, prevention & control)
• Animals
• Antihypertensive Agents (pharmacology)
• Arteries (drug effects, metabolism, physiopathology)
• Blood Pressure (drug effects)
• Disease Models, Animal
• Endothelin A Receptor Antagonists (pharmacology)
• Endothelin B Receptor Antagonists (pharmacology)
• Epoprostenol (metabolism)
• Hypertension (chemically induced, metabolism, physiopathology, prevention & control)
• Isoxazoles (pharmacology)
• Kidney (drug effects, metabolism, physiopathology)
• Male
• Oxidative Stress (drug effects)
• Pyrimidines (pharmacology)
• Rats, Inbred WKY
• Receptor, Endothelin A (drug effects, metabolism)
• Receptor, Endothelin B (drug effects, metabolism)
• Signal Transduction
• Sulfonamides (pharmacology)
• Sunitinib
• Thiophenes (pharmacology)