A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea.

Humberto Morales-Loredo, David Jones, Adelaeda Barrera, Perenkita J Mendiola, Joshua Garcia, Carolyn Pace, Minerva Murphy, Nancy L Kanagy, Laura V Gonzalez Bosc

American journal of physiology. Renal physiology 2019 May 01

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Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg-1·day-1 macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO2 7 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.

Citation

Humberto Morales-Loredo, David Jones, Adelaeda Barrera, Perenkita J Mendiola, Joshua Garcia, Carolyn Pace, Minerva Murphy, Nancy L Kanagy, Laura V Gonzalez Bosc. A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea. American journal of physiology. Renal physiology. 2019 May 01;316(5):F1041-F1052