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.
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Obstructive sleep apnea (OSA) is characterized by recurrent episodes of pharyngeal collapse during sleep resulting in intermittent hypoxia (IH), and is associated with high incidence of hypertension and accelerated renal failure. In rodents, endothelin-1 (ET-1) contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate (GFR) in end-stage chronic kidney disease (CKD) patients. 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: A) control, B) 0.2% adenine, C) 0.2% adenine + 30 mg/kg/day of macitentan for 2 weeks followed by 2 weeks of recovery diet. Rats were then exposed for 4 weeks to air or IH (20 short exposures/hr to 5% O2 and 5% CO2 7 hr/day during sleep). Macitentan prevented increases in mean arterial blood pressure caused by CKD, IH and by 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 two weeks and macitentan feeding continued for two more weeks. 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 CKD patients with 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.
