Abstract P343: A Dual Endothelin A/B Receptor Blocker in a Rat Model of Sleep Apnea and Chronic Kidney Disease

Abstract

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of pharyngeal collapse during sleep resulting in intermittent hypoxia (IH) and sleep fragmentation. OSA affects 5% to 20% of the US population, is associated with high incidence of hypertension, and is a prognostic indicator of accelerated renal failure. More than 20 million people in the US have chronic kidney disease (CKD). In rodents, endothelin-1 (ET-1) contributes to IH-induced hypertension, and ET-1 levels inversely correlate with GFR in end-stage CKD patients. These findings provide the rationale to test the hypothesis that a dual ET receptor antagonist will attenuate the development of hypertension and renal dysfunction in a combined rat model of 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 (dual ET A /ET B receptor antagonist, Actelion Pharmaceuticals) for 2 weeks followed by 2 weeks of recovery (regular chow or chow+macitentan). Rats were then exposed to sham or IH (20 short exposures/hr to 5% O 2 and 5% CO 2 7 hr/day during sleep) for 4 weeks. Changes in mean arterial blood pressure (MAP) recorded by telemetry are in Figure 1A and estimated glomerular filtration rate in Figure 1B . In summary, macitentan prevents increases in blood pressure caused by CKD, IH and by the combination of CKD+IH. However, it does not improve kidney 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 in our experimental conditions.