AUTHOR=Polak Jan , Punjabi Naresh M. , Shimoda Larissa A. TITLE=Blockade of Endothelin-1 Receptor Type B Ameliorates Glucose Intolerance and Insulin Resistance in a Mouse Model of Obstructive Sleep Apnea JOURNAL=Frontiers in Endocrinology VOLUME=Volume 9 - 2018 YEAR=2018 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00280 DOI=10.3389/fendo.2018.00280 ISSN=1664-2392 ABSTRACT=Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/d), BQ-788 (ETB antagonist; 200 nmol/kg/d) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/hr) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1mg/kg) were injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. 14-day IH increased fasting glucose levels (122±7 vs. 157±8 mg/dL, PG: 118±6 vs. 139±8; both p<0.05) and impaired glucose tolerance (AUCglucose: 19249±1105 vs. 29124±1444, PG AUCglucose: 18066±947 vs. 25135±797; both p<0.05) in vehicle treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21969±662; p<0.05). 14-day IH also induced IR (AUCglucose: 7185±401 vs 8699±401; p<0.05). Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281±401, p<0.05) and reduced worsening of IR with IH (AUCglucose: 7302±401, p<0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.