Effect of chronic administration of endothelin receptor type a antagonist (bq-610) on functional lifespan of the corpus luteum in sheep

Abstract

To test the role of endothelin 1 (END1) in luteolysis, an END receptor type A antagonist (BQ-610) was delivered into the corpus luteum (CL) during spontaneous luteolysis in sheep. On day 9 of the estrous cycle, an osmotic mini-pump containing 2 mg of BQ-610 (n = 12) or vehicle (n = 9) were implanted surgically in the ewes. Corpora lutea were collected 12 h after onset of estrus, or on the afternoon of day 21 in ewes that had not returned to estrus, and from untreated ewes on day 10 to 12 of the estrous cycle (mid-cycle CL). Three of 12 BQ-610-treated ewes did not show estrus before day 21 compared to 0 of 9 vehicle-treated ewes. Estrous cycles in vehicle-treated ewes averaged 15.5 ± 0.2 days. In the three BQ-610-treated ewes, luteal weights on day 21 were greater than in vehicle-treated ewes on the day of estrus (0.62 ± 0.05 versus 0.39 ± 0.03 g, respectively; P < 0.001), as were luteal contents of progesterone (P4) (20958.2 ± 1830.9 μg/g versus 1291.2 ± 1057.1 μg/g respectively; P<0.0001). Serum concentrations of P4 in the three BQ-610-treated ewes remained above 1.5 ng/mL through day 21 (P<0.01). Their luteal tissue appeared normal with 53.3 ± 5.8% of apoptotic cells, whereas luteal tissue in vehicletreated ewes was markedly disorganized and in an advanced stage of structural regression. Expression of mRNA of several genes involved in progesterone production or structural luteolysis was different in CL from vehicle-treated compared to CL of BQ-610-treated ewes or mid-cycle CL. In conclusion, chronic infusion of BQ-610 blocked luteolysis and lengthened the estrous cycle in three of 12 ewes. Furthermore, functional features of CL of those three ewes were similar to mid-cycle CL. Overall this study indicates that END1 might plays mediatory role during spontaneous luteolysis in the ewe via endothelin receptor type A.