Intrauterine infusion of BQ-610, an endothelin type A receptor antagonist, delays luteolysis in dairy heifers

Three separate in vivo experiments were conducted to evaluate the putative role of endothelin-1 (ET-1) during luteal regression in heifers. In Experiment 1, a single intraluteal injection of 500 μg BQ-610 [(N,N-hexamethylene) carbamoyl-Leu-d-Trp (CHO)-d-Trp], a highly specific endothelin A (ETA) receptor antagonist, did not diminish the decline in plasma progesterone following a single exogenous injection of 25 mg prostaglandin F2 alpha (PGF2α) administered at midcycle of the estrous cycle. In Experiment 2, six intrauterine infusions of 500 μg BQ-610 given every 12 h on days 16-18 delayed spontaneous luteolysis, as evidenced by an extended elevation (P = 0.054) of plasma progesterone concentration. In Experiment 3, heifers were administered six intrauterine infusions of BQ-610 or saline on days 16-19, and peripheral blood samples were collected from day 11 to 16 (before infusion), hourly on days 16-19 (during infusion), and on days 20-25 (after infusion). BQ-610 treated heifers had markedly higher (P < 0.0001) levels of plasma progesterone compared with saline controls, and this effect was most notable during the infusion period (treatment by period interaction; P ≤ 0.05). Heifers infused with BQ-610 also had higher progesterone levels on day 21 (treatment by time interaction; P ≤ 0.05). Mean plasma concentrations of 13,14-dihydro-15-keto-PGF2α (PGFM), the primary metabolite of PGF2α, were measured in the samples collected hourly and were not different (P ≥ 0.05) between treatments. These results indicate that the in vivo antagonism of the ETA receptor can delay functional luteolysis, and supports the theory that ET-1 regulates luteal function in ruminants.