Introduction Fetal hypoxia, a common consequence of complicated pregnancies, leads to the development of cardiac dysfunction in adult offspring by impairing cardiac tolerance to an ischemia/reperfusion (I/R) insult. Extensive evidence demonstrates that cardiac I/R upregulates the endothelin-1 (ET-1) system leading to elevated levels of ET-1 (a peptide with potent physiological and pathophysiological effects on the cardiovascular system). Active ET-1 exerts its effects via the endothelin-A receptors (ETAR; of which enhanced activation has been associated with impaired post-I/R cardiac function) and endothelin-B receptors (ETBR; which are essential for post-I/R cardiac recovery). However, whether activation of ETAR contributes to cardiac dysfunction in adult offspring exposed to prenatal hypoxia is unknown. We hypothesize that, in adult offspring exposed to prenatal hypoxia, cardiac ETAR expression is increased, and its inhibition improves post-I/R cardiac recovery. Methods Pregnant Sprague-Dawley rats (n=4-6 dams/group) were exposed to normoxia (21% O2; normoxia) or hypoxia (11% O2; p-hypoxia) from gestational day 15-21 (term=22 days). Cardiac function was assessed ex vivo in 4-month old male and female offspring (n=1-2 offspring/dam) by subjecting isolated hearts to I/R (25 min. of ischemia with 40 min. of reperfusion). The contribution of ETAR to cardiac dysfunction was assessed by pre-infusion with an ETAR antagonist (ABT-627) before I/R (ABT-627 was recirculated during reperfusion). ETAR and ETBR levels were assessed in non-ischemic left ventricle tissues by Western blotting. Data (mean±SEM) were compared by two-way ANOVA (Sidak's post hoc test), or by unpaired t-test. Results : ABT-627 induced a dramatic reduction in cardiac recovery after I/R in prenatally hypoxic males compared to their respective controls (control: 60.5±16.3% vs ABT-627: 4.4±2.6%, p=0.009), without effect in normoxic males. In contrast, ABT-627 improved I/R recovery in prenatal hypoxia-exposed females (control: 53.5±10.6% vs ABT-627: 87±5.6%, p=0.05) with no effect in normoxic females. In males, exposure to prenatal hypoxia did not alter cardiac ETAR levels, but decreased ETBR levels compared to the normoxic group (normoxia: 100±3.2% vs p-hypoxia: 70.6±4%, p=0.0003), without changes in females. Conclusion Prenatal hypoxia alters the cardiac ET-1 system in a sex-specific manner. Inhibition of ETAR in prenatally hypoxic males impaired cardiac recovery post-I/R, potentially due to lower ETBR expression; while cardiac recovery was improved by ETAR inhibition in females. Activation of ETAR may thus be essential for cardiac tolerance to I/R in prenatally hypoxic males, while it may contribute to the development of cardiac dysfunction in females. Our data suggests that developmental influences and sex differences need to be considered during the implementation of therapeutic strategies to prevent the long-term effects of pregnancy complications on offspring cardiac health.