We previously demonstrated that exogenously administered calcitonin gene-related peptide (CGRP), a potent vasodilator peptide, decreased pulmonary arterial pressure and increased pulmonary blood flow in fetal sheep. To evaluate whether this peptide plays a role in the rapid increase of pulmonary blood flow during the feto-neonatal transition, we studied 12 near-term fetal sheep and examined how CGRP-receptor blockade affects the increase of pulmonary blood flow due to in-utero oxygen ventilation. During fetal surgery, catheters were inserted into the left pulmonary artery (LPA) to administer drugs and into the main pulmonary and carotid arteries to measure pressures. A tracheal tube was inserted, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. In-utero ventilation was performed twice in each fetus over 15 min with 100% oxygen: 5 fetuses for the control and 7 for the CGRP-receptor blockade studies. In the control studies, we repeated an in-utero ventilation twice and statistically compared LPA blood flow and other hemodynamic variables at 0, 5, 10, and 15 min after ventilation. There were no significant differences between the first and second ventilations: the peak LPA blood flow was 845 ± 309 and 898± 406 ml/min* 100gm lung weight, respectively. In the CGRP-receptor blockade studies, one ventilation was done during infusion of CGRP8-37, the CGRP-receptor antagonist, into the LPA and the other was done during vehicle infusion. CGRP8-37 was infused from 15 min prior to onset of ventilation until 15 min after (mean: 531 μg/kg), and the receptor blockade was confirmed by injecting agonist, CGRP (mean 0.54 μg). There were no significant differences at 0, 5, and 10 min, but LPA blood flow was significantly lower with CGRP8-37 infusion at 15 min: the peak LPA blood flow was 978 ± 306 ml/min with CGRP8-37 infusion and 1120 ± 418 ml/min* 100gm lung weight with vehicle. These data suggest that CGRP is not involved in the initial increase of pulmonary blood flow during the transition, but may have some role in maintaining the high pulmonary blood flow after 15 min.