Calcitonin gene-related peptide (CGRP) is a potent vasodilator. We studied the hemodynamic effects of exogenously administered CGRP on pulmonary blood flow in 7 near-term fetal sheep. Catheters were inserted into the left pulmonary artery (LPA) to administer drugs, and into the main pulmonary and carotid arteries, as well as the left atrium, to measure pressures. An ultrasonic flow transducer was placed around the LPA to measure flow continuously. In addition, LPA resistance was calculated. In each examination, we first studied the hemodynamic effects of a single injection of CGRP into the LPA, compared with those produced by acetylcholine; then we studied the effects of 4 additional sequentially repeated injections of the same dose of CGRP, each injection separated by 5 min. The first injection of CGRP (1.36± 0.13 μg/kg [mean ± SD]) increased LPA blood flow significantly, from 17 ± 10 to 120 ± 21 mL/min, and decreased main pulmonary and carotid arterial pressures, from 58 ± 5 to 48± 6 mm Hg and from 56 ± 3 to 46 ± 5 mm Hg, respectively, with a concomitant decrease in LPA resistance from 1.57 to 0.24 mm Hg · mL· min-1. These changes were restored to baseline within 5 min, and were quite similar to those with acetylcholine (0.55 ± 0.06 μg/kg). With repeated injections of CGRP, LPA blood flow increased significantly in a stepwise fashion with concomitant decreases in LPA resistance. Heart rate(from pressure signal) also increased in a stepwise fashion, while pulmonary and carotid arterial pressures showed no significant decrease. We conclude that exogenously administered CGRP has a pulmonary vasodilatory effect in fetal sheep and increases fetal pulmonary blood flow, and that this effect is cumulative with repeated injections. We also suggest that repeated injections of this peptide probably increase fetal heart rate through a direct positive chronotropic effect, and not through a secondary response following a decrease in systemic blood pressure. These findings suggest a role for endogenous CGRP in the remarkable decrease in pulmonary vascular resistance during the transition from fetal to neonatal life.