Almitrine is a piperazine derivative known to stimulate breathing in the adult but cause apnea in fetal sheep. In fetal sheep (127-133 d gestation; term = 147 d) we confirmed this finding, but found that almitrine (4 mg/kg, i.v. or intra-arterial) had a biphasic effect, briefly stimulating and then suppressing breathing movements for at least 3 h. In 2- to 3-d-old (n = 4) and 7- to 14-d-old (n = 4) lambs almitrine increased both tidal volume and breath frequency, increased arterial partial pressure of oxygen and pH, and decreased partial pressure of carbon dioxide. The changes of tidal volume, partial pressure of oxygen and partial pressure of carbon dioxide were less in the 2- to 3-d-old compared with the 7- to 14-d-old lambs. The distribution of the nuclear phosphoprotein FOS, a marker of neuronal activation was examined in fetal and newborn brains. FOS protein was increased in cardiorespiratory areas of the medulla and pons, in the periaqueductal region of the midbrain, and in the supraoptic and paraventricular regions of the hypothalamus. In the pons, FOS protein was increased in the medial parabrachial and subcoeruleus nuclei in the fetuses but not in the 2- to 3- or 7- to 14-d-old lambs. These observations are similar to those reported for hypoxia, and consistent with the hypothesis that both almitrine and hypoxia inhibit fetal breathing movements by an action on a select group of pontine neurons. Whether these neurons respond directly to these stimuli or receive input from the other centers is yet to be elucidated. The mechanisms that change the almitrine (and hypoxia) response from inhibition to excitation at birth have not been identified, but may be important in preventing apnea in the newborn.