Pulmonary Surfactant Release in Fetal Rabbits as Affected by Enprofylline

Abstract

Respiratory distress syndrome in the newborn is associated with a deficiency of pulmonary surfactant, the main component of which is dipalmitoylphosphatidylcholine (1). A number of pharmacological agents have been found to influence the synthesis of pulmonary surfactant. The effect of glucocorticoids has been studied most extensively, and accelerated lung maturation has been demonstrated in experimental (2, 3) as well as clinical studies (4,5). Xanthines are widely used in lung diseases such as asthma and apnea in premature infants, but the mechanism of action of these drugs is still relatively unknown. Increased release of pulmonary surfactant into the alveolar space might be one effect of xanthines. Several animal studies indicate increased synthesis and/or secretion of fetal surfactant after administration of aminophylline (theophylline ethylenediamine) to the mother or directly to the fetus (3, 6, 7), but other studies have not confirmed this effect (8). Enprofylline (3-propylxanthine), a new xanthine derivative, exhibits potent antiasthmatic characteristics (9). However, the effects of this substance and those of theophylline differ in several respects; most importantly, theophylline is a potent adenosine antagonist, while enprofylline is not (10). Our investigation is an assessment of fetal surfactant release following enprofylline infusion to the doe. MATERIALS AND METHODSEight pregnant New Zealand rabbits were used. Time of mating was known within 1 h. At a gestational age of 27.9 days (term 3 1 days), four does were injected intravenously with enprofylline, 5 mg/kg, during a 5-min period, and, in an identical manner, four controls received the same volume of Ringer's solution. Following this loading dose, the rabbits were continuously infused over the next 2 h with enprofylline, 20 mg/kg, and the controls with the same volume of Ringer's solution. On completion of the infusion, the maternal rabbits were killed with a lethal intravenous dose of thiopental sodium and the abdomen was opened. To prevent the fetuses from making inspiratory efforts, they were injected intracranially with 0.5 ml thiopental sodium while still in utero. The fetuses then were delivered through uterine incisions. The trachea of each fetus was exposed, and a polyethylene tube (PE 50) was inserted just below the larynx. From each fetus, about 25 p1 of lung fluid was collected for evaluation of surface activity with the pulsating bubble surfactometer (1 1). This instrument is particularly appropriate for assessing the effect that surface properties of fetal pulmonary fluid will have on the initial aeration with the first breath and on subsequent breathing. The surfactometer's sample chamber, filled with the airway fluid, communicates with ambient air through a vertical capillary. As fluid is withdrawn from the chamber, air is forced to move down the capillary, the cylindrical "airway," and a bubble, with a radius of 0.55 mm, is developed. While the first breath is thus simulated, the negative pressure in the sample liquid surrounding...