We sought to define the effects of maturation and hyperoxic stress on nitric oxide (NO)-induced modulation of bronchopulmonary responses to stimulation of vagal preganglionic nerve fibers. Experiments were performed on decerebrate, paralyzed, and ventilated rat pups at 6-7 days (n = 21) and 13-15 days of age (n = 23) breathing room air and on rat pups 13-15 days of age (n = 19) after exposure to hyperoxia (>/=95% inspired O(2) fraction for 4-6 days). Total lung resistance (RL) and lung elastance (EL) were measured by body plethysmograph. Vagal stimulation and release of acetylcholine caused a frequency-dependent increase in RL and EL in all animals. The RL response was significantly potentiated in normoxic animals by prior blockade of nitric oxide synthase (NOS) (P < 0.05). Hyperoxic exposure increased responses of RL to vagal stimulation (P < 0.05); however, after hyperoxic exposure, the potentiation of contractile responses by NOS blockade was abolished. The response of EL was potentiated by NOS blockade in the 13- to 15-day-old animals after both normoxic and hyperoxic exposure (P < 0.01). Morphometry revealed no effect of hyperoxic exposure on airway smooth muscle thickness. We conclude that NO released by stimulation of vagal preganglionic fibers modulates bronchopulmonary contractile responses to endogenously released acetylcholine in rat pups. Loss of this modulatory effect of NO could contribute to airway hyperreactivity after prolonged hyperoxic exposure, as may occur in bronchopulmonary dysplasia.
Although apnea is common in premature babies, there is a paucity of information concerning the pathophysiologic basis of these episodes and their relationship to other perinatal conditions such as hyperbilirubinemia. Unconjugated hyperbilirubinemia in premature infants, even in moderately high levels, may cause encephalopathy affecting brainstem functions and has been linked to increased incidence of apnea in these infants. Thus, there is a need to clarify mechanisms by which bilirubin may alter respiratory control and induce apnea of prematurity. In this study, bilirubin or placebo was infused i.v. in 9-d-old rat pups (n ϭ 36). Serum hyperbilirubinemia peaked in the first hours after bilirubin infusion. Twenty-four hours after bilirubin infusion, respiration was recorded by plethysmography at rest and under hypercapnic and hypoxic conditions. In treated pups, minute ventilation in room air was significantly reduced, hyperventilatory response to CO 2 was blunted, and hypoxic ventilatory depression was increased, compared with placeboinjected rat pups. Brainstem bilirubin deposition and immunoreactivity to bilirubin was detected in the brainstem on histologic analysis. We speculate that high serum bilirubin levels may cause prolonged inhibition of brainstem autonomic function and that this could underlie the exacerbation of apnea noted in premature babies who have experienced jaundice. A pnea is a frequent occurrence in premature babies, affecting up to 84% of infants weighing Ͻ1000 g at birth (1,2). The long-term implications of this phenomenon for human development are unclear; however, some studies have suggested an association between apnea of prematurity and abnormal motor and mental development (3-5). Apneic episodes are considered to be the consequence of immature respiratory control by neuronal networks within the brainstem. However, despite advances in the field of developmental respiratory neurobiology in recent years, the pathophysiologic basis of these episodes has not yet been completely elucidated and there is a paucity of information concerning their relationship to other widespread perinatal conditions such as hyperbilirubinemia.Hyperbilirubinemia of the newborn infant is very common, and the line separating physiologic and pathologic jaundice has been difficult to define (6). In severe cases this condition can be harmful due to the risk of bilirubin encephalopathy or development of kernicterus (7). In premature infants, in particular, bilirubin encephalopathy and kernicterus have been shown to occur at a lower threshold of serum bilirubin, compared with term babies (8,9). Furthermore, an association between moderate hyperbilirubinemia and poorer neurodevelopmental outcomes has been suggested in a large, retrospective multicenter study of premature infants (10). A preliminary observation from our laboratory by DiFiore et al. suggests that a significant relationship exists between apnea of prematurity and the prior occurrence (11) have also reported a correlation between bilirubin enceph...
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