Developmental changes in respiratory, febrile, and cardiovascular responses to PGE₂ in newborn lambs

Abstract

PGE(2) has centrally mediated respiratory, febrile, and cardiovascular effects that markedly differ between fetal and adult life. We hypothesized that the transition from fetal to adult responses to PGE(2) occurs in the newborn period. Thus effects of an intracarotid infusion of PGE(2) (3 microg/min for 60 min) were determined in unanesthetized newborn lambs at 5, 10, and 15 days after birth. At 5 days, PGE(2) reduced central CO(2) sensitivity, reduced lung ventilation due to a decrease in breathing frequency, and induced hypercapnia. By 15 days, these effects of PGE(2) had waned significantly. In contrast, phasic (expiratory) thyroarytenoid muscle electromyogram activity, number of short apneas, and incidence of Biot periodic breathing were similarly increased at all three ages. PGE(2) induced a sustained fever at 10 and 15 days. Heart rate and mean arterial blood pressure were unchanged in contrast to marked increases observed by others in adults. Results showed that the transition from fetal to adult respiratory and febrile responses to PGE(2) occurs in early postnatal life, whereas adult cardiovascular responses develop later in life in sheep.

The induced prostaglandin E 2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

“…This finding is consistent with evidence that prostaglandin synthesis inhibitors, which block endogenous prostaglandin production, increase fetal breathing movements and central respiration during early postnatal life (26)(27)(28). Developmental changes occur in the modulatory effects of prostaglandin with an initial inhibition of ventilation during the perinatal period (18,26,27,29) followed by smaller changes in respiration with increasing age (19). However, PGE 2 may still disrupt regular breathing with induction of apnea at older ages (19).…”

“…Developmental changes occur in the modulatory effects of prostaglandin with an initial inhibition of ventilation during the perinatal period (18,26,27,29) followed by smaller changes in respiration with increasing age (19). However, PGE 2 may still disrupt regular breathing with induction of apnea at older ages (19). Developmental changes could be secondary to alterations in brainstem PGE 2 receptor expression beyond the perinatal period, although EP3R gene and protein are expressed in adult rodent RVLM (20,21,30).…”

“…We previously showed that indomethacin, a nonspecific COX inhibitor, attenuates the respiratory depression induced by IL-1␤ (5). PGE 2 itself depresses breathing in fetal and newborn sheep in vivo (17)(18)(19) and inhibits respiration-related neurons in vitro (5). Furthermore, EP3 receptors (EP3R) for PGE 2 are located in the NTS and RVLM (20,21).…”

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

“…The inability of indomethacin to stimulate breathing beyond basal levels in such animals may be explained by the critical transition in the respiratory effects of PGE 2 during early postnatal development. Although PGE 2 inhibits breathing movements in the fetus and directly after birth (14,15), it later induces little or no change in central respiration during normal conditions (17). Consequently, the effects of indomethacin on eupneic breathing will vary depending on the animal's immune state and the specific stage of perinatal development at which it is given.…”

“…In addition, prostaglandin is considered to be one of the inhibitory neuromodulators contributing to respiratory depression during anoxia (46). In addition to its effects on neuronal activity, prostaglandin may diminish the responsiveness to anoxia by reducing central chemosensitivity to CO 2 (12,17,30,31). Prostaglandin may do so by acting on PGE 2 receptors highly expressed in the NTS, nucleus ambiguus, and parabrachial nucleus or by hyperpolarizing pre-Bötzinger neurons recently shown to possess intrinsic hypoxic chemosensitivity and respond to changes in PCO 2 .…”