C H Lee

The effect of fetal breathing movements on pulmonary blood flow in fetal sheep.

ABSTRACT: In the fetus, normal lung growth requires both fetal breathing movements (FBM) and adequate pulmonary blood flow. We postulated that FBM intermittently increase pulmonary blood flow and may stimulate lung growth through that effect. To test the hypothesis that normal intermittent FBM cause associated intermittent increases in pulmonary blood flow, we studied eight chronically instrumented fetal sheep (gestational ages 125–143 d) on 34 occasions (total study time = 65.7 h). Each fetus had a cuff electromagnetic flow transducer around the left pulmonary artery, electrocortical electrodes, and catheters in the trachea, main pulmonary artery, carotid artery, and amniotic cavity. Mean blood flow though the left pulmonary artery averaged 59 ± 8 mL/min (mean ± SEM; per kg: 25 ± 4 mL/kg/min) and was similar in both the presence (61 ± 9 mL/min) and absence (57 ± 7 mL/min) of FBM and during both high and low voltage electrocortical activity. In contrast, in utero phasic pulmonary blood flow varied with FBM, increasing during the inspiratory phase and decreasing during the expiratory phase. Both pulmonary and systemic vascular pressures showed changes in the opposite directions. Arterial pH and blood gas tensions were normal and did not change with FBM or electrocortical activity. We conclude that FBM do not increase mean blood flow through the left pulmonary artery; thus, it is unlikely that FBM stimulate lung growth through changes in pulmonary blood flow.

Meclofenamate and prostaglandin E2 affect breathing movements independently of glucose concentrations in fetal sheep.

Fetal breathing movements in sheep are stimulated by infusions of a prostaglandin synthetase inhibitor, meclofenamate; they are inhibited by prostaglandin E2. Recent studies suggest that these effects are mediated through changes in fetal plasma glucose concentrations. We infused into chronic fetal sheep preparations (1) glucose, (2) meclofenamate, and (3) prostaglandin E2, followed by prostaglandin E2 and glucose together. Infusions of glucose alone did not affect fetal breathing movements despite a significant twofold increase in glucose concentrations. During meclofenamate infusions, fetal breathing movements increased from 34.9% to 80.6% (p less than 0.005); glucose concentrations did not change. During prostaglandin E2 infusions, fetal breathing movements decreased from 36.5% to 4.1% (p less than 0.005) without any change in glucose concentrations; the addition of glucose did not alter the effects of prostaglandin E2 on fetal breathing movements. We conclude that fetal infusions of glucose in sheep do not affect fetal breathing movements and the effects on these breathing movements produced by meclofenamate and prostaglandin E2 are independent of the changes in plasma glucose concentrations.

BREATHING MOVEMENTS TRANSIENTLY INCREASE LUNG VOLUMES 1N FETAL SHEEP

Recent studies indicate that fetal breathing movements (FBM) stimulate fetal lung growth. We chronically studied 18 fetal sheep to determine if FBM affect lung growth by transiently increasing the total volume of fluid (TVF) in the potential airways and air spaces. In 14 fetuses, the trachea was ligated; a catheter with an exteriorized loop diverted all tracheal fluid into a soft intrauterine bag. In 4 fetuses, the trachea was patent; we aspirated tracheal fluid through a small catheter after occluding the glottis with an inflated balloon tipped catheter. On alternate days, we aspirated fluid from the lungs after ≥9 minutes of either FBM or no FBM. The order of collection varied. Using inulin dilution, 64.8±9.6% of the TVF was aspirated through the tracheal catheters (mean ±SD; similar after FBM or no FBM). In every fetus, the volume aspirated after FBM was greater than that aspirated after no FBM. These volumes, in fetuses with the ligated trachea, were 20.5±7.9 ml/kg after no FBM and 28.9±9.8 ml/kg after FBM (p<0.01). In fetuses with the patent trachea, these volumes were 20.7±2.5 after no FBM and 24.5±2.4 ml/kg after FBM (p<0.05). The daily incidence of FBM (both groups) and the tracheal fluid production rate (ligated group) were similar on both study days for each fetus. We conclude: FBM intermittently increase the volume of fluid that can be aspirated from the fetal lungs. This suggests that the TVF in the potential airways and air spaces also increases; this increase in volume may stimulate lung growth. (USPHS HL-27356)

EFFECT OF MECLOFENAMATE (M) ON FETAL BREATHING MOVEMENTS AND PULMONARY BLOOD FLOW

Prostaglandin synthetase inhibitors (PGSI) increase the incidence and amplitude of fetal breathing movements (FBM) and increase pulmonary blood flow (Qp) in fetal sheep. To determine if these effects are interrelated or caused by the same mechanisms, we studied 4 chronically instrumented fetal sheep (gestation 134-138d). Each fetus had an electromagnetic flow probe on the left pulmonary artery (LPA) and catheters in the trachea (to evaluate FBM), main pulmonary artery, carotid artery, jugular vein (JV), and amniotic cavity. Studies were done a minimum of 7 d postoperatively. After a control period (48-150 min), the PGSI, M, was infused into the JV at a dose of 8.53 mg.kg over 10 min, then 0.51 mg/kg/hr for 2.5-4.0 h. There were no changes in heart rate, blood pressure or arterial pH, PCO2 or PO2. Other results are shown in Table.Qp did not correlate with incidence of FBM, nor with pH, PCO2, or PO2. We speculate that the early rise in Qp was due to constriction of the ductus arteriosus, or possibly to changes in pulmonary vascular resistance. We conclude that M causes an early rise in Qp independent of changes in FBM, and that the later increase in FBM does not lead to an increase in Qp.

PULMONARY BLOOD FLOW (Qp) AND BREATHING MOVEMENTS IN FETAL SHEEP

Post-natally, Qp is influenced by respiratory movements, but little is known of the relationship between Qp and fetal breathing movements (FBM). To define this relationship, we studied 6 chronically instrumented fetal sheep (gest. 125-143 d) for a total of 2602 min. Each fetus had an electromagnetic flow probe on the left pulmonary artery (LPA), electrocortical (ECoG) electrodes, and catheters in the trachea (to evaluate FBM), main pulmonary artery, carotid artery and amniotic cavity. Mean Qp to LPA showed a wide range and was similar during high and low voltage ECoC and in the presence or absence of FBM (Table).Fluctuations in mean Qp did not relate to arterial pH, PCO2 or PO2, or to changes in ECoG activity, or onset or cessation of FBM. In contrast, phasic Qp consistently changed with FBM. During the inspiratory phase, Qp increased while pulmonary and carotid arterial blood pressures decreased; during the expiratory phase, Qp decreased while blood pressures increased. We conclude that in fetal sheep: (a) mean Qp shows wide fluctuations not related to FBM, ECoG activity, arterial pH, PCO2 or PO2; (b) during FBM phasic Qp increases during inspiration and decreases during expiration.

290 DENERVATION OF PERIPHERAL OSMORECEPTORS AND LUNG RECEPTORS DOES NOT AFFECT PRODUCTION OF TRACHEAL FLUID IN FETAL SHEEP

The factors that affect production of fetal tracheal fluid have not been completely elucidated. We studied 14 chronically catheterized fetal sheep (120-130 days) to determine if bilateral sections of the carotid sinus and vagus nerves affect production of tracheal fluid. Each fetus had ligation of the trachea and cannulation with a catheter (100 cm long, 1.5 mm I.D.) that diverted all tracheal fluid into a soft intrauterine bag. A loop of catheter was exteriorized to permit collection of fluid from the lungs and bag. Fluid was collected once daily for 6 days after surgery. Seven fetuses had bilateral sections of the carotid sinus and vagus nerves; 7 had sham operations, all fetuses had similar arterial blood gas tensions, pH and mean blood pressures and low voltage electrocortical activity. The incidence of fetal breathing movements was lower in the denervated fetuses; however the production of tracheal fluid was not significantly different except for POD# 1 (table).(Values are mean±;SD; POD=post operative day; p<0.05) We conclude that denervation of peripheral chemoreceptors and lung receptors with afferent nerves in the vagus nerve does not affect production of tracheal fluid in fetal sheep.(USPHSHL27356)

1557 PROSTAGLANDIN (PG) SYNTHESIS INHIBITORS AND FETAL BREATHING MOVEMENTS (FBM) IN SHEEP BEFORE DELIVERY

In fetal sheep, plasma PGE2 concentrations are high and FBM are intermittent, only in low voltage electrocortical activity (ECoA). Before delivery, as FBM decrease, PGE2 concentrations rise. Meclofenamate, a PG synthesis inhibitor, stimulates FBM even in high voltage ECoA (HVSA), while PGE2 inhibits FBM. Therefore, before delivery, the rise in plasma PGE2 concentration may decrease FBM. To test this hypothesis, we suppressed PG production by continuously infusing Meclofenamate (0.8 mg/kg/h) into 5 fetal sheep (Mec) for 5-13d until delivery (133 to 150d gest). We infused solvent into 4 controls (Con) for 5-lld (131 to 146d gest). Both groups had similar daily pH, PCO2 PO2 and ECoA. Other results are:Though Meclofenamate decreased PGE2 concentrations, both groups had a similar decrease in the incidence of FBM during the two days before delivery. However, Meclofenamate increased the incidence of FBM in HVSA until the day before delivery. We conclude that the decrease in the incidence of FBM before delivery is not dependent on high plasma PGE2 concentrations.

REGULATION OF FETAL BREATHING MOVEMENTS (FBM) IN SHEEP BY PROSTAGLANDIN (PG) E 2

In sheep, FBM occur intermittently, and only during low voltage, fast electrocortical activity; at birth, when PGE2 concentrations ([PGE2]) fall, breathing becomes continuous. Meclofenamate (Mec), a PG synthetase inhibitor, decreases [PGE2] and stimulates FBM to occur almost continuously, even during high voltage, slow electrocortical activity (HVSA). To investigate the role of PGE2 in regulating FBM, we studied 6 fetal sheep at 127-134d gestation. We infused Mec for 34 hr; after 12 hr we added incremental doses of PGE2, each for 2-3 hr. These caused no changes in pH, Pco2, Po2, or blood pressure. Mec decreased [PGE2] to neonatal levels and increased the incidence of FBM, especially during HVSA. Effects of PGE2 on FBM during Mec are:The relationship between PGE2 dose and FBM can be described by a curvilinear equation (r =0.77, p <0.001). At a dose of 36 ng/kg/ min, PGE2 closely reproduced the pattern of FBM seen during control periods. These data support the hypotheses: a) endogenous PGE2 inhibits FBM during HVSA, and b) at birth, the fall in circulating [PGE2] contributes to the onset of continuous breathing. (Supported by USPHS HL 27356 Pulmonary SCOR and ALA Fellowship Grant.)

LONG TERM PROSTAGLANDIN SYNTHESIS INHIBITORS |[lpar]|PGSI|[rpar]| AND TRACHEAL FLUID |[lpar]|TF|[rpar]| PRODUCTION IN FETAL SHEEP

In fetal sheep, TF production is relatively constant during the last month of gestation; it decreases in the few days before birth, a time when fetal plasma PGE2 concentrations ([PGE2]) are rising. Short term (12 h) infusions of PGE2 decrease TF production, suggesting that the rise in endogenous [PGE2] may be responsible for the prepartum decrease in TF production. To investigate the possible role of PGE2 in the control of TF production before birth, we studied 5 chronically catheterized fetal sheep from 131-150d gestation. In 4 animals, we infused meclofenamate (Mec), a PGSI, at 1.4-2.8 mg/h (a dose previously shown to decrease [PGE2]); the infusion was continued until birth or fetal demise (5-13d). A control animal received an infusion of vehicle only, for 11d. Each day we collected tracheal fluid from a tracheal cannula and a soft, intrauterine collection bag. TF production in experimental and control animals was similar to previously reported normal values. During the 2 days prior to birth TF production progressively decreased in all animals to 30% of the usual rate; this decrease is similar to that previously reported. Thus, Mec did not prevent the prepartum decrease in TF production. We conclude that in the last few days before birth, the rise in [PGE2] does not cause the fall in TF production. (Supported by USPHS Grant HL 27356 (Pulmonary SCOR) and ALA Fellowship Grant.)

PERIPHERAL CHEMORECEPTOR DEN ERVATICN AFFECTS FETAL BREATHING MOVEMENTS (FBM) IN SHEEP

FBM in chronic ovine fetal preparations are not affected by vagus or carotid sinus nerve sections. However, the aortic bodies may acquire respiratory chemoreceptivity after carotid body denervation. To better define the role of these chemoreceptors on the control of FBM, we chronically studied 14 fetuses; 7 had bilateral section of carotid sinus and vagus nerves and 7 had sham operations. FBM (by tracheal catheter) and electrocortical activity (ECoA) were recorded continuously after surgery. The incidence of FBM and amplitudes of tracheal pressure during 2 periods, 1-5 and 6-13 postoperative (PO) days were:[Values=[Xmacr ](SD); all comparisons of denerv to sham, p<0.05 except day 5.] ECoA, arterial pH, PO2, PCO2 and blood pressures were similar in both groups. Throughout this study, the daily mean incidence of FBM and tracheal pressures during FBM in the denervated group were lower than in the sham group. We conclude that total peripheral chemoreceptor denervation significantly affects the incidence and amplitudes of FBM in sheep. (USPHS HL-27356).