Jack R. Hessler

The Onset of Breathing at Birth Stimulates Pulmonary Vascular Prostacyclin Synthesis

Summary: The purpose of the present study was to determine if pulmonary prostacyclin synthesis was stimulated by spontaneous onset of breathing by unanesthetized fetuses at birth. Cannulae were implanted and flow cuffs placed in fetal lambs and goats (0.93 term). Fetuses were delivered by cesarean section at 0.95 term and began breathing spontaneously. Prostacyclin in blood was determined by radioimmunoassay of its hydrolysis product, 6-ketoprostaglandin F1α using methods that produced the same values in duplicate samples as did gas chromatography with electron capture detection. Fetal pulmonary prostacyclin production (left lung) [(left pulmonary venous concentration — pulmonary arterial concentration) × left pulmonary blood flow] was undetectable [−1.7 ± 1.0 (SEM) ng PGI2·kg−1·min−1] and fetal pulmonary vascular resistance (left lung) high (5.1 ± 0.9 mm Hg · kg·min · ml−1). Pulmonary prostacyclin production increased to 30.1 ± 12.3 ngPGI2 · kg−1 · min−1 and pulmonary vascular resistance declined to 0.5 ± 0.1 mm Hg · kg · min · ml−1 15 min after-birth. Pulmonary vascular resistance remained low even though pulmonary prostacyclin production fell 2-5 h after birth. These results, coupled with earlier studies using indomethacin to inhibit prostaglandin synthesis, support the hypothesis that pulmonary prostacyclin synthesis participates in the decline of pulmonary vascular resistance that accompanies the onset of ventilation at birth, but may be less important in maintenance of low pulmonary vascular resistance once reduced pulmonary vascular tone has been established.

Effects of indomethacin upon cerebral hemodynamics of newborn pigs.

ABSTRACT: Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 ± 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2 with the balance N2 (hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 ± 12 to 218 ± 19 ml/100 g-min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 ± 5 ml/100 g-min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 ± 19 ml/100 g-min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1α, thromboxane B2, and prostaglandin E2 demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.

Pulmonary and systemic vascular effects of exogenous prostaglandin I2 in fetal lambs

Effects of PGI2 upon pulmonary vascular resistance and systemic arterial pressure of near term fetuses were evaluated in anesthetized, exteriorized, unventilated fetal lambs by means of an open-chest, pump-perfused lung preparation. These effects were compared to those of PGE1 and PGE2 in the same animals. Intrapulmonary arterial infusions of PGI2 produced dose-dependent decreases in pulmonary vascular resistance and systemic arterial pressure. Effects of PGI2 upon pulmonary vascular resistance are intermediate with respect to those of PGE1 (greater) and PGE2 (less). PGI2 is a potent hypotensive compound when administered to fetal lambs, producing dose-dependent decreases in systemic arterial pressure. When the three prostaglandins are infused into the pulmonary artery, effects on systemic arterial pressure of PGE1 and PGI2 are nearly identical. Effects of PGE2 are considerably less. PGI2 is a potent dilator of fetal lamb vessels and could play a role in circulatory control during perinatal transition.

Mechanisms of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.

Effects of sodium chloride on pregnant sheep with reduced uteroplacental perfusion pressure.

This study investigated the effects of NaCl supplementation (5 mEq/kg/day) on the arterial pressure of pregnant and nonpregnant sheep with and without reduction of uteroplacental perfusion pressure. In pregnant sheep receiving NaCl supplementation during the third trimester, reduction of aortic pressure caudal to the kidneys to 65% of the upstream pressure (occlusion) caused a progressive increase in mean arterial pressure from 89 +/- 3 to 110 +/- 3 mm Hg over 2 weeks. Occlusion was accompanied by a decrease in urine flow. Six of seven sheep died or were killed because of severe respiratory distress. No abnormalities were detected in nonpregnant sheep or pregnant sheep receiving NaCl supplementation only. Pregnant sheep that were occluded but received no supplementary NaCl did not become hypertensive but aborted about 2 weeks after occlusion. These results indicate that reduction of uteroplacental perfusion pressure causes hypertension in NaCl-supplemented pregnant sheep but not in sheep receiving a normal, low sodium diet.

Changes in plasma arginine vasopressin during transition from fetus to newborn following minimal trauma delivery of lambs and goats

Vasopressin in umbilical arterial and venous blood is high at delivery and may be important in the maintenance of arterial pressure and absorption of lung liquid. We used chronically instrumented near-term fetal lambs and goats to investigate the changes in plasma vasopressin that occur during perinatal cardiovascular transition following cesarean section without labor. Plasma arginine vasopressin was more than 5 times greater 15 min following birth than immediately prior to clamping the umbilicus, and it fell progressively over the ensuing 2-5 h to levels not significantly different from before birth. Fifteen min after delivery, neither arterial pressure, blood gases, nor pH appeared to account for the increase.

Surgery increases fetal plasma prostacyclin

Pulmonary arterial prostacyclin (as 6-keto-PGF1 alpha) concentrations of near term, fetal lambs and goats were determined following fetal surgery and 24, 48, and 72 hrs later. Blood gases, pH, and arterial pressure were determined also. At the end of 2.5 hrs of surgery including exteriorization of the uterus and fetal thoracotomy, pulmonary arterial concentration of 6-keto-PGF1 alpha was 948 +/- 80 (SEM) pg/ml of blood. Twenty-four hrs later it had fallen to 435 +/- 92 pg/ml and remained constant for the duration of monitoring. Maternal arterial 6-keto-PGF1 alpha concentration was much lower (105 +/- 20 pg/ml of blood). No significant changes in fetal PaO2, PaCO2, pH, or arterial pressure were observed, although PaCO2 appeared to be elevated and pH reduced following surgery. These values normalized within 24 hrs. We conclude that surgical perturbation increases fetal arterial prostacyclin concentration. Increased prostacyclin levels are transient, reaching stable values within 24 hrs following completion of extensive surgery.

Effects of hexoprenaline on the lecithin/sphingomyelin ratio and pressure-volume relationships in fetal rabbits

A placebo-controlled, double-blind trial was carried out on 74 New Zealand White rabbit fetuses from 15 does to assess the effect of a fetal injection of hexoprenaline on surfactant release. After the uterus was exposed, half the fetuses received 0.1 ml (0.25 microgram) of hexoprenaline injected intraperitoneally through the intact uterine wall; the other half received an equivalent volume of placebo. After 3 hours, the abdomen was reopened, and the fetuses were surgically delivered and killed before breathing. The lecithin/sphingomyelin (L/S) ratios, obtained from lung washings, revealed a mean of 1.59:1 for the placebo group and 1.92:1 for the hexoprenaline group (p less than 0.001). Pressure/volume curves were generated from the lungs of 24 fetuses from 10 does, and the volume of air in the lungs for each pressure was analyzed in four ways: total volume, volume per gram of fetal body weight, volume per gram of dry lung weight, and as a percentage of total lung capacity at a pressure of 40 cm H2O. A first and second inflation-deflation curve was obtained for each experiment. The lungs from the hexoprenaline-treated group retained significantly more air than those from the placebo group. The most significant comparison was obtained when lung volume was expressed per gram of dry lung weight. The possibility of administering a beta 2-sympathomimetic drug to the mother in advanced preterm labor, specifically to release surfactant in the fetal lung, is suggested.

Effect of bradykinin on the pulmonary vascular resistance in the term fetus

It is possible to separately measure two areas of resistance in the pulmonary circulation: proximal resistance (RP), or the resistance from a point at which pulmonary arterial pressure is measured to the vessels acting as Starling resistors, and distal resistance (RD), or the resistance from the Starling resistor vessels to a point at which pulmonary venous pressure is measured. A model has been set up in the near term fetal goat utilizing a Starling resistor concept of the pulmonary circulation and requires that the circulation to a portion of the left lung be isolated and perfused at a constant flow. Resistance in the different segments are calculated from figures derived in the experimental procedure previously reported in the Fed. Pro. 29:775-6, 1970. Previous work has demonstrated that the drop in resistance which occurs with expansion of the lung and with increased PaO2 occurs in both RP and RD. During hypoxia in the newborn both RP and RD increase. In the unventilated lung bradykinin infusion into the pulmonary artery (60–240 η.g./min.) produced a significant decrease in the RP to 52% of control values, no change in RD, and a decrease in the pressure tending to close the Starling resistor vessles (Ps). In the ventilated lung, there was a significant decrease in the RP (64% of control values) with no changes in either RD or Ps. These data indicate that bradykinin has an immediate and direct effect on the pulmonary vasculature and significantly reduces its resistance to flow. This effect is mediated through the resistance vessels proximal to the area of the Starling resistor.