Prostacyclin does not change during an oxygen induced increase in pulmonary blood flow in the fetal lamb

The role of prostacyclin in mediating the increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb was investigated. Plasma concentrations of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin, were measured during an increase in pulmonary blood flow caused by a rise in oxygen tension in eight intrauterine fetal lambs. Fetal oxygen tension was increased by placing the pregnant ewes in a hyperbaric chamber and having them breathe 100% oxygen at three atmospheres absolute pressure. This increased fetal PaO2 from 27 +/- 3 to 60 +/- 6 torr (mean +/- S.E., p less than or equal to 0.0001) and increased the proportion of right ventricular output distributed to the fetal lungs from 6 +/- 2 to 45 +/- 7% (mean +/- S.E., p less than or equal to 0.001). However, the fetal plasma concentration of 6-keto-PGF1 alpha did not change, 186 +/- 26 to 208 +/- 40 pg/ml (mean +/- S.E.). Indomethacin decreased plasma concentrations of 6-keto-PGF1 alpha in each of three fetuses but did not decrease the proportion of right ventricular output distributed to their lungs. The increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb is not associated with an increase in plasma concentrations of 6-keto-PGF1 alpha. Prostacyclin does not appear to be involved in the increase in pulmonary blood flow caused by the increase in oxygen tension at birth.     

Effects of severe reduction in maternal placental blood flow on blood flow distribution in the sheep fetus

To test the hypothesis that fetal lambs are able to maintain oxygen delivery to myocardial, brain and adrenal tissues during reduction in uterine blood flow to 25% of control, we performed experiments on five ewes and their fetuses. A snare occluder was placed around the maternal common hypogastric artery and catheters were placed for measurement of blood pressures, flows, blood gas tensions, pH and oxygen content. After a five day recovery period, control measurements were made. The snare occluder was then closed until the artery was fully occluded. The arterial occlusion caused uteroplacental blood flow to fall to 32 +/- 4% and maternal placental blood flow to fall to 25 +/- 3% of control values. This level of asphyxia was maintained for 19 +/- 3 minutes, when maternal and fetal blood flows were measured again. In response to occlusion, fetal ascending aortic PO2 fell from 21 +/- 2 (SEM) to 13 +/- 2 mmHg (P less than or equal to 0.01), oxygen content from 4.3 +/- 0.3 to 1.4 +/- 0.2 mM (P less than or equal to 0.01) and pH from 7.37 +/- 0.01 to 7.21 +/- 0.05 (P less than or equal to 0.01). PCO2 rose from 48 +/- 1 to 62 +/- 3 mmHg (P less than or equal to 0.01). Fetal arterial blood pressure increased from 51 +/- 3 to 61 +/- 3 mmHg (P less than or equal to 0.001) and heart rate decreased from 172 +/- 10 to 104 +/- 4 beats.min-1 (P less than or equal to 0.01). The heart, brain and adrenals showed vasodilation in response to the asphyxic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporal response of the fetal pulmonary circulation to pharmacologic vasodilators

To determine the temporal response of the fetal pulmonary circulation to pharmacologic vasodilators and to assess vasoreactivity following vasodilation, we infused either acetylcholine, histamine, or bradykinin directly into the left pulmonary artery of 21 chronically prepared fetal sheep. Blood flow (Q) to the left lung was measured by electromagnetic flow transducer. Left pulmonary artery infusion of acetylcholine at 1.5 micrograms.min-1 for 2 hr produced an increase in Q from 59 +/- 8 ml.min-1 to a peak of 113 +/- 10 ml.min-1 at 20 min into the infusion (P less than 0.001). After the peak at 20 min, Q steadily declined toward baseline to 66 +/- 7 ml.min-1 at the end of the 2-hr infusion period (P less than 0.01). Q in the 1/2-hr period following infusion was significantly less than the baseline period (47 +/- 6; P less than 0.04) with no change in pulmonary artery pressure. Similar patterns were seen with 2-hr infusions of histamine (150 ng.min-1) and bradykinin (100 ng.min-1). After a 2-hr infusion of one of the agents, a repeat infusion with that agent or a different one resulted in a diminished response. We conclude that fetal pulmonary vasodilation in response to local infusion of acetylcholine, histamine, or bradykinin is not sustained over a 2-hr period, and that following 2-hr exposure to vasodilators, pulmonary vascular resistance is increased and pulmonary vasoreactivity to pharmacologic vasodilators is decreased.     

Repetitive reduction of uterine blood flow and its influence on fetal transcutaneous PO2 and cardiovascular variables

The influence of repeated asphyxia on fetal transcutaneous PO2, relative local skin perfusion, heart rate, blood gases and pH was investigated in 15 experiments on 8 acutely instrumented sheep fetuses in utero between 125 and 145 days gestation (term is 147 days). Uterine blood flow was intermittently arrested (11 times within 33 min) by intra-vascular maternal aortic occlusion, exposing the fetuses to repeated episodes of asphyxia of 30 (n = 3), 60 (n = 9) and 90 (n = 3) s duration. The fetal transcutaneous PO2 fell as the duration of asphyxia (2 alpha less than 0.01), heart rate deceleration area (2 alpha less than 0.01) and acidaemia (2 alpha less than 0.01) increased. With decreasing skin perfusion, which was dependent on the duration of asphyxia (2 alpha less than 0.001) and acidaemia (2 alpha less than 0.001), a discrepancy developed between transcutaneous and arterial PO2. The increase (delta) in transcutaneous-arterial PO2 difference was related linearly to the duration of asphyxia (2 alpha less than 0.01), the mean haemoglobin oxygen saturation (2 alpha less than 0.001), acidaemia (2 alpha less than 0.001) and relative local skin flow (2 alpha less than 0.05). It was highest after severe episodes of asphyxia (90 s), when O2 saturation, skin blood flow and arterial blood pH values were low. Fetal heart rate deceleration area was only correlated with the cutaneous-arterial PO2 difference when the mean fetal haemoglobin oxygen saturation was below 35%. Thus, a discrimination of heart rate decelerations that are significant for the fetus seems to be possible, when associated with low transcutaneous PO2 values. We conclude that in the sheep fetus transcutaneous PO2 measurements during repeated asphyxial episodes yield information on fetal oxygenation and on the skin vasomotor response.     

Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia

The effect of hypobaric hypoxaemia on the concentration of metabolic substrates in the ovine fetus and pregnant ewe with implanted vascular catheters, was investigated. At 120 to 141 days of gestation sheep were subjected to hypobaria (mean fetal carotid PO2 12.7 +/- 0.7 torr; n = 9) or normobaria (mean fetal carotid PO2 22.7 +/- 0.7 torr; n = 11; P less than 0.001). At 141 days gestation mean fetal weight was 3.46 +/- 0.72 kg in the hypobaric group compared to 4.15 +/- 0.51 in the normobaric group (P less than 0.05). Concentrations of glucose in maternal and fetal plasma and fructose in fetal plasma were similar in hypobaric and normobaric fetuses. The concentration of lactate in fetal plasma rose from 1.68 +/- 1.34 to 8.79 +/- 5.8 mmol/l (P less than 0.001) within 24 h of onset of hypoxia, but fell to 3.36 +/- 1.13 mmol/l by day 3 of treatment, though still significantly above the concentration of lactate in the control fetuses (1.47 +/- 0.47; P less than 0.001). There was no significant effect of hypoxia on the concentration of lactate or alanine in maternal plasma. Alanine concentration in the plasma of fetuses subjected to hypoxia significantly increased within 24 h of exposure (0.28 +/- 0.10 vs 0.58 +/- 0.39 mmol/l; P less than 0.01) and remained elevated for the duration of the study. There was no significant effect of gestational age on the concentration of metabolic substrates in either the control or experimental groups. Hypoxia is associated with a sustained rise in the concentration of plasma lactate and alanine in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

The response of the umbilical artery pulsatility index in fetal sheep to acute and prolonged hypoxaemia and acidaemia induced by embolization of the uterine microcirculation

In eight chronically-instrumented sheep, embolization of the uterine microcirculation was performed to evaluate the response of the umbilical artery pulsatility index to prolonged fetal hypoxaemia and acidaemia. From four days after surgery onwards, fetal arterial oxygen content [( O2]a) was progressively reduced by administration of microspheres into the uterine circulation. Measurements included fetal [O2]a, PO2, PCO2, pH, base excess, heart rate, blood pressure and umbilical artery pulsatility index. Fetal survival varied between less than 2 and less than 8 days, while mean fetal survival was less than 4 days. From baseline condition to the last evaluation preceding the diagnosis of fetal death, [O2]a decreased from 3.10 +/- 0.36 to 0.87 +/- 0.27 mM, pH decreased from 7.36 +/- 0.03 to 7.22 +/- 0.08, base excess decreased from -0.3 +/- 1.5 to -7.3 +/- 3.2 and blood pressure increased from 35.0 +/- 7.1 to 40.7 +/- 8.7 (means +/- SD). The umbilical artery pulsatility index (1.05 +/- 0.19 at baseline condition) did not significantly change (1.08 +/- 0.12 prior to fetal death). It is concluded that a condition of prolonged hypoxaemia and acidaemia in fetal sheep, induced by repeated embolizations of the uterine circulation, is not associated with consistent changes in the umbilical artery pulsatility index.     

The effect of prolonged hypobaric hypoxia on growth of fetal sheep

The effect of prolonged hypobaric hypoxia on fetal sheep was studied. Pregnant ewes were subjected to an atmospheric pressure of 429 torr from 30 days to 135 days gestation (long-term study). Average fetal weight for the hypoxaemic group (3.35 +/- 0.53 kg; n = 4; mean +/- SD) was significantly lower than for the controls (4.23 +/- 0.29 kg; n = 7; P less than 0.05). A short-term study was undertaken with fetuses (n = 8) which were catheterized at 110 days gestation and whose dams were subjected to hypobaric hypoxia from 120 to 141 days gestation. The mean carotid PO2 of fetuses in the hypoxic group was 12.7 +/- 0.7 torr compared to 22.7 +/- 0.7 torr for the control group (n = 9; P less than 0.001) throughout the period of treatment. Fetal arterial oxygen content fell from 6.5 +/- 1.7 to 4.9 +/- 0.4 ml/dl (P less than 0.05), but rose to control values after 7 days due to an increase in fetal haemoglobin concentration (9.6 +/- 1.1 to 13.0 +/- 1.9 g/dl, P less than 0.001) and packed cell volume (33 +/- 3 to 45 +/- 4%, P less than 0.001). In the hypoxaemic fetuses, pH fell initially from 7.34 +/- 0.02 to 7.28 +/- 0.03 (P less than 0.05) and then recovered to 7.32 +/- 0.03 within 24 h. Mean fetal weight of the short-term hypoxic group was 3.46 +/- 0.72 kg compared to 4.15 +/- 0.51 for the control group (P less than 0.05). Both long- and short-term hypoxia produced a similar reduction in fetal body weight. The adrenal glands were significantly heavier in the hypoxic fetuses than in controls. Placental weight was not effected by hypoxia, but exposure from 30 days gestation reduced the average size of cotyledons (P less than 0.05). It is concluded that the fetal sheep increases its ability to acquire and transport oxygen in response to chronic hypoxia, but this compensation is not sufficient to prevent growth retardation or changes to the pattern of tissue growth.     

Fetal pulmonary vasodilation after exogenous platelet-activating factor

To determine the fetal pulmonary vascular response to platelet-activating factor (PAF), we studied the hemodynamic effects of the infusion of PAF directly into the left pulmonary artery in 21 chronically catheterized fetal lambs. Left pulmonary arterial blood flow (Q) was measured with electromagnetic flow transducers. Ten-minute infusions of low-dose PAF (10-100 ng/min) produced increases in Q from a baseline of 71 +/- 5 to 207 +/- 20 ml/min (P less than 0.001) without changes in pulmonary arterial pressure. Pulmonary vasodilation with PAF was further confirmed through increases in Q with brief (15-s) infusions and increases in the slope of the pressure-flow relationship as assessed by rapid incremental compressions of the ductus arteriosus during PAF infusion. Infusion of Lyso-PAF had no effect on Q or pulmonary arterial pressure. Treatment with CV-3988, a selective PAF receptor antagonist, but not with meclofenamate, atropine, or diphenhydramine and cimetidine blocked the response to PAF infusion and did not affect baseline tone. Systemic infusion of high-dose PAF (300 ng/min) through the fetal inferior vena cava increased pulmonary arterial pressure (46.5 +/- 1.0 to 54.8 +/- 1.9 mmHg, P less than 0.01) and aorta pressure (44.3 +/- 1.0 to 52.7 +/- 2.2 mmHg, P less than 0.01) while also increasing Q. Neither PAF nor CV-3988 changed the gradient between pulmonary arterial and aorta pressures, suggesting that PAF does not affect ductal tone. We conclude that PAF is a potent fetal pulmonary vasodilator and that the effects are not mediated through cyclooxygenase products or by cholinergic or histaminergic effects.     

Bradykinin produces pulmonary vasodilation in fetal lambs: role of prostaglandin production

Bradykinin produces pulmonary vasodilation and also stimulates production of other pulmonary vasodilators, including prostaglandin I2 (PGI2) and endothelial-derived relaxing factor. In 12 chronically instrumented fetal lambs, we therefore investigated potential mediation of the bradykinin response by PGI2 or other cyclooxygenase products. A 15-min infusion of bradykinin (approximately 1 microgram/kg estimated fetal wt/min) increased fetal pulmonary blood flow by 522% (P less than 0.05) and decreased pulmonary vascular resistance by 86% (P less than 0.05); plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration also increased (P less than 0.05). After cyclooxygenase inhibition by indomethacin (3 mg), bradykinin increased pulmonary blood flow by only 350% (P less than 0.05) and decreased pulmonary vascular resistance by 83% (P less than 0.05); plasma 6-keto-PGF1 alpha concentrations did not increase. The increase in pulmonary blood flow produced by bradykinin was greater before administration of indomethacin than after (P less than 0.05). These studies demonstrate that bradykinin produces fetal pulmonary vasodilation by at least two mechanisms, one dependent on and the other independent of PGI2 production, the latter mechanism predominating.     

Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension.

During the latter third of gestation, the number of resistance vessels in the lungs of the fetal sheep increases by 10-fold even after correction for lung growth. We measured pulmonary arterial pressure and blood flow directly and calculated total pulmonary resistance (pressure divided by flow) in intrauterine fetal lambs at 93-95 days and at 136 days of gestation (term is 145-148 days). In addition, we used a hyperbaric chamber to increase oxygen tension in the fetuses and measured the effect on the pulmonary circulation. When corrected for wet weight of the lungs, pulmonary blood flow did not change with advancing gestation (139 +/- 42 to 103 +/- 45 ml.100 g-1.min-1). Pulmonary arterial pressure increased (42 +/- 5 to 49 +/- 3 mmHg); thus total pulmonary resistance increased with advancing gestation from 0.32 +/- 0.12 to 0.55 +/- 0.21 mmHg.100 g.min.ml-1. If the blood flow is corrected for dry weight of the lungs, neither pulmonary blood flow nor total pulmonary resistance changed with advancing gestation. Increasing oxygen tension increased pulmonary blood flow 10-fold in the more mature fetuses but only 0.2-fold in the less mature fetuses. At the normal low oxygen tension of the fetus, pulmonary blood flow does not increase between these two points of gestation in the fetal lamb despite the increase in vessel density in the lungs. However, during elevated oxygen tension, pulmonary blood flow does increase in proportion to the increase in vessel density.     

Maximal vascular leg conductance in trained and untrained men

Lower leg blood flow and vascular conductance were studied and related to maximal oxygen uptake in 15 sedentary men (28.5 +/- 1.2 yr, mean +/- SE) and 11 endurance-trained men (30.5 +/- 2.0 yr). Blood flows were obtained at rest and during reactive hyperemia produced by ischemic exercise to fatigue. Vascular conductance was computed from blood flow measured by venous occlusion plethysmography, and mean arterial blood pressure was determined by auscultation of the brachial artery. Resting blood flow and mean arterial pressure were similar in both groups (combined mean, 3.0 ml X min-1 X 100 ml-1 and 88.2 mmHg). After ischemic exercise, blood flows were 29- and 19-fold higher (P less than 0.001) than rest in trained (83.3 +/- 3.8 ml X min-1 X 100 ml-1) and sedentary subjects (61.5 +/- 2.3 ml X min-1 X 100 ml-1), respectively. Blood pressure and heart rate were only slightly elevated in both groups. Maximal vascular conductance was significantly higher (P less than 0.001) in the trained compared with the sedentary subjects. The correlation coefficients for maximal oxygen uptake vs. vascular conductance were 0.81 (trained) and 0.45 (sedentary). These data suggest that physical training increases the capacity for vasodilation in active limbs and also enables the trained individual to utilize a larger fraction of maximal vascular conductance than the sedentary subject.     

Adenosine causes a biphasic response in the ovine fetal placental vasculature

We have reported in a previous study that adenosine infusion causes fetal placental vascular resistance to increase after 2 min. To determine whether this action is followed by a more prolonged vasodilation, we studied 7 mature fetal lambs. At surgery, catheters were inserted into the fetal hindlimb arteries and veins. After a five day recovery period, control blood flow measurements were made by radiolabeled microsphere technique immediately after an infusion of 0.9% NaCl, (vehicle, 1.03 ml.min-1) into a fetal vein for 2 min. Within 5 min of the control blood flow measurement, adenosine (10 mg/min) was infused for 2 min. Blood flow measurements were repeated 5, 10, 15, 20 and 30 min after the end of the infusion period. Fetal arterial blood pressure dropped from 50 +/- 1 to 34 +/- 5 mmHg immediately after the adenosine infusion and returned to the control value within 5 min after the infusion. No further blood pressure response was detected. However, placental vascular resistance fell from 0.334 +/- 0.040 to 0.269 +/- 0.027 (P less than 0.05) at the 15 min measurement, remained low through the 20 min measurement (P less than 0.001) and was not different from control levels 30 min after the adenosine infusion. We conclude that the fetal placental vasculature responds to systemic adenosine infusion in a biphasic manner. The immediate reaction to adenosine is a transient vasoconstriction in the fetal placental vasculature followed by vasodilation 15 to 20 min after the initial exposure to adenosine.     

Fasudil inhibits the myogenic response in the fetal pulmonary circulation

In addition to high pulmonary vascular resistance (PVR) and low pulmonary blood flow, the fetal pulmonary circulation is characterized by mechanisms that oppose vasodilation. Past work suggests that high myogenic tone contributes to high PVR and may contribute to autoregulation of blood flow in the fetal lung. Rho-kinase (ROCK) can mediate the myogenic response in the adult systemic circulation, but whether high ROCK activity contributes to the myogenic response and modulates time-dependent vasodilation in the developing lung circulation are unknown. We studied the effects of fasudil, a ROCK inhibitor, on the hemodynamic response during acute compression of the ductus arteriosus (DA) in chronically prepared, late-gestation fetal sheep. Acute DA compression simultaneously induces two opposing responses: 1) blood flow-induced vasodilation through increased shear stress that is mediated by NO release and 2) stretch-induced vasoconstriction (i.e., the myogenic response). The myogenic response was assessed during acute DA compression after treatment with N(omega)-nitro-L-arginine, an inhibitor of nitric oxide synthase, to block flow-induced vasodilation and unmask the myogenic response. Intrapulmonary fasudil infusion (100 microg over 10 min) did not enhance flow-induced vasodilation during brief DA compression but reduced the myogenic response by 90% (P<0.05). During prolonged DA compression, fasudil prevented the time-dependent decline in left pulmonary artery blood flow at 2 h (183+/-29 vs. 110+/-11 ml/min with and without fasudil, respectively; P<0.001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation.     

Lung liquid secretion, flow and volume in response to moderate asphyxia in fetal sheep

The effects of moderate fetal asphyxia, induced by constriction of the maternal common internal iliac artery, on lung liquid secretion, tracheal fluid efflux and lung liquid volume have been investigated in unanaesthetized fetal sheep (111-142 days) in utero. During periods of fetal asphyxia the percent oxygen saturation, PO2, pH, and PCO2 of fetal carotid arterial blood changed from 57.2 +/- 1.3% (mean +/- SEM), 22.9 +/- 0.6 mmHg, 7.35 +/- 0.01 and 45.6 +/- 1.0 mmHg to 26.3 +/- 0.5% (P less than 0.001), 14.7 +/- 0.2 mmHg (P less than 0.001), 7.28 +/- 0.02, (P less than 0.001) and 47.8 +/- 0.4 mmHg (P less than 0.02), respectively. Fetal asphyxia, over 6 h, decreased the efflux of tracheal fluid from 7.07 +/- 0.47 ml/h to 3.97 +/- 0.36 ml/h (P less than 0.01) and, over 4 h, decreased the rate of lung liquid secretion from 9.42 +/- 1.76 ml/h to 4.91 +/- 1.54 ml/h (P less than 0.005), whereas it had no significant effect on lung liquid volume. The incidence of fetal breathing movements decreased from 52.9 +/- 2.5% to 22.6 +/- 3.5% during 6-h periods of fetal asphyxia. Thus, although fetal asphyxia decreased the net production of lung liquid, lung liquid volume was maintained probably, because the net efflux of fluid from the lungs via the trachea decreased to a similar extent.     

Role of oxidative phosphorylation and ATP release in mediating birth-related pulmonary vasodilation in fetal lambs

We investigated the hypothesis that birth-related pulmonary vasodilation is mediated in part by an increase in oxidative phosphorylation and ATP release in response to oxygen exposure at birth. Studies were done in fetal lambs to evaluate the independent effects of oxygen, lung distension alone, or lung distension accompanied by oxygenation and shear stress on fetal pulmonary blood flow and resistance and plasma ATP levels in the pulmonary artery. The effect of each intervention was evaluated in lambs assigned to one of three groups: control or pretreatment with 2,4-dinitrophenol or antimycin-A, inhibitors of oxidative phosphorylation. Exposure to oxygen alone or with lung distension was associated with increases in plasma ATP levels and pulmonary blood flow and a decrease in pulmonary vascular resistance. Plasma ATP levels did not change during lung distension alone. 2,4-Dinitrophenol and antimycin-A attenuated the pulmonary vasodilator response to oxygen but did not attenuate the response to lung distension alone. An increase in oxidative phosphorylation and ATP release during oxygen exposure may contribute to birth-related pulmonary vasodilation in fetal lambs.     

Hypoxia-induced alterations of norepinephrine vascular reactivity in isolated perfused cat lung

Past work in the isolated perfused cat lung has shown that acute hypoxia (H) changes the response to norepinephrine (NE) from vasoconstriction to vasodilation but has no effect on the response to serotonin (S). These results could be related to the increase in pulmonary arterial pressure or vascular resistance during the hypoxic pressor response or a direct effect of H. We addressed this question, in the same preparation, by comparing responses to NE under four conditions in each experimental animal (n = 12): 1) NE infused during normoxia; 2) NE infused after vascular resistance (Rpv) was increased with serotonin; 3) NE infused after Rpv was increased by H; 4) NE infused after lobar pressure was raised by an increase in flow (P/F). PO2 values during H were varied (27-56 Torr). S and H produced a 137 +/- 35 and 43 +/- 8% delta Rpv increase in lobar vascular resistance, respectively. P/F increased lobar pressure 91 +/- 10%. Only NE infusion during H demonstrated significant differences in lobar pressure and Rpv compared with control normoxic periods. There was no correlation between responses to NE during S, H, and P/F and degree to which each stimulus increased Rpv or lobar pressure (r = 0.003, 0.28, 0.24). A significant relationship between response to NE during H vs. PO2 during H was observed (r = 0.78; P less than 0.001). In a subset of animals, we repeated the infusion of NE during H and P/F post-beta-blockade. The decrease in vascular response to NE during H and the correlation of PO2 with NE response were abolished (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of vascular reactivity to serotonin in the dog lung

Experiments were conducted to compare the effects of cyclooxygenase inhibition (COI) on vascular reactivity to serotonin (5-HT) in the isolated blood-perfused canine left lower lung lobe (LLL) and in isolated canine intrapulmonary lobar artery rings with and without a functional endothelium. LLLs (n = 6), perfused at constant blood flow, were challenged with bolus doses of 50, 100, and 250 micrograms 5-HT before COI, after COI with 45 microM meclofenamate, and after infusion of prostacyclin (PGI2) during COI. Lobar vascular resistance was segmentally partitioned by venous occlusion. Pulmonary arterial pressure increased from 13.5 +/- 1.0 to 16.3 +/- 0.8 cmH2O (P less than 0.01) after COI but declined to 13.1 +/- 1.1 cmH2O (P less than 0.01) subsequent to PGI2 infusion (91.3 +/- 14.5 ng.min-1.g LLL-1). The pulmonary arterial pressure changes were related to changes in postcapillary resistance. The dose-dependent pressor response to 5-HT was potentiated by COI (P less than 0.01) but reversibly attenuated (P less than 0.05) by PGI2 infusion. Isolated intrapulmonary artery rings (2-4 mm diam) exhibited a dose-related increase in contractile tension to 5-HT. The response to 5-HT was enhanced (P less than 0.05) in rings devoid of a functional endothelium. However, COI (10 microM indomethacin) did not alter (P greater than 0.05) the dose-related increase in contractile tension to 5-HT in rings with an intact endothelium. Our results suggest that both PGI2 and endothelium-derived relaxing factors modulate pulmonary vascular reactivity to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of bronchial arterial PO2 on pulmonary vascular resistance

In six anesthetized and mechanically ventilated adult sheep, the bronchial artery was perfused with blood from an oxygenator-pump circuit. When the lungs were ventilated with 100% O2 and the bronchial O2 tension (PbrO2) was approximately 600 Torr, the mean of the pulmonary vascular resistances (PVR) measured at the beginning (3.32 +/- 0.29 units) and end (3.17 +/- 0.13 units) of the experiment was 3.24 +/- 0.20 units. When the PbrO2 was changed to 58 +/- 1 Torr, the PVR (2.99 +/- 0.14 units) did not change significantly. However, when the lungs were ventilated with air as PbrO2 was decreased to 91 +/- 4, 77 +/- 3, 56 +/- 2, and 42 +/- 1 Torr, the PVR increased to 3.67 +/- 0.18, 4.03 +/- 0.16, 4.79 +/- 0.19, and 4.71 +/- 0.35 units, respectively. However, when the PbrO2 was decreased further to 26 +/- 1 and 13 +/- 1 Torr, the PVR decreased to 3.77 +/- 0.28 and 3.91 +/- 0.30 units, respectively. In contrast, the bronchial vascular resistance decreased monotonically as PbrO2 decreased. The bronchial circulation supplies vasa vasorum to the walls of all but the smallest pulmonary arteries, and it is therefore suggested that the PO2 of the bronchial circulation is responsible for the bimodal response of the pulmonary vasculature, with stimulation of hypoxic pulmonary vasoconstriction at moderate hypoxemia and of hypoxic pulmonary vasodilation at profound hypoxemia. The physiological and pathophysiological significance of the influence of systemic PO2 on pulmonary vascular tone is discussed.     

Effect of metabolic acidosis on fetal renal haemodynamics

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.     

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.