Stiffened erythrocytes augment the pulmonary hemodynamic response to hypoxia

Isolated rat lungs were perfused with suspensions containing normal and stiffened erythrocytes (RBCs) during normoxic and hypoxic ventilation to assess the effect of reduced RBC deformability on the hypoxic pressor response. RBC suspensions were prepared with cells previously incubated in isotonic phosphate-buffered saline with or without 0.0125% glutaraldehyde. The washed RBCs were resuspended in isotonic bicarbonate-buffered saline (with 4% albumin) to hematocrits of approximately 35%. The lungs were perfused with control and experimental cell suspensions in succession while pulmonary arterial pressure was measured during normoxic (21% O2) and hypoxic (3% O2) ventilation. On the attainment of a peak hypoxic pressor response, flow rate was changed so that pressure-flow curves could be constructed for each suspension. RBC deformability was quantified by a filtration technique using 4.7-microns-pore filters. Glutaraldehyde treatment produced a 10% decrease in RBC deformability (P less than 0.05). Over the range of flow rates, Ppa was increased by 15-17% (P less than 0.05) and 26-31% (P less than 0.05) during normoxic and hypoxic ventilation, respectively, when stiffened cells were suspended in the perfusate. The magnitude of the hypoxic pressor response was 50-54% greater with stiffened cells over the three flow rates. In a separate set of experiments, normoxic and hypoxic arterial blood samples from conscious unrestrained rats were used to investigate the effects of acute hypoxia on RBC deformability. Deformability was measured with the same filtration technique. There was no difference in the deformability of hypoxic compared with normoxic RBCs. We conclude that the presence of stiffened RBCs enhances the hemodynamic response to hypoxia but acute hypoxia does not affect RBC deformability.     

Reversal of pulmonary hypoxic vasoconstriction with pentoxifylline and aminophylline in isolated lungs

Pentoxifylline (Pent) is a xanthine known to improve erythrocyte deformability and thought to have little effect on smooth muscle tone. In this study I examined the direct effects of Pent on the pulmonary vasculature of isolated lungs and compared them with the effects of aminophylline. The object was to study whether Pent can reverse the hypoxic pressor response (HPR) by its hemorheological property. Changes in pulmonary arterial pressure (Pa) of isolated lungs (pigs and rats) perfused at constant flow rate were monitored to reflect changes in vascular resistance. During normoxia, injection of Pent (5 mg/kg animal weight) in pig lungs depressed the Pa from 12.8 +/- 1.8 to 8.1 +/- 0.8 mmHg (1 mmHg = 133.3 Pa); whereas during hypoxia, Pa was depressed from 34.0 +/- 2.3 to 12.3 +/- 1.4 mmHg. To identify the mechanism of this vasodepressor effect (being either vasodilation or improved erythrocyte deformability), I tested the effect of Pent in lungs perfused with cell-free perfusate. In these plasma-perfused lungs, the vasodepressor effects of Pent were similar to those observed during blood perfusion (slight depression in Pa during normoxia, but large during hypoxia). Similar experiments in blood and plasma perfused pig lungs revealed that aminophylline (5 mg/kg) also produced similar vasodepressor responses. The effects of Pent in rat lungs were comparable; no effect during normoxia, but a depressor effect during hypoxia. Vasoconstriction in pig lungs induced by angiotensin infusion was also abolished by Pent.(ABSTRACT TRUNCATED AT 250 WORDS)     

慢性常压缺氧和缺氧伴CO_2潴留大鼠红细胞变形能力与能量代谢的研究

本工作研究了慢性常压缺氧和缺氧伴ＣＯ＿２潴留肺动脉高压大鼠红细胞变形能力和红细胞内ＡＴＰ含量的变化。结果表明,慢性常压缺氧和缺氧伴ＣＯ＿２潴留大鼠不同切应力下的红细胞变形指数和红细胞内ＡＴＰ含量均明显低于其对照组,且该两组红细胞内ＡＴＰ含量与不同切应力下的红细胞变形指数呈显著正相关。提示慢性缺氧和伴ＣＯ＿２潴留大鼠红细胞内ＡＴＰ含量降低可能是导致红细胞变形能力降低的诸因素之一,后者又可导致和加重肺动脉高压的形成。     

Erythrocyte deformability and segmental pulmonary vascular resistance: osmolarity and heat treatment

The site and nature of change in resistance to blood flow in canine left lung lobe preparation after changes in blood viscosity were assessed by using the arterial and venous occlusion (AVO) technique and the vascular pressure-flow relationship. Blood viscosity was changed by erythrocyte (RBC) shrinkage and swelling with hypertonic and hypotonic NaCl solutions and by RBC membrane rigidification with heat treatment (49 degrees C for 1 h). The results show that although all three methods of changing blood viscosity increased the pulmonary vascular resistance (PVR) by 15-50%, the site and nature of the change in PVR were different in each case. The AVO data showed that the increase in PVR with heat treatment of RBC's was due entirely (100%) to increased resistance of the middle microvascular segment, whereas deviation from normal osmolarity potentiated the resistance in arterial, middle, and venous segments. By examining the effect of osmolarity in plasma-perfused lobes, it was possible to separate the increase in PVR due to changes in RBC deformability from those due to other factors. The increase in arterial and venous resistances with hypertonic solution was attributed in part (approximately 50%) to factors other than RBC's; however, the increase in middle resistance was entirely due to RBC crenation. The increase in arterial and venous resistances with hypotonic solutions was small and was apparently caused by factors other than RBC swelling, whereas the increase in middle resistance was partially (approximately 50%) due to RBC swelling and partially to other factors (e.g., endothelial cell hydration).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of acute hypoxia upon brilliant cresyl blue-induced disintegration of erythrocytes in rabbits and cats

The disintegration of erythrocytes by brilliant cresyl blue was studied in rabbits and cats during two hypoxic periods resulting in apnoea which was followed by artificial ventilation and recovery. The rate of erythrocyte disintegration was measured after 2 hours' incubation in isotonic NaCl or Krebs-Ringer solution plus brilliant cresyl blue (0.5 mmol.l-1). Significant increases of disintegration rates were found in rabbits during recovery in both incubation solutions. Erythrocytes in cats seemed to be more resistant to acute hypoxia, as their disintegration rate rose only in isotonic NaCl solution, and that only transiently. Brilliant cresyl blue--induced erythrocyte disintegration in cats did not differ from the control values during 10 min of spontaneous breathing after the first and the second period of hypoxia in the isotonic NaCl solution, but it was significantly lower in Krebs-Ringer solution. The possible factors influencing the erythrocyte disintegration rate in acute hypoxia are discussed.     

Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction

Lipoxygenase products (leukotrienes) have been proposed as the mediators of pulmonary hypoxic vasoconstriction. However, the supporting data are inconclusive because the lipoxygenase and leukotriene receptor blockers that reduce hypoxic vasoconstriction (such as diethylcarbamazine and the FPL's) have confounding effects. We investigated BW 755C, a potent inhibitor of both lipoxygenase and cyclooxygenase, in eight intact anesthetized dogs with acute left lower lobe atelectasis. We examined two manifestations of hypoxic vasoconstriction: shunt fraction, as an inverse indicator of regional constriction in response to local hypoxia, and the pulmonary pressor response to global alveolar hypoxia, as an index of general hypoxic vasoconstriction. During normoxia, shunt fraction, measured using a sulfur hexafluoride infusion, was 32.0 +/- 7.0%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient produced by 10% O2 inhalation, averaged 4.5 +/- 1.8 mmHg. Then, during normoxia, BW 755C was administered. Shunt fraction fell in all eight dogs from the previous mean of 32% to 25.5 +/- 6.1% (t = 6.5, P less than 0.0005). The hypoxic pressor response rose in all dogs, from the previous 4.5 mmHg to 9.0 +/- 3.5 mmHg (t = 4.5, P less than 0.005). BW 755C enhances hypoxic vasoconstriction, an effect consistent with its activity as a cyclooxygenase inhibitor. These data do not support a substantive role for the lipoxygenase pathway in hypoxic vasoconstriction.     

Failure of histamine antagonists to prevent hypoxic pulmonary vasoconstriction in dogs.

The role of histamine as a mediator of hypoxic pulmonary vasoconstriction was examined in intact anesthetized dogs. Antagonism of histamine vasoconstrictor (H1) receptors with a classic antihistaminic drug (chlorpheniramine) failed to prevent or modify the pulmonary vascular responses to hypoxia (10% O2). Blockade of histamine vasodilator (H2) receptors with a newly synthesized blocking agent (metiamide) potentiated the vasoconstriction induced by hypoxia and prevented the normal increase in heart rate. Combined H1- and H2-receptor blockade also did not prevent or reduce the hypoxic pulmonary pressor response, although it did effectively abolish the cardiovascular actions of infused histamine. In other dogs, histamine infused (3.6 mug/kg per min) during hypoxia attenuated the pulmonary vasoconstriction induced by hypoxia. The results imply that, in the dog, histamine does not mediate hypoxic pulmonary vasoconstriction. However, histamine does appear to be released during hypoxia, and it may play a role in modulating the pulmonary vascular responses to hypoxia by opposing the hypoxia induced vasoconstriction. The results also imply that histamine may be responsible for the increase in heart rate during hypoxia.     

Ozone inhibits prostacyclin synthesis in pulmonary endothelium

The effects of ozone on lung arachidonate metabolism in-vitro were studied in cultured bovine pulmonary endothelial cells exposed for 2 hours to ozone in concentrations up to 1.0 ppm. A concentration-dependent decrease in prostacyclin synthesis was found (90% decrease at the highest ozone level of 1.0 ppm). The inhibition of prostacyclin synthesis was not due to a decreased release of arachidonic acid from membrane lipids. We also examined the hypoxic pulmonary vasoconstrictive response to 10% oxygen inhalation in anesthetized dogs in-vivo after exposure to 1.0 ppm ozone for 1 hour. Pulmonary vascular resistance was significantly increased after ozone exposure, similar to the findings in dogs given indomethacin (15 mg/kg). The percentage change in the hypoxic pulmonary pressor response was similar between the ozone exposure and indomethacin-treated groups, although due to the variance of the pulmonary vascular resistance values during hypoxia the results did not reach statistical significance. These results suggest that ozone inhalation affects pulmonary endothelial arachidonate metabolism in-vivo as well as in-vitro.     

Hypoxia-induced activation in small isolated pulmonary arteries from the cat

Effects of hypoxia on force development and membrane potential were studied in isolated small (less than 300 microns diam) and large (greater than 500 microns diam) pulmonary arteries from cats. There was a consistent and reproducible hypoxic constrictor response in small pulmonary arteries that began at PO2 values between 350 and 300 Torr and reached a maximum at PO2 between 50 and 30 Torr. In the small artery smooth muscle cell the membrane potential, which was -51 +/- 1.4 mV at a PO2 of 400 Torr, was depolarized to -37 +/- 2 mV at a PO2 of 50 Torr. In contrast, larger arteries did not exhibit significant hypoxic constriction or depolarization upon exposure to low PO2. Constriction in small arteries was not blocked by phentolamine. Treatment with a low dose of indomethacin (10(-9) M) augmented the response; however, a larger dose of indomethacin (10(-3) M) blocked the constriction to hypoxia but not to 30 mM KCl. Depolarization during hypoxia was not blocked by ouabain. Results of this study suggest that the hypoxic response of these isolated small pulmonary vessels may be like that seen in the intact lung. Furthermore, these data suggest that hypoxic vasoconstriction may be mediated by electrical events occurring at the pulmonary arterial muscle cell membrane either directly or via mediators released from the vessel wall.     

Hypoxic pulmonary vasoconstriction during steady and pulsatile flow in ferrets

We examined the effects of hypoxia and pulsatile flow on the pressure-flow relationships in the isolated perfused lungs of Fitch ferrets. When perfused by autologous blood from a pump providing a steady flow of 60 ml/min, the mean pulmonary arterial pressure rose from 14.6 to 31.3 Torr when alveolar PO2 was reduced from 122 to 46 Torr. This hypoxic pressor response was characterized by a 10.1-Torr increase in the pressure-axis intercept of the extrapolated pressure-flow curves and an increase in the slope of these curves from 130 to 240 Torr X l-1 X min. With pulsatile perfusion from a piston-type pump, mean pulmonary arterial pressure increased from 17.5 to 36.3 Torr at the same mean flow. This hypoxic pressor response was also characterized by increases in the intercept pressure and slope of the pressure-flow curves. When airway pressure was raised during hypoxia, the intercept pressure increased further to 25 +/- 1 Torr with a further increase in vascular resistance to 360 Torr X l-1 X min. Thus, in contrast to the dog lung, in the ferret lung pulsatile perfusion does not result in lower perfusion pressures during hypoxia when compared with similar mean levels of steady flow. Since the effects of high airway pressure and hypoxia are additive, they appear to act at or near the same site in elevating perfusion pressure.     

Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period

Newborn rats were exposed to hypoxia (10% O2 + N2) from 24 h to day 6 of neonatal life and then returned to room air until 45 days of age (experimental). The rats were anaesthetized, heparinized, and exsanguinated. The chest was opened and the lungs were perfused with diluted autologous blood at a constant flow rate (Q). The pulmonary arterial pressure (Pa) and venous pressure (Pv) were monitored. The properties of the pulmonary vasculature were assessed by measuring baseline vascular resistance, PVR = (Pa-Pv)/Q, segmental pressure gradients (double occlusion technique), pressure-flow relationship, hypoxic pressor response (HPR, 3% O2), and the response to 0.5 microgram bolus of angiotensin II (AII). These were compared with similar measurements on age-matched control animals never exposed to hypoxia. The perfusate hematocrit and gases were not significantly different between the two groups. The PVR normalized to body weight was 30% higher in the experimental groups (p less than 0.005). The double occlusion results (obtained at a flow rate of 13 mL/min) revealed that this increase in resistance was primarily due to the increase in the postcapillary resistance. HPR was primarily in the upstream segment in both groups but was larger in the experimental group. In contrast, the response to AII occurred in both the upstream as well as in the downstream vascular segments and did not differ between the two groups. We conclude that adult rats exposed to hypoxia in the neonatal period have elevated pulmonary vascular resistance and increased vascular reactivity to hypoxia.     

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured "on-line" using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.     

Failure of acute hypoxia to alter pulmonary prostaglandin metabolism in dogs

We studied the effects of acute hypoxia (Fi02 = 0.09-0.11, 20 min.) on transpulmonary plasma prostaglandin (PG) concentrations in ten anesthetized, paralyzed, artificially ventilated dogs. Concentrations of 6-keto-PGF1 alpha, TxB2, PGE2, PGF2 alpha, and 13,14-dihydro-15-keto-PGF2 alpha were measured from the pulmonary artery and abdominal aorta using radioimmunoassay. In an additional six dogs, the effects of arachidonic acid (AA) infusions (100 mcg/kg/min) during normoxia and acute hypoxia were determined. Compared to normoxic conditions, acute hypoxia increased pulmonary artery pressure (p less than 0.05), decreased both the arterial oxygen tension (PaO2) and the alveolar-to-arterial oxygen tension gradient (A-aDO2) (p less than 0.05), but did not affect transpulmonary plasma PG concentrations. AA infusions significantly (p less than 0.05) increased 6-keto-PGF1 alpha independent of FiO2. Acute hypoxia failed to elicit a pulmonary pressor response in the AA-treated animals although PaO2 and A-aDO2 decreased (p less than 0.05). These data in healthy dogs suggest that (1) acute hypoxia does not alter net pulmonary PG metabolism, (2) prostacyclin synthesis is stimulated by increased plasma AA concentrations and (3) this effect may block normal pressor responses to hypoxic stimuli.     

Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30-50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.     

Effects of prostaglandins of the E-series on pulmonary and systemic circulations of newborn goats during normoxia and hypoxia.

Effects of exogenous prostaglandins of the E-series on pulmonary and systemic circulations of newborn goats were investigated during normoxia and hypoxia. Pulmonary arterial infusion of prostaglandins E1 and E2 decreased pulmonary vascular resistance 20% and 14%, respectively, without systemic effects. Prostaglandin E1 abolished the pulmonary pressor response to hypoxia. Prostaglandin E2 was less effective in counteracting this hypoxic response. The increased pulmonary vascular resistance and augmented response to hypoxia following indomethacin administration was reversed by prostaglandin E1. Infusion of prostaglandin E1 directly into the pulmonary circulation may be of benefit to the distressed newborn with elevated pulmonary vascular resistance.     

Attenuation of pulmonary and systemic vasoconstriction with pentoxifylline and aminophylline

The effects of acute administration of therapeutic doses (1-10 mg/kg) of pentoxifylline and aminophylline on the resistance of the systemic and pulmonary circuits in anaesthetized dogs and pigs were tested. During room air breathing, neither of the two substances caused a significant change in systemic vascular resistance (SVR) or pulmonary vascular resistance (PVR). During hypoxia (10% O2 and nitrogen), however, both substances caused a significant reduction in PVR (p less than 0.05) without affecting SVR. The largest dose of pentoxifylline decreased PVR from 7.8 +/- 2.8 to 4.4 +/- 1.5 in dogs and from 9.9 +/- 1.4 to 5.8 +/- 0.6 mmHg.L-1.min in pigs. Aminophylline was equally effective and selective in lowering PVR but not SVR during hypoxia. When SVR was elevated in dogs by continuous infusion of angiotensin, pentoxifylline lowered SVR from 139 +/- 27 to 83 +/- 20 mmHg.L-1.min (p less than 0.05). The simultaneous small elevation in PVR during angiotensin infusion was also attenuated to base-line value by pentoxifylline injection. These results suggest that xanthines, in therapeutic doses, can have a profound vasodilator effect on either the systemic or on the pulmonary circuit, only wherever the vessels are constricted. The vasodilatory effect of pentoxifylline is viewed as a second beneficial effect besides the benefit derived from its action on erythrocyte deformability.     

Behavioral thermoregulation by hypoxic rats.

To address whether a shift in hypothalamic thermal setpoint might be a significant factor in induction of hypoxic hypothermia, behavioral thermoregulation was examined in 7 female Sprague-Dawley rats implanted with radiotelethermometers for deep body temperature (Tb) measurement in a thermocline during normoxia (PO2 = 125 torr) and hypoxia (PO2 = 60 torr). Normoxic rats (TNox) selected a mean ambient temperature of 19.7 +/- 1.4 (SE) degrees C and maintained Tb at 37.0 +/- 0.2 degrees C. Hypoxic rats selected a significantly higher ambient temperature (THox = 28.6 +/- 2.2 degrees C) but maintained Tb significantly lower at 35.5 +/- 0.3 degrees C. Without a thermal gradient (ambient temperature = 25 degrees C), Tb during hypoxia was 35.4 +/- 0.4 degrees C. The maintenance of a lower body temperature during hypoxia through behavioral thermoregulation despite having warmer temperatures available supports the hypothesis that the thermoregulatory setpoint of hypoxic rats is shifted to promote thermoregulation at a lower Tb, effectively reducing oxygen demand when oxygen supply is limited.     

Attenuation of hypoxic pulmonary vasoconstriction by verapamil in intact dogs.

The hypothesis that hypoxic pulmonary vasoconstriction is mediated directly by depolarization of the vascular smooth muscle was tested in anesthetized dogs. Pulmonary vascular responses to hypoxia were first determined in eight dogs during 20-min exposures to 10% O2. Each animal was then treated with verapamil (0.5 mg/kg, iv), to block transmembrane Ca2+ influx in an attempt to abolish the vasoconstrictor responses to hypoxia. The hypoxic exposures were then repeated, and the pulmonary vascular responses were compared to the control responses. Verapamil administration attenuated hypoxic pulmonary vasoconstriction, but did not abolish the responses to hypoxia. Pulmonary vascular resistance increased 87% during the control hypoxic exposure, but increased only 38% during hypoxia after verapamil. The response to another vasoconstrictor, prostaglandin F2alpha, was not reduced by verapamil indicating a different mechanism of mediation. These results suggest that the pulmonary vasoconstrictor response to alveolar hypoxia, in the intact dog, involves transmembrane Ca2+ influx, and are consistent with the idea that hypoxia acts primarily by directly depolarizing vascular smooth muscle, rather than acting indirectly through a chemical mediator.     

Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs

We studied whether intravenously administered inhibitors of leukotriene synthesis (diethylcarbamazine, DEC) or end-organ effect (FPL-55712) would change the distribution of regional pulmonary blood flow (rPBF) caused by left lower lobe (LLL) alveolar hypoxia in dogs. Both drugs failed to alter rPBF. In addition, the pressor response to whole-lung hypoxia was not blocked by an FPL-55712 infusion. On the other hand, nitroprusside, as a nonspecific vasodilator also administered intravenously, was able to partially reverse the effects of LLL hypoxia on rPBF. Thus our data do not support a role for leukotriene mediation of hypoxic pulmonary vasoconstriction in dogs.     

Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs.

The purpose of this study was to determine whether pulmonary venous pressure increases during alveolar hypoxia in lungs of newborn pigs. We isolated and perfused with blood the lungs from seven newborn pigs, 6-7 days old. We maintained blood flow constant at 50 ml.min-1.kg-1 and continuously monitored pulmonary arterial and left atrial pressures. Using the micropuncture technique, we measured pressures in 10 to 60-microns-diam venules during inflation with normoxic (21% O2-69-74% N2-5-10% CO2) and hypoxic (90-95% N2-5-10% CO2) gas mixtures. PO2 was 142 +/- 21 Torr during normoxia and 20 +/- 4 Torr during hypoxia. During micropuncture we inflated the lungs to a constant airway pressure of 5 cmH2O and kept left atrial pressure greater than airway pressure (zone 3). During hypoxia, pulmonary arterial pressure increased by 69 +/- 24% and pressure in small venules increased by 40 +/- 23%. These results are similar to those obtained with newborn lambs and ferrets but differ from results with newborn rabbits. The site of hypoxic vasoconstriction in newborn lungs is species dependent.