Excess nitric oxide decreases cytochrome P-450 2J4 content and P-450-dependent arachidonic acid metabolism in lungs of rats with acute pneumonia

Recently, we demonstrated that pulmonary CYP2J4 content, a prominent source of EETs and HETEs formation in rat lungs, is reduced in pneumonia. Therefore, the purpose of this study was to determine the role of iNOS-derived NO in reduced pulmonary CYP2J4 protein content and decreased CYP metabolites in pneumonia. Rats were randomized to control, control plus 1400W (iNOS inhibitor), pneumonia, and pneumonia plus 1400W groups. Pseudomonas organisms were injected into lungs of pneumonia rats. At 40 h after surgery, rats were treated with either saline or 1400W for 4 h before death. Venous plasma samples were obtained for measuring nitrites/nitrates (NOx). There was no significant effect of 1400W on blood pressure measured in control or pneumonia rats, whereas 1400W reduced the elevated plasma NOx levels in pneumonia rats by half. CYP primary metabolites of AA formed at significantly lower rates in pulmonary microsomes from pneumonia rats compared with control rats. Treatment of pneumonia rats with 1400W resulted in a significant increase in the rate of formation of pulmonary EETs and omega-terminal HETEs compared with untreated pneumonia rats. The reduction in CYP2J4 protein content in pneumonia lung microsomes was also partially prevented by 1400W. Therefore, excess NO from iNOS decreases the pulmonary production of EETs and omega-HETEs in acute pneumonia. Inhibition of iNOS restores CYP2J4 protein content and CYP activity in acute pneumonia, indicating an important NO-CYP interaction in pulmonary responses to infection. We speculate CYP2J4 and its AA metabolites are involved in the modulation of pulmonary function in health and disease.     

Effects of gas composition and pH on kinetics of lung angiotensin-converting enzyme

Given the pH dependence of enzymes in general and the potential importance of a blood and alveolar gas composition dependency on the interpretation of changes in the hydrolysis of angiotensin-converting enzyme (ACE) substrates by pulmonary endothelial ACE, we examined the influence of Pco2 and Po2 on the hydrolysis of a synthetic ACE substrate (benzoyl-phenylalanyl-alanyl-proline, BPAP) on passage through isolated rabbit lungs. Perfusate pH values of about 7.1, 7.4, and 7.9 were obtained by ventilating the lungs with gas containing different CO2 concentrations and Po2 values of approximately 110 and approximately 10 Torr were obtained by varying the concentration of O2 in the ventilating gas mixture. In the range studied neither acidosis nor alkalosis produced any significant changes in BPAP hydrolysis or in the kinetic parameters, Vmax and Km, for the hydrolysis process. On the other hand, a reduction in BPAP hydrolysis was detected when the Po2 was reduced from 110 to 10 Torr. The Vmax for BPAP hydrolysis by the lung was inversely correlated with the magnitude of the hypoxic vasoconstriction that occurred, suggesting that the reduced BPAP hydrolysis with hypoxia was due to the loss of perfused surface area due to the vasoconstriction. The results suggest that correlations between Pco2 and/or pH and whole-lung ACE activity that might occur in diseased lungs do not imply causalty. The hemodynamic consequences of changing Po2 (i.e., hypoxic vasoconstriction) may alter whole-organ ACE activity in the sense of changing the perfused surface area (i.e., the amount of ACE in contact with flowing perfusate).     

Perinatal history of hypoxia leads to lower vascular pressures and hyporeactivity to angiotensin II in isolated lungs of adult rats

The most dramatic changes in pulmonary circulation occur at the time of birth. We hypothesized that some of the effects of perinatal hypoxia on pulmonary vessels are permanent. We studied the consequences of perinatal exposure to hypoxia (12 % O2 one week before and one week after birth) in isolated lungs of adult male rats (approximately 12 weeks old) perfused with homologous blood. Perfusion pressure-flow relationship was tilted towards lower pressures in the perinatally hypoxic as compared to the control, perinatally normoxic rats. A non-linear, distensible vessel model analysis revealed that this was due to increased vascular distensibility in perinatally hypoxic rats (4.1 +/- 0.6 %/mm Hg vs. 2.3 +/- 0.4 %/mm Hg in controls, P = 0.03). Vascular occlusion techniques showed that lungs of the perinatally hypoxic rats had lower pressures at both the pre-capillary and post-capillary level. To assess its role, basal vascular tone was eliminated by a high dose of sodium nitroprusside (20 microM). This reduced perfusion pressures only in the lungs of rats born in hypoxia, indicating that perinatal hypoxia leads to a permanent increase in the basal tone of the pulmonary vessels. Pulmonary vasoconstrictor reactivity to angiotensin II (0.1-0.5 microg) was reduced in rats with the history of perinatal-hypoxia. These data show that perinatal hypoxia has permanent effects on the pulmonary circulation that may be beneficial and perhaps serve to offset the previously described adverse consequences.     

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats.

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular reactivity in isolated lungs of rats with spontaneous systemic hypertension.

Pulmonary vascular reactivity to acute hypoxic challenges and to KCl was measured in isolated blood-perfused lungs of six rats with spontaneous systemic hypertension (SHR) and in six normotensive rats. Baseline perfusion pressure did not differ significantly between SHR (11.0 +/- 1.0 mm Hg) and normotensive controls (12.3 +/- 1.5 mm Hg). Reactivity to acute hypoxia was equal in both groups. In SHR the dose-response of perfusion pressure to KCl was shifted significantly towards lower perfusion pressures as compared with normotensive controls. These results suggest that, even though magnitude of hypoxic pulmonary vasoconstriction is not changed, the mechanism of the response may be altered in SHR.     

Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs

Leukotriene inhibitors preferentially inhibit hypoxic pulmonary vasoconstriction in isolated rat lungs. If lipoxygenase products are involved in the hypoxic pressor response they might be produced during acute alveolar hypoxia and a leukotriene inhibitor should block both the vasoconstriction and leukotriene production that occurs in response to hypoxia. We investigated in isolated blood perfused rat lungs whether leukotriene C4 (LTC4) could be recovered from whole lung lavage fluid during ongoing hypoxic vasoconstriction. Lung lavage from individual rats had slow reacting substance (SRS)-like myotropic activity by guinea pig ileum bioassay. Pooled lavage (10 lungs) as analyzed by reverse phase high performance liquid chromatography had an ultraviolet absorbing component at the retention time for LTC4. At radioimmunoassay, and SRS myotropic activity by bioassay. LTC4 was not found during normoxic ventilation, during normoxic ventilation after a hypoxic pressor response, or during vasoconstriction elicited by KCl. Diethylcarbamazine citrate, a leukotriene synthesis blocker, concomitantly inhibited the hypoxic vasoconstriction and LTC4 production. Thus 5-lipoxygenase products may play a role in the sequence of events leading to hypoxic pulmonary vasoconstriction.     

Time course of hypoxic pulmonary vasoconstriction after endotoxin infusion in unanesthetized sheep

Endotoxin [lipopolysaccharide (LPS)] has been reported to reduce hypoxic pulmonary vasoconstriction and thus increases venous admixture. The time course of this failure of pulmonary blood flow regulation was investigated in six chronically instrumented unanesthetized sheep after infusion of Escherichia coli LPS (1 microgram/kg). The change in left pulmonary arterial blood flow (LPBF, ultrasonic transit time) in response to unilateral lung hypoxia (10 min of N2 alternately to the left and right lungs) was compared before and at various time intervals after the administration of LPS. During baseline conditions, LPBF was 33% of total cardiac output and decreased to 15% when the left lung was ventilated with a hypoxic gas mixture. One hour after endotoxin infusion, LPBF remained at 33% of total cardiac output yet only decreased to 28% during the hypoxic challenge. The response to one-lung hypoxia was still significantly depressed 10 h post-LPS administration. It is concluded that hypoxic pulmonary vasoconstriction is almost completely abolished for a prolonged time period after a small dose of LPS.     

Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia.

The objective of the present study was to examine the impact of early stages of lung injury on ventilatory control by hypoxia and hypercapnia. Lung injury was induced with intratracheal instillation of bleomycin (BM; 1 unit) in adult, male Sprague-Dawley rats. Control animals underwent sham surgery with saline instillation. Five days after the injections, lung injury was present in BM-treated animals as evidenced by increased neutrophils and protein levels in bronchoalveolar lavage fluid, as well as by changes in lung histology and computed tomography images. There was no evidence of pulmonary fibrosis, as indicated by lung collagen content. Basal core body temperature, arterial Po(2), and arterial Pco(2) were comparable between both groups of animals. Ventilatory responses to hypoxia (12% O(2)) and hypercapnia (7% CO(2)) were measured by whole body plethysmography in unanesthetized animals. Baseline respiratory rate and the hypoxic ventilatory response were significantly higher in BM-injected compared with control animals (P = 0.003), whereas hypercapnic ventilatory response was not statistically different. In anesthetized, spontaneously breathing animals, response to brief hyperoxia (Dejours' test, an index of peripheral chemoreceptor sensitivity) and neural hypoxic ventilatory response were augmented in BM-exposed relative to control animals, as measured by diaphragmatic electromyelograms. The enhanced hypoxic sensitivity persisted following bilateral vagotomy, but was abolished by bilateral carotid sinus nerve transection. These data demonstrate that afferent sensory input from the carotid body contributes to a selective enhancement of hypoxic ventilatory drive in early lung injury in the absence of pulmonary fibrosis and arterial hypoxemia.     

Contribution of oxygen radicals to altered NO-dependent pulmonary vasodilation in acute and chronic hypoxia

Chronic hypoxia (CH) increases pulmonary arterial endothelial nitric oxide (NO) synthase (NOS) expression and augments endothelium-derived nitric oxide (EDNO)-dependent vasodilation, whereas vasodilatory responses to exogenous NO are attenuated in CH rat lungs. We hypothesized that reactive oxygen species (ROS) inhibit NO-dependent pulmonary vasodilation following CH. To test this hypothesis, we examined responses to the EDNO-dependent vasodilator endothelin-1 (ET-1) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP) in isolated lungs from control and CH rats in the presence or absence of ROS scavengers under normoxic or hypoxic ventilation. NOS was inhibited in lungs used for SNAP experiments to eliminate influences of endogenously produced NO. Additionally, dichlorofluorescein (DCF) fluorescence was measured as an index of ROS levels in isolated pressurized small pulmonary arteries from each group. We found that acute hypoxia increased DCF fluorescence and attenuated vasodilatory responses to ET-1 in lungs from control rats. The addition of ROS scavengers augmented ET-1-induced vasodilation in lungs from both groups during hypoxic ventilation. In contrast, upon NOS inhibition, DCF fluorescence was elevated and SNAP-induced vasodilation diminished in arteries from CH rats during normoxia, whereas acute hypoxia decreased DCF fluorescence, which correlated with augmented reactivity to SNAP in both groups. ROS scavengers enhanced SNAP-induced vasodilation in normoxia-ventilated lungs from CH rats similar to effects of hypoxic ventilation. We conclude that inhibition of NOS during normoxia leads to greater ROS generation in lungs from both control and CH rats. Furthermore, NOS inhibition reveals an effect of acute hypoxia to diminish ROS levels and augment NO-mediated pulmonary vasodilation.     

一氧化氮对急、慢性缺氧大鼠血流动力学及缺氧性肺血管收缩反应的影响

观察了吸入０．００４％的一氧化氮（ＮＯ）对急、慢性缺氧大鼠血流动力学、缺氧性肺血管收缩反应（ＨＰＶ）、血气及高铁血红蛋白（ＭｅｔＨｂ）的影响。结果表明：（１）常氧吸入ＮＯ时能明显降低慢性缺氧大鼠肺动脉平均压（Ｐｐａ）和肺血管阻力（ＰＶＲ）,但对正常大鼠的Ｐｐａ和ＰＶＲ无明显影响;（２）慢性缺氧大鼠急性缺氧时ＨＰＶ较正常大鼠弱,吸入ＮＯ不但降低两者的急性缺氧肺动脉高压,且完全逆转两者的ＨＰＶ;（３）吸入ＮＯ对急、慢性缺氧大鼠体循环血流动力学、血气及ＭｅｔＨｂ含量无明显影响。提示吸入ＮＯ能选择性降低急、慢性缺氧性肺动脉高压,且逆转ＨＰＶ。     

Red blood cells prevent inhibition of hypoxic pulmonary vasoconstriction by nitrite in isolated, perfused rat lungs

Nitrite reduction to nitric oxide (NO) may be potentiated by a nitrite reductase activity of deoxyHb and contribute to systemic hypoxic vasodilation. The effect of nitrite on the pulmonary circulation has not been well characterized. We explored the effect of nitrite on hypoxic pulmonary vasoconstriction (HPV) and the role of the red blood cell (RBC) in nitrite reduction and nitrite-mediated vasodilation. As to method, isolated rat lungs were perfused with buffer, or buffer with RBCs, and subjected to repeated hypoxic challenges, with or without nitrite. As a result, in buffer-perfused lungs, HPV was reduced at nitrite concentrations of 7 muM and above. Nitrite inhibition of HPV was prevented by excess free Hb and RBCs, suggesting that vasodilation was mediated by free NO. Nitrite-inhibition of HPV was not potentiated by mild acidosis (pH = 7.2) or xanthine oxidase activity. RBCs at 15% but not 1% hematocrit prevented inhibition of HPV by nitrite (maximum nitrite concentration of approximately 35 muM) independent of perfusate Po(2). Degradation of nitrite was accelerated by hypoxia in the presence of RBCs but not during buffer perfusion. In conclusion, low micromolar concentrations of nitrite inhibit HPV in buffer-perfused lungs and when RBC concentration is subphysiological. This effect is lost when RBC concentration approaches physiological levels, despite enhanced nitrite degradation in the presence of RBCs. These data suggest that, although deoxyHb may generate NO from nitrite, insufficient NO escapes the RBC to cause vasodilation in the pulmonary circulation under the dynamic conditions of blood flow through the lungs and that RBCs are net scavengers of NO.     

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.     

Atrial natriuretic peptide lowers pulmonary arterial pressure in hypoxia-adapted rats

To test the hypothesis that atrial natriuretic peptide (ANP) has a direct vasodilator effect on the pulmonary vasculature that is enhanced in hypoxia-induced pulmonary hypertension in the rat, we determined the effects of ANP on mean pulmonary (MPAP) and systemic arterial pressure (MSAP) in intact conscious Sprague-Dawley rats exposed to 10% O2 or room air for 4 wk. Catheters were placed in the pulmonary artery through the right jugular vein by means of a closed-chest technique. MPAP and MSAP were monitored before and after intravenous injections of graded doses of ANP. ANP produced dose-related decreases in MPAP that were greater in the hypoxic group than in air controls. There were no significant between-group differences in the systemic depressor responses to ANP or in the ANP-induced reduction in cardiac output. ANP lowered MPAP significantly in isolated perfused lungs from both hypoxia-adapted and air control rats, and this effect was significantly greater in the hypoxic than the air control lungs. These data indicate that ANP lowers pulmonary arterial pressure in rats with hypoxia-induced pulmonary hypertension, mainly by a direct vasodilator effect on the pulmonary vasculature.     

Effects of leukotriene B4 on permeability, prostacyclin and thromboxane release by normal and oxygen-preexposed isolated, perfused rat lungs

This study assessed the hemodynamic and permeability effects of exogenous, synthetic leukotriene B4 (LTB4) on normal rat lungs and lungs from rats preexposed to oxygen for 48 h, which were isolated and perfused at constant flow in vitro. Adult, Sprague-Dawley rats were exposed to air or greater than 97% O2 for 48 h. After exposure, their lungs were removed from the thorax, ventilated with normoxic gas, and perfused at 12 ml/min with Krebs-Ringer bicarbonate buffer which contained 5 mM glucose and 3 mg/ml albumin. A total of 5.55 micrograms of synthetic LTB4 was infused in three separate boluses over 15 minutes. Perfusion and airway pressures were monitored, and the lungs release of 6-ketoprostaglandin F1 alpha and thromboxane B2 (TXB2) into the effluent from the pulmonary vasculature was measured by radioimmunoassay. The LTB4 had no measureable effects on pulmonary vascular pressures. LTB4 infusion caused a pronounced increase in permeability, indicated by increased albumin concentrations in alveolar lavage fluid from O2-preexposed lungs. Release of TXB2 from both air- and O2-preexposed lungs was increased after LTB4 infusion, while the change in 6-ketoprostaglandin F1 alpha release was not statistically significant. Both the increase in permeability enhanced TXB2 released after LTB4 infusion were inhibited by 10 microM indomethacin in the perfusate. These data indicate that exogenous LTB4 increases microvascular permeability in O2-exposed lungs in association with increased release of TXB2 into the pulmonary vascular effluent.     

多巴胺对急性间歇性低氧诱导的大鼠颈动脉体低氧敏感性的影响*

目的: 观察急性间歇性低氧刺激后大鼠颈动脉体对低氧的敏感性以及多巴胺对颈动脉体低氧敏感性的影响。方法: 将分离SD大鼠的颈动脉体-窦神经移入到孵育槽,然后把分离的窦神经吸入到记录的玻璃电极中行电信号记录。记录基线部分缓冲液充入气体为95% O₂+ 5% CO₂混合气,低氧应激给予5% O₂+ 5% CO₂+ 90% N₂混合气,低氧刺激给予30 s,95% O₂ + 5% CO₂给予90 s,共10个循环,每组实验大鼠数量n大于等于5。结果: 大鼠离体的颈动脉体,给予急性间歇性低氧应激,再给予低氧刺激,窦神经较之前低氧刺激放电活动增强。但加入多巴胺后,可以抑制窦神经对低氧的反应,急性间歇性低氧后,多巴胺对窦神经的低氧放电活动抑制作用加强。结论: 大鼠颈动脉体给予急性间歇性低氧可增强窦神经对低氧的反应,多巴胺可抑制急性低氧诱导的颈动脉体对低氧敏感性的增强。     

Hydrogen sulfide mediates hypoxic vasoconstriction through a production of mitochondrial ROS in trout gills

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response that diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts. This response is important for the local matching of blood perfusion to ventilation and improves pulmonary gas exchange efficiency. HPV is an ancient and highly conserved response, expressed in the respiratory organs of all vertebrates, including lungs of mammals, birds, and reptiles; amphibian skin; and fish gills. The mechanism underlying HPV and how cells sense low Po(2) remains elusive. In perfused trout gills (Oncorhynchus mykiss), acute hypoxia, as well as H(2)S, caused an initial and transient constriction of the vasculature. Inhibition of the enzymes cystathionine-β-synthase and cystathionine-γ-lyase, which blocks H(2)S production, abolished the hypoxic response. Individually blocking the four complexes in the electron transport chain abolished both the hypoxic and the H(2)S-mediated constriction. Glutathione, an antioxidant and scavenger of superoxide, attenuated the vasoconstriction in response to hypoxia and H(2)S. Furthermore, diethyldithiocarbamate, an inhibitor of superoxide dismutase, attenuated the hypoxic and H(2)S constriction. This strongly suggests that H(2)S mediates the hypoxic vasoconstriction in trout gills. H(2)S may stimulate the mitochondrial production of superoxide, which is then converted to hydrogen peroxide (H(2)O(2)). Thus, H(2)O(2) may act as the "downstream" signaling molecule in hypoxic vasoconstriction.     

Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs

Leukotriene inhibitors preferentially inhibit hypoxic pulmonary vasoconstriction in isolated rat lungs. If lipoxygenase products are involved in the hypoxic pressor response they might be produced during acute alveolar hypoxia and a leukotriene inhibitor should block both the vasoconstriction and leukotriene production that occurs in response to hypoxia. We investigated in isolated blood perfused rat lungs whether leukotriene C₄ (LTC₄) could be recovered from whole lung lavage fluid during ongoing hypoxic vasoconstriction. Lung lavage from individual rats had slow reacting substance (SRS)-like myotropic activity by guinea pig ileum bioassay. Pooled lavage (10 lungs)_as analyzed by reverse phase high performance liquid chromatography had an ultraviolet absorbing component at the retention time for LTC₄. At this retention time the element had both LTC₄ immunoreactivitiy by radioimmunoassay, and SRS myotropic activity by bioassay. LTC₄ was not found during normoxic ventilation, during normoxic ventilation after a hypoxic pressor response, or during vasoconstriction elicited by KCL. Diethylcarbamazine citrate, a leukotriene synthesis blocker, concomitantly inhibited the hypoxic vasoconstriction and LTC₄ production. Thus 5-lipoxygenase products may play a role in the sequence of events leading to hypoxic pulmonary vasoconstriction.     

Blunted pulmonary pressor responses to hypoxia in blood perfused, ventilated lungs isolated from oxygen toxic rats: Possible role of prostaglandins

To determine the effects of high oxygen (O₂) tension on pulmonary vascular reactivity, we exposed rats either to 100% O₂ for 48 hrs or 40% O₂ for 3 to 5 weeks. Lungs from all rats were isolated, blood perfused and ventilated, and pressor responses to airway hypoxia and to infused angiotensin II were measured. We found that chronic subtoxic hyperoxia did not augment subsequent hypoxic vasoconstriction, and that 48 hrs of 100% O₂ markedly blunted hypoxic vasoconstriction. Meclofenamate restored hypoxic vasoconstriction to control levels in the lungs with blunted responses. Evidence for O₂ toxicity in the lungs exposed to 100% O₂ included interstitial swelling with alveolar exudates seen by light microscopy, and lung edema by water content calculations. We conclude that 1) chronic subtoxic hyperoxia does not influence subsequent hypoxic vasoconstriction, and 2) a dilator prostaglandin produced in the lung is a potent inhibitor of hypoxic vasoconstriction in O₂ toxic lungs.     

Rapid onset of hypoxic vasoconstriction in isolated lungs.

A fast-response O2 analyzer that samples air at low flow rates allows the quasi-instantaneous measurement of O2 concentration change in the airways of isolated blood-perfused rat lungs. This instrument and an oximeter were used to measure the stimulus-response delay time of hypoxic pulmonary vasoconstriction when the lungs were challenged with 10, 5, or 3% O2. The estimate for the shortest delay time between accomplished fall in airway O2 concentration and the onset of hypoxia-induced vasoconstriction was approximately 7 s. We found that the slope of pressure rise, but not the stimulus-response delay time, correlated with the magnitude of hypoxic vasoconstriction. Oscillations in pulmonary arterial pressure were observed when the lungs were challenged with 10% O2 but not when the challenge was 12, 5, or 3%, indicating perhaps that these oscillations were a threshold phenomenon. Established hypoxic vasoconstriction was sensitive to brief changes in airway O2 concentration. Vasodilation occurred when the gas mixture was switched from 3 to 21% O2 for two to five breaths, and vasoconstriction occurred when the gas was changed during a single breath from 5 to 3% O2.     

Hypoxic pulmonary vasoconstriction in reptiles: a comparative study of four species with different lung structures and pulmonary blood pressures

Low O2 levels in the lungs of birds and mammals cause constriction of the pulmonary vasculature that elevates resistance to pulmonary blood flow and increases pulmonary blood pressure. This hypoxic pulmonary vasoconstriction (HPV) diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts and is considered important for the local matching of ventilation to blood perfusion. In the present study, the effects of acute hypoxia on pulmonary and systemic blood flows and pressures were measured in four species of anesthetized reptiles with diverse lung structures and heart morphologies: varanid lizards (Varanus exanthematicus), caimans (Caiman latirostris), rattlesnakes (Crotalus durissus), and tegu lizards (Tupinambis merianae). As previously shown in turtles, hypoxia causes a reversible constriction of the pulmonary vasculature in varanids and caimans, decreasing pulmonary vascular conductance by 37 and 31%, respectively. These three species possess complex multicameral lungs, and it is likely that HPV would aid to secure ventilation-perfusion homogeneity. There was no HPV in rattlesnakes, which have structurally simple lungs where local ventilation-perfusion inhomogeneities are less likely to occur. However, tegu lizards, which also have simple unicameral lungs, did exhibit HPV, decreasing pulmonary vascular conductance by 32%, albeit at a lower threshold than varanids and caimans (6.2 kPa oxygen in inspired air vs. 8.2 and 13.9 kPa, respectively). Although these observations suggest that HPV is more pronounced in species with complex lungs and functionally divided hearts, it is also clear that other components are involved.