1. The effects of the scavengers of reactive oxygen species superoxide dismutase and catalase, the iron chelator desferrioxamine and the nitric oxide synthase inhibitor N G -nitro- l -arginine methyl ester and saline (control vehicle) on hypoxic pulmonary vasoconstriction, a measure of albumin flux and an index of lipid peroxidation (palmitic:linoleic acid ratio) were investigated after ischaemia—reperfusion in an isolated, blood-perfused rat lung model. 2. Lungs treated immediately before reperfusion with catalase (5 000 units), desferrioxamine (2 mg/kg), N G -nitro- l -arginine methyl ester (5 mmol/l) or saline showed a significant augmentation in pre-ischaemia—reperfusion hypoxic pulmonary vasoconstriction (57.7 ± 6.0%, 82.7 ± 28.8%, 95.2 ± 36.6% and 45.95 ± 10.53% respectively), an increase in albumin flux (0.35 ± 0.04, 0.31 ± 0.06, 0.29 ± 0.04 and 0.33 ± 0.02) and an increase in pre-ischaemia—reperfusion palmitic:linoleic acid ratio (0.64 ± 0.08, 0.51 ± 0.19, 0.5 ± 0.04 and 0.17 ± 0.07). Superoxide dismutase (2 750 i.u.) administered immediately before reperfusion prevented completely the changes in hypoxic pulmonary vasoconstriction (−0.3 ± 5.4%), albumin flux (0.09 ± 0.11) and palmitic:linoleic acid ratio (–0.06 ± 0.12). In control lungs (2 h of continuous perfusion), superoxide dismutase, catalase, desferrioxamine and saline did not affect hypoxic pulmonary vasoconstriction (5.5 ± 4.9%, 1.0 ± 3.1%, −5.1 ± 1.8% and 3.0 ± 6.6%). However, N G -nitro- l -arginine methyl ester significantly augmented hypoxic pulmonary vasoconstriction (275.1 ± 39.3%). There was no effect of superoxide dismutase, catalase, desferrioxamine, N G -nitro- l -arginine methyl ester or saline in control lungs on albumin flux (0.10 ± 0.04, 0.11 ± 0.01, 0.1 ± 0.01, 0.12 ± 0.01 and 0.11 ± 0.01 respectively) or palmitic:linoleic acid ratio (–0.08 ± 0.08, 0.73 ± 0.76, −0.03 ± 0.12, 0.01 ± 0.17 and 0.00 ± 0.0 respectively). 3. We conclude that superoxide dismutase attenuates ischaemia—reperfusion-induced increases in albumin flux and hypoxic pulmonary vasoconstriction, and prevents consumption of linoleic acid in the isolated, blood-perfused rat lung.

1. The endothelium has been shown to modulate the pulmonary vascular response to hypoxia in the rat. Acute lung injury is associated with loss of hypoxic pulmonary vasoconstriction and increased pulmonary vascular permeability. Similar loss of the vascular response to hypoxia is seen after ischaemia-reperfusion injury of the myocardium. 2. The effects of reperfusion injury on pulmonary endothelial integrity, as shown by the albumin escape index and hypoxic pulmonary vasoconstriction, were investigated in isolated, blood-perfused rat lungs. 3. Ischaemia for 0.5 h, which itself caused no increase in the albumin escape index, was followed by reperfusion for 0.25 h, 0.5 h and 1 h. Controls were subjected to 2 h of perfusion only ( n = 5 in all groups). The pulmonary pressor response to hypoxia (fractional inspired oxygen concentration, 3%) was measured before and after ischaemia-reperfusion, and the dilator response to acetylcholine was measured after ischaemia-reperfusion in all cases. 4. Ischaemia-reperfusion significantly increased the albumin escape index after 0.5 h (mean ± SEM, 1.40 ± 0.27) and 1 h (2.0 ± 0.30) compared with controls (0.54 ± 0.30, P <0.05 in both cases). The pulmonary pressor response to hypoxia was augmented significantly after reperfusion when compared with baseline hypoxic pulmonary vasoconstriction (change from baseline: 13.2 ± 4.63 and 22.2 ± 7.1% after 0.5 and 1.0 h of reperfusion, respectively, P <0.05). Vasorelaxation of sustained hypoxic vasoconstriction using acetylcholine was similar in both control lungs and those subjected to ischaemia-reperfusion. 5. These results suggest that the pressor response to hypoxia is augmented after damage to the pulmonary vascular endothelium induced by ischaemia-reperfusion. Although this may be due to diminished release of endothelium-derived relaxing factors, the normal vasodilator response to acetylcholine suggests the phenomenon is not due to a reduction in the release of endothelium-derived relaxing factor/nitric oxide.

1. To test whether almitrine might improve the arterial partial pressure of O 2 in patients with chronic obstructive airways disease by improvement of ventilation-perfusion matching, we looked at the interaction between hypoxic and almitrine-induced vasoconstriction in isolated rat lungs perfused with blood at constant flow. Increases in pressure represented increases in resistance. 2. Almitrine, given in increasing doses between challenges with 2% O 2 , enhanced hypoxic vasoconstriction at low doses but attenuated it at high doses. 3. Stimulus-response curves to hypoxia of increasing severity gave a sigmoid curve. 4. Almitrine solvent caused small changes in pulmonary artery pressure and shifted the stimulus-response curve slightly in a parallel fashion. 5. Small doses of almitrine enhanced the action of mild to moderate hypoxia, medium doses attenuated moderately severe hypoxia, whereas high doses depressed vasoconstriction due to all degrees of hypoxia. 6. These effects of almitrine on hypoxic vasoconstriction were compared with the effect of solvent by analysis of variance; the results substantiated significant enhancement of hypoxia by small doses and attenuation by large doses. 7. In patients, if similar effects apply, small doses of almitrine would assist ventilation-perfusion matching, but large doses might worsen it. 8. Almitrine-induced vasoconstriction was attenuated by a fall in perfusate temperature in a similar manner to hypoxic vasoconstriction. It was also attenuated by three drugs, chlorpheniramine, propanolol and diethylcarbamazine, all of which also decrease hypoxic vasoconstriction. The similarity between hypoxic and almitrine-induced pulmonary vasoconstriction is further confirmed.

1. The role of platelet-activating factor in the attenuated hypoxic pulmonary vasoconstriction associated with lung injury was evaluated using specific platelet-activating factor antagonists and an isolated perfused lung preparation. 2. Intratracheal bleomycin was administered to rats to produce acute lung injury. Animals received intratracheal saline (control), intratracheal bleomycin or the platelet-activating factor anatagonists BN 52021, WEB 2170 or WEB 2086 before and after bleomycin treatment. Forty-eight hours after intratracheal administration of bleomycin or saline the animals were killed. 3. The increases in pulmonary artery pressure during two periods of hypoxic ventilation and in response to 0.2 μg of angiotensin II were measured. Acetylcholine-induced vasodilatation after pre-constriction with prostaglandin F 2α was also measured. To quantify lung injury, the wet/ dry ratio of lung weight was determined. 4. Bleomycin treatment attenuated the first and second hypoxic pressor responses by 93% and 77%, respectively, but not the pressor response to angiotensin II nor the vasodilator response to acetylcholine. BN 52021 plus bleomycin augmented the first hypoxic pressor response compared with bleomycin treatment alone, but the structurally unrelated platelet-activating factor antagonists WEB 2170 and WEB 2086 had no significant effect on the bleomycin-induced attenuation of hypoxic pulmonary vasoconstriction. None of the platelet-activating factor antagonists blocked the increase in the wet/dry lung weight ratio induced by bleomycin. 5. Bleomycin-induced lung injury selectively attenuates hypoxic pulmonary vasoconstriction, an effect that does not appear to be mediated by platelet-activating factor. The mechanism remains to be elucidated, but may involve destruction of the hypoxic ‘sensor’ within the respiratory tract.

1. To further understand the vasodilator actions of atrial natriuretic peptide and its role in hypoxic pulmonary hypertension, we studied the effects of atrial natriuretic peptide in the isolated perfused rat lung during normoxic ventilation and after elevation of pulmonary artery pressure by either hypoxic ventilation or infusion of prostaglandin F 2α . Control animals were compared with littermates that had become adapted to a 10% O 2 environment for 3 weeks. Atrial natriuretic peptide was compared with atriopeptin I and atriopeptin III in order to study its structure-activity relationship. 2. Five experiments, each involving six control and six chronically hypoxic rats, were performed. During normoxic ventilation, atrial natriuretic peptide (30 ng-3 μg) produced a dose-dependent reduction in pulmonary artery pressure in chronically hypoxic rats, but had no action in the control animals. 3. Atrial natriuretic peptide dose-dependently abolished hypoxic pulmonary vasoconstriction to a greater extent in chronically hypoxic rats (EC 50 98 ng) than in control rats (EC 50 298 ng; P < 0.001). Bolus atrial natriuretic peptide (100 ng) produced a plasma concentration of 22.6 pmol/l at 1 min, which is within the pathophysiological range. Initial plasma atrial natriuretic peptide levels were 9.4 pmol/l in control animals and 27.4 pmol/l in chronically hypoxic rats. 4. Chronically hypoxic rats were more sensitive to atriopeptin I, atriopeptin III and atrial natriuretic peptide than were the control rats ( P < 0.05). Atrial natriuretic peptide and atriopeptin III were equipotent and were 10 times more potent than atriopeptide I in both groups ( P < 0.001). 5. Although atrial natriuretic peptide lowered pulmonary artery pressure in isolated perfused lungs pre-constricted with prostaglandin F 2α (5 μg/min), there was no difference between the control and chronically hypoxic groups, and the EC 50 296 ng in the chronically hypoxic rats was significantly ( P < 0.001) less than that seen in the chronically hypoxic despite similar levels of induced constriction by the two stimuli. 6. A set dose of atrial natriuretic peptide produced the same percentage reduction in hypoxic pulmonary vasoconstriction despite differing levels of pre-constriction produced by ventilating with 7%, 5%, 3% or 0% O 2 . There was no change in the arterial partial pressure of O 2 or the alveolar-arterial gradient after injection of atrial natriuretic peptide, suggesting that its effects are not due to a reduction in pulmonary oedema. 7. Atrial natriuretic peptide relaxes pre-constricted pulmonary arteries in the isolated perfused rat lung in a dose-dependent manner within the pathophysiological range. The greater action of atrial natriuretic peptide in chronic hypoxia could be due to its action at the new sites of hypoxic pulmonary vasoconstriction, the newly muscularized alveolar arteries which develop during adaptation to hypoxia.

1. Overall mean pulmonary arterial pressure (MPAP)/cardiac index (CI) relationships were investigated in 13 pentobarbital anaesthetized dogs ventilated consecutively with a fraction of inspired O 2 (F 1 o 2 ) of 0.4 and with a F 1 o 2 of 0.1. This sequence of alternated F 1 o 2 0.4 and F 1 o 2 0.1 was repeated (1) in the dogs with a strong pulmonary pressor response to hypoxia (more than 20% increase in pulmonary vascular resistance) ( n = 6) under a continuous infusion of the leukotriene receptor blocker FPL 57231 (2 mg min −1 kg −1 ), and (2) in the dogs with a weak pressor response to hypoxia ( n = 7) after cyclo-oxygenase inhibition by acetylsalicylic acid (1 g intravenously). Five-point MPAP/CI plots were constructed by opening a femoral arteriovenous fistula or by stepwise inflations of an inferior vena cava balloon catheter. The MPAP/CI plots were rectilinear in all experimental conditions. 2. In responders, hypoxia was associated with an increase in MPAP over the entire range of CI studied (1–5 litres min −1 m −2 ). Infusion of FLP 57231 abolished the vasoconstricting effect of hypoxia. 3. In non-responders, MPAP was not affected by hypoxia over the entire range of CI. After acetylsalicylic acid administration, hypoxia resulted in a significant rise in MPAP from 2 to 5 litres min −1 m −2 . 4. Infusion of FLP 57231 decreased mean systemic arterial pressure at both F 1 o 2 0.4 and F 1 o 2 0.1, while acetylsalicylic acid had no effect on systemic haemodynamics. 5. Stability of pulmonary vascular tone at F 1 o 2 0.4 and at F 1 o 2 0.1 and reproducibility of the hypoxic pressor response was ascertained in an additional group of five dogs with CI kept constant and MPAP measurements every 6 min during four consecutive periods of 30 min (i.e. maximum time needed to generate a MPAP/CI plot) alternately at F 1 o 2 0.4 and at F 1 o 2 0.1. 6. These results suggest that pulmonary vascular reactivity to hypoxia is regulated by balanced actions of vasoconstricting leukotrienes and vasodilating prostaglandins in anaesthetized dogs. They also indicate a vasodilating effect of FPL 57231 on systemic vessels.

1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed. 1. Hypoventilation of one lobe of lung was studied in open-chest anaesthetized dogs. Lobar blood flow, pulmonary-artery pressure and gas exchange were measured, the latter from breath-by-breath analysis with a mass spectrometer. 2. Hypoventilation of the lobe by reducing the respiratory pump stroke led, at each step, to a reduction in blood flow to that lobe. The flow ( ) reduction was variable, but always less than the ventilation ( ) reduction, so that the ratio to the lobe was reduced. O 2 tension and pH fell and CO 2 tension rose in effluent blood. Thus regulation achieved by flow reduction varied between individuals and was of low gain. 3. Anatomical or series dead space ( V D series) was reduced in proportion to ventilation. When V D series was less than the apparatus dead space, some gas exchange still took place. 4. Oxygen uptake ( ) and CO 2 output ( ) were reduced during hypoventilation. fell more than , so that the respiratory exchange ratio ( R ) was reduced. 5. Whether the deterioration in gas tensions in effluent blood during hypoventilation of the lobe was due to shunt of blood past unventilated alveoli, or to mismatching, was not resolved. 6. The plateau phase of the CO 2 -output curves at low tidal volumes was usually regular; thus either hypoventilation was uniform, or some ventilation units were totally closed.