Regional Alveolar Hypoxia Research Articles

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100% O2.

Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100 % O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.

Exposure to 100% Oxygen Abolishes the Impairment of Fracture Healing after Thoracic Trauma.

In polytrauma patients a thoracic trauma is one of the most critical injuries and an important trigger of post-traumatic inflammation. About 50% of patients with thoracic trauma are additionally affected by bone fractures. The risk for fracture malunion is considerably increased in such patients, the pathomechanisms being poorly understood. Thoracic trauma causes regional alveolar hypoxia and, subsequently, hypoxemia, which in turn triggers local and systemic inflammation. Therefore, we aimed to unravel the role of oxygen in impaired bone regeneration after thoracic trauma. We hypothesized that short-term breathing of 100% oxygen in the early post-traumatic phase ameliorates inflammation and improves bone regeneration. Mice underwent a femur osteotomy alone or combined with blunt chest trauma 100% oxygen was administered immediately after trauma for two separate 3 hour intervals. Arterial blood gas tensions, microcirculatory perfusion and oxygenation were assessed at 3, 9 and 24 hours after injury. Inflammatory cytokines and markers of oxidative/nitrosative stress were measured in plasma, lung and fracture hematoma. Bone healing was assessed on day 7, 14 and 21. Thoracic trauma induced pulmonary and systemic inflammation and impaired bone healing. Short-term exposure to 100% oxygen in the acute post-traumatic phase significantly attenuated systemic and local inflammatory responses and improved fracture healing without provoking toxic side effects, suggesting that hyperoxia could induce anti-inflammatory and pro-regenerative effects after severe injury. These results suggest that breathing of 100% oxygen in the acute post-traumatic phase might reduce the risk of poorly healing fractures in severely injured patients.

From the Journal archives: Understanding the mechanism(s) regulating hypoxic pulmonary vasoconstriction: how an early study has led to novel translational approaches

Hypoxic pulmonary vasoconstriction (HPV) is a fundamental physiological process whereby ventilation/perfusion matching is optimized through the constriction of the pulmonary circulation supplying poorly ventilated lung units. In their 1981 paper in the Journal, Noble, Kay, and Fisher used a series of animal experiments to show that alveolar carbon dioxide (CO2) plays a critical role in the regulation of hypoxic pulmonary vasoconstriction. At physiological concentrations, CO2 potentiates the HPV response, and the absence of alveolar CO2 blunts HPV. The enhancement of HPV by CO2 resulted in reduced perfusion of specific hypoxic lung regions, thereby improving systemic oxygenation in lung-ventilated dogs. William H. Noble, J. Colin Kay, Joseph A. Fisher Can Anaesth Soc J 1981; 28: 422-30. To determine the dominant effect of variations in alveolar carbon dioxide tension on hypoxic pulmonary vasoconstriction. The group found that 1) increasing alveolar carbon dioxide concentrations enhanced hypoxic pulmonary vasoconstriction; 2) this enhancement improved oxygenation in ventilated dogs with regional alveolar hypoxia; and 3) this enhanced oxygenation was not due to increased cardiac output. Increased alveolar carbon dioxide enhances hypoxic pulmonary vasoconstriction. In clinical scenarios where hypoventilated or hypoxic lung regions exist, e.g., one-lung ventilation or lung consolidation, permissive hypercapnea may improve oxygenation.

Hypoxia-Induced Inflammation in the Lung

Acute lung injury (ALI) is a severe form of hypoxic lung disease responsible for a large number of deaths worldwide. Despite recent advances in supportive care, no reduction in mortality has been evident since the introduction of a standard consensus definition almost two decades ago. New strategies are urgently required to help design effective therapies for this condition. A key pathological feature of ALI involves regional alveolar hypoxia. Because alveolar hypoxia in isolation, such as that encountered at high altitude, causes an inflammatory pulmonary phenotype in the absence of any other pathogenic stimuli, these regions may not be passive bystanders but may actually contribute to the pathogenesis and progression of lung injury. Unique transcriptional responses to hypoxia in the lung apparently allow it to express an inflammatory phenotype at levels of hypoxia that would not produce such a response in other organs. We will review recent advances in our understanding of these unique transcriptional responses to moderate levels of alveolar hypoxia, which may provide new insights into the pathogenesis of ALI.

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6(-/-) mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6(-/-) but not in WT mice. This effect was mirrored by a lack of hypoxia-induced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6(-/-) mice. In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6(-/-) PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.

Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia.

Pulmonary microvascular occlusion by abnormally adherent and/or nondeformable sickle red blood cells (SS cells) may contribute to the pathogenesis of acute chest syndrome of sickle cell disease. We hypothesized that regional alveolar hypoxia reduces SS cell deformability and, by causing regional vasoconstriction, slows regional perfusion, facilitating endothelial adhesion and mechanical entrapment of cells. In isolated rat lungs perfused at constant average flow with physiological salt solution, we separately ventilated the two lungs: one with 95% O2 and the other with 0, 2.5, 5, or 21% O2. We infused a bolus of 99mTc-labeled SS cells or normal human AA cells along with 113Sn-labeled 15-mu m microspheres as a perfusion marker, then sliced the lungs and counted 99mTc and 113Sn. Weight-normalized perfusion decreased with hypoxia (P < 0.02). Retention of AA cells (perfusion-normalized) averaged approximately 1% in lungs ventilated with 95% O2 and increased only twofold with 0% O2. In contrast, retention of SS cells averaged 3-fold higher than that of AA cells at 95 and 5% O2, 15-fold higher at 2.5% O2, and 25-fold higher at 0% O2 (P < 0.01). Histological examination demonstrated entrapment of individual SS cells in alveolar capillaries of hypoxic but not well-oxygenated lungs. Relief of hypoxia, but not increased perfusate flow, caused prompt efflux of most entrapped cells, which were primarily high-density (high mean corpuscular hemoglobin concentration) cells. Thus substantial retention of SS cells does not occur without hypoxia, but regional hypoxia and/or the resulting vasoconstriction causes extraordinary regional retention of dense SS cells, a phenomenon that appears to be due more to mechanical entrapment of nondeformable cells in capillaries than to endothelial adhesion.

Beta-Adrenergic mechanisms attenuated hypoxic pulmonary vasoconstriction during systemic hypoxia in cats.

In this study, we examined how locally mediated hypoxic pulmonary vasoconstriction is modulated by autonomic nervous system activation during global alveolar hypoxia (GAH) accompanied by systemic hypoxemia. Using an X-ray television system on the in vivo cat lung, we measured changes in the internal diameter (ID) during GAH and regional alveolar hypoxia (RAH) without systemic hypoxemia in identical small pulmonary arteries and veins (100-600 microns ID). We also analyzed the effects of the autonomic nervous system blockade on the hypoxic ID changes. During GAH the ID of the arteries reduced by 5 +/- 1 and 3 +/- 1% with 10 and 5% O2 inhalations, respectively, whereas during RAH the arterial ID reduced by 12 +/- 1 and 18 +/- 1% with 10 and 5% O2 inhalations, respectively. The magnitude of the ID reduction was significantly smaller during GAH than during RAH. After pretreatment with propranolol, however, GAH induced large ID reductions (16 +/- 1 and 23 +/- 1% with 10 and 5% O2 inhalations) with patterns very similar to those seen during RAH. Phentolamine and atropine had no effect on the response during GAH. The ID reductions during RAH, on the other hand, were unaffected by all the blockers. The results indicate that, in the cat, alveolar hypoxia per se acts locally to constrict the small pulmonary vessels and that the hypoxic vasoconstriction is attenuated by a beta-receptor-mediated vasodilator effect during GAH with systemic hypoxemia. In addition, we found that, after adrenalectomy plus ganglion blockade with hexamethonium bromide, the GAH-induced ID reduction with 5% O2 inhalation was enhanced from 3 to 19%.(ABSTRACT TRUNCATED AT 250 WORDS)

Matched Ventilation-Perfusion Becomes Mismatched Ventilation-Perfusion Lung Imaging After Resolution of Carcinoma of the Bronchus

Airway occlusion results in regional alveolar hypoxia followed by reflex hypoxic pulmonary arterial constriction. Ventilation-perfusion imaging demonstrates matched defects. In the two patients reported, occlusion of the main bronchus by bronchogenic carcinoma was resolved--in one case by radiation therapy, and in the other by removal of the tumor mass in the bronchus by bronchial slitted biopsy. The initially matched ventilation-perfusion findings became mismatched. While ventilation was presumed to be normal, pulmonary perfusion was not completely reversed.

Effect of Regional Alveolar Hypoxia on Gas Exchange in Pulmonary Edema

We studied the effects of left lower lobe (LLL) alveolar hypoxia on ventilation-perfusion (VA/Q) heterogeneity in anesthetized dogs with acute (1-h-old) and mature (24-h-old) permeability pulmonary edema, induced by intravenous administration of 0.05 ml/kg of oleic acid. The left upper lobe was removed and a bronchial divider was placed to allow separate ventilation of the right lung (fraction of inspired oxygen [FIO2] = 1.0) and the LLL (FIO2 = 1.0 or 0.05). Gas exchange was assessed using the multiple inert gas elimination technique. In acute pulmonary edema, LLL hypoxia reduced LLL blood flow and increased true shunt of the LLL compared with a hyperoxic control group. VA/Q heterogeneity of the LLL was markedly increased, indicated by increases in the logarithmic standard deviation of the perfusion distribution (log SDQ) and the retention index of dispersion corrected for shunt (DISPR*). Increases in true shunt and log SDQ were significantly greater than those observed with lobar hypoxia in normal lungs before oleic acid injury. In mature oleic acid injury, LLL alveolar hypoxia resulted in a similar reduction in LLL blood flow and increase in inert gas shunt and DISPR*. We conclude that lobar alveolar hypoxia increased VA/Q heterogeneity of the hypoxic lobe to a greater degree in oleic acid-induced pulmonary edema compared with normal lungs. Phase of oleic acid injury (acute versus mature) did not affect gas exchange during alveolar hypoxia.

Effect of positive end-expiratory pressure on hypoxic pulmonary vasoconstriction in the dog

We studied the effects of uni- and bilateral positive end-expiratory pressure (PEEP) on pulmonary artery pressure-flow (Ppa/Q) relationships during unilateral hypoxia in anesthetized dogs. A bronchial divider was inserted, the right lung was ventilated with 100% O2, and the left lung was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Left lung blood flow (QL) and aortic flow (QT) were measured by electromagnetic flow probes. Simultaneous Ppa/Q relations for both lungs, with Q on the ordinate, were obtained by altering QT via an arteriovenous fistula and an inferior vena cava occluder. Ppa/Q slopes (delta Q/delta Ppa) and extrapolated zero-flow Ppa intercepts (Pzf) were obtained by linear regression analysis. Bilateral PEEP increased Pzf for both lungs (P less than 0.01) but did not alter delta Q/delta Ppa of either lung. Unilateral PEEP decreased ipsilateral blood flow (P less than 0.001) and increased Pzf for the ipsilateral lung (P less than 0.05). Left lung PEEP did not affect the slope of the left lung Ppa/Q relationship (delta QL/delta Ppa). Hypoxic ventilation of the left lung decreased QL (P less than 0.001), increased Pzf (P less than 0.05), and decreased delta QL/delta Ppa (P less than 0.001). Neither uni- nor bilateral PEEP altered this flow diversion away from the left lung or the reduction in delta QL/delta Ppa with left lung hypoxia. We conclude that PEEP and alveolar hypoxia increase pulmonary vascular resistance at different loci, such that their effects are additive. A net increase in 10 cmH2O of PEEP does not inhibit the pulmonary vascular response to regional alveolar hypoxia.

Effect of Increased Intracranial Pressure on Regional Hypoxic Pulmonary Vasoconstriction

The effects of increased intracranial pressure (ICP) and increased cardiac output (QT) on the pulmonary vascular response to regional alveolar hypoxia were compared in pentobarbital-anesthetized, closed-chested dogs. A bronchial divider was inserted, the right lung (RL) was continuously ventilated with 100% O2, and the left lung (LL) was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Sulfur hexafluoride (SF6) was used to measure differential lung blood flow and the multiple inert gas technique assessed gas exchange. The response to LL alveolar hypoxia (hypoxic pulmonary vasoconstriction, HPV) was studied in each animal prior to, during, and after the ICP was increased by infusing mock cerebrospinal fluid (CSF) into a lateral ventricle so that cerebral perfusion pressure was 25 mmHg. During both control periods, QT was randomly altered by opening (high QT) or closing (normal QT) two arteriovenous fistulas. Increasing ICP significantly increased QT (P less than 0.01), pulmonary artery pressure (PAP) (P less than 0.05), and mixed venous oxygen tension (PVO2) (P less than 0.05), compared with normal QT controls. Opening the arteriovenous fistulas achieved similar increases in QT (P less than 0.01), PAP (P less than 0.05), and PVO2 (P less than 0.05). The percentage of blood flow to the LL (QL/QT%) during hyperoxia was 43.9 +/- 0.8% (mean +/- SE) and did not vary with manipulation of QT or ICP. QL/QT% during LL hypoxia was significantly increased by both increased ICP (24.6 +/- 3.5%) and high QT (23.1 +/- 1.0%) compared with normal QT (16.8 +/- 2.1) controls (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Regional alveolar hypoxia does not affect air embolism-induced pulmonary edema

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema resulting from venous air embolization. Anesthetized dogs had the left upper lobe removed and a double-lumen tube placed so that right lung and left lower lobe (LLL) could be ventilated independently. Air was infused into the femoral vein for 1 h during bilateral ventilation at an inspiratory O2 fraction (FIO2) of 1.0. After cessation of air infusion the LLL was then ventilated with a hypoxic gas mixture (FIO2 = 0.05) in six animals and an FIO2 of 1.0 in six other animals. Lung hydroxyproline content was measured as an index of lung dry weight. LLL bloodless lobar wet weight-to-hydroxyproline ratio was 0.33 +/- 0.06 mg/micrograms in the animals exposed to LLL hypoxia and 0.37 +/- 0.03 mg/micrograms (NS) in the animals that had a LLL FIO2 of 1. Both values were significantly higher than our laboratory normal values of 0.19 +/- 0.01 mg/micrograms. We subsequently found in four more dogs exposed to global alveolar hypoxia before and after air embolism that the air injury itself significantly depressed the hypoxic vasoconstrictor response. We conclude that regional alveolar hypoxia has no effect on pulmonary edema formation due to air embolism. The most likely reason for these findings is that the air embolism injury itself interfered with hypoxic pulmonary vasoconstriction.

Alveolar hypoxia, inhibition of hypoxic pulmonary vasoconstriction, and permeability edema

We previously reported that regional alveolar hypoxia reduces oleic acid-induced permeability edema formation [Cheney et al. (1987). J. Appl. Physiol. 62: 1690–1697]. In order to define the role of hypoxic pulmonary vasoconstriction (HPV) on this effect, we studied the effects of regional alveolar hypoxia on permeability edema formation with this response inhibited. Dogs weighing 25 ± 1 kg in which the HPV response had been inhibited by the administration of minoxidil (1 mg/kgi.v.) were anesthetized, mechanically ventilated and had a bronchial divider placed so the left lower lobe (LLL) could be ventilated with an FI O 2 = 0.05 or FI O 2 = 1, while the right lung was continously ventilated with an FI O 2 = 1.0. In 10 study animals the LLL was ventilated with an FI O 2 = 0.05 for 4 h after induction of bilateral permeability pulmonary edema with 0.05 ml/kg of intravenous oleic acid. In six control animals the LLL was ventilated with an FI O 2 = 1 for 4 h after the same injury. Postmortem gravimetric analysis indicates that alveolar hypoxia of the LLL with the HPV response inhibited had no effect on pulmonary edema formation. We conclude that inhibition of HPV abolishes the protective effect of regional alveolar hypoxia on oleic acid-induced permeability edema formation.

Quantifying the effects of mixed venous PO 2 on regional pulmonary perfusion with positron emission tomography during lobar hypoxic ventilation in dogs

The mixed venous PO 2 (P vO 2) can affect vascular tone during hypoxic pulmonary vasoconstriction. Therefore, a decrease in intrapulmonary shunt would be expected if P vO 2 decreases during regional alveolar hypoxia. We tested this possibility by first ventilating the left lower lobe (LLL) with 0% oxygen and the rest of the lung (RU with 100% oxygen. As a result, regional pulmonary blood flow (rPBF) to the LLL, measured by positron emission tomography, decreased to 49% of its baseline value. When the FiO 2 of the RL was then lowered to room air (but the LLL was still ventilated with 0% oxygen), P vO 2 fell from 51 ± 8 to 38 ± 5 mm Hg ( P < .05). However, rPBF to the LLL actually increased by 33%, mean pulmonary perfusion pressure increased by 63%, and cardiac output did not change. In contrast, after ventilating the LLL with 10% oxygen, no change in rPBF occurred after altering the FiO 2 in the RL in the same fashion, despite a comparable decrease in P vO 2 , as mean pulmonary perfusion pressure only increased by 29%. Thus, the effect of physiologic changes in P vO 2 (about 13 mm Hg) on vascular tone is modest (resulting in an approximate 30% change). However, the effect on intrapulmonary shunt will depend on the balance of effects in parallel compartments caused by the maneuver which changes the P vO 2 .

Effect of regional alveolar hypoxia on permeability pulmonary edema formation in dogs.

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema formation. Anesthetized dogs had a bronchial divider placed so that the left lower lobe (LLL) could be ventilated with a hypoxic gas mixture (HGM) while the right lung was continuously ventilated with 100% O2. Bilateral permeability edema was induced with 0.05 ml/kg oleic acid and after 4 h of LLL ventilation with an HGM (n = 9) LLL gross weight was 161 +/- 13 (SE) g compared with 204 +/- 13 (SE) g (P less than 0.05) in the right lower lobe (RLL). Bloodless lobar water and dry weight were also significantly lower in the LLL as compared with the RLL of the study animals. In seven control animals in which the LLL fractional inspired concentration of O2 (FIO2) was 1.0 during permeability edema, there were no differences in gravimetric variables between LLL and RLL. In eight additional animals, pulmonary capillary pressure (Pc), measured by simultaneous occlusion of left pulmonary artery and vein, was not significantly different between LLL FIO2 of 1.0 and 0.05 either before or after pulmonary edema. We conclude that, in the presence of permeability pulmonary edema, regional alveolar hypoxia causes reduction in edema formation. The decreased edema formation during alveolar hypoxia is not due to a reduction in Pc.

Effects of regional alveolar hypoxia and hypercapnia on small pulmonary vessels in cats.

Using an X-ray TV system, we analyzed responses in the internal diameter (ID), flow velocity, and volume flow in small pulmonary vessels (100-600 microns ID) during unilobar hypoxia and hypercapnia in cats. In the hypoxic and hypercapnic lobes, the ID reduced in proportion to the degree of hypoxia and hypercapnia, respectively. The ID reduction was larger in the arteries than in the veins for a given stimulus. In the arteries, the ID reduced nonuniformly in the series-arranged vessels in response to both stimuli. The percentage ID reduction was maximal in the arteries of 200-300 microns ID, in which it was 21, 26, 28, and 36% with 5% O2, 0% O2, 5% CO2, and 10% CO2 inhalations, respectively. On the other hand, in the veins, uniform ID reduction occurred for a given stimulus. In the contralateral normoxic lobe, the ID did not change significantly. In both hypoxic and hypercapnic lobes, the flow velocity and volume flow of the small arteries decreased, with 5% O2, by 18 and 40%, respectively, and, with 5% CO2, by 23 and 50%, respectively. In contrast, in the normoxic lobe, they increased significantly during 5% O2 and 5% CO2 inhalations. We concluded that regional alveolar hypoxia and hypercapnia induced a local vasoconstriction particularly in the small arteries of 200-300 microns ID and decreased the flow velocity and volume flow in the same lung region.

Influence of isoflurane on hypoxic pulmonary vasoconstriction in dogs.

The authors studied the influence of locally administered isoflurane anesthesia on the pulmonary vascular response to regional alveolar hypoxia (hypoxic pulmonary vasoconstriction [HPV]) over a range of cardiac outputs (COs) in seven mechanically ventilated, closed-chest dogs. The right lung was ventilated with 100% O2 throughout the study. The left lung was ventilated with either 100% O2 (normoxia) or an hypoxic gas mixture (hypoxia). Different alveolar concentrations of isoflurane (0, 1, and 2.5 MAC) were administered to the left lung in a randomized sequence. The CO was altered by opening and closing surgically produced arteriovenous fistulae, at all isoflurane concentrations, and by hemorrhage at 0 MAC isoflurane. The magnitude of the HPV response was measured by differential CO2 elimination in the absence of isoflurane and by venous admixtures in all phases. During normoxia, the left lung effective flow (QL%) measured from differential CO2 excretion was 39.9 +/- 1.2% of the total blood flow and decreased to 18.8 +/- 2.6% when ventilated with the hypoxic gas mixture. Venous admixture (QVA/QT%) was significantly correlated with QL% during hypoxic ventilation in the absence of isoflurane. QVA/QT% was 22.3 +/- 2.7% during hypoxia with normal CO, and it increased significantly to 27.7 +/- 1.1% when the CO was increased 43%. It was not significantly altered (23.6 +/- 3.6%) when the CO was decreased by 54%. Isoflurane 2.5 MAC significantly increased QVA/QT% during hypoxic ventilation of the left lung to 33.9 +/- 2.6% with low CO and 35.4 +/- 1.7% with normal CO. Isoflurane 1 MAC increased QVA/QT% to 27.2 +/- 2.7% with normal CO and 28.1 +/- 2.6% with high CO.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired angiotensin conversion and bradykinin clearance in experimental canine pulmonary emphysema.

Chronic hypoxic lung diseases are associated with abnormal blood pressure regulation. Because the lung is the principal site of angiotensin conversion and because hypoxia decreases converting enzyme activity, we examined whether angiotensin converting enzyme activity was impaired in lung disease. 12 dogs received a 6 wk course of aerosolized and intratracheal papain that produced moderate panlobular emphysema. These dogs and 24 control dogs were anesthetized and sampling catheters were placed under fluoroscopic control. Angiotensin conversion was measured by a blood pressure response bioassay. Pulmonary converting enzyme activity was also assessed by infusing bradykinin (BK) and using radioimmunoassay to measure the instantaneous clearance of BK and the concentration of BK in the pulmonary artery which first produced spillover of BK into left atrial blood. Angiotensin conversion was reduced in the emphysematous dogs to 81.1% (13.2 SD) from 92% (6 SD) in the control dogs (P < 0.01). Instantaneous clearance of BK in the emphysematous dogs was only slightly reduced (93%), despite reduction in their Pao(2) to 75 mm Hg, indicating that the greatest proportion of the perfused vascular bed was exposed to alveolar Po(2) of >90 mm Hg. However, the barrier to BK passage provided by the lung, and measured by the spillover level, was reduced (1/4) to (1/2) that observed in control animals. That the defect was promptly corrected by supplemental oxygen indicates that regional pulmonary vascular converting enzyme activity had been impaired by regional alveolar hypoxia, which permitted some peptide to pass through the lungs unmetabolized. Determination of peptide metabolism in the lungs may provide a useful measure of regional alveolar hypoxia and may lead to new ways of assessing lung injury.

Strength of pulmonary vascular response to regional alveolar hypoxia.

Regional alveolar hypoxia in the lung induces regional pulmonary vasoconstriction which diverts blood flow from the hypoxic area. However, the predominant determinant of the distribution of perfusion in the normal erect lung is gravity so that more perfusion occurs at the base than at the apex. To determine the strength of the regional alveolar hypoxic response in diverting flow with or against the gravity gradient a divided tracheal cannula was placed in anesthetized dogs and unilateral alveolar hypoxia created by venilating one lung with nitrogen while ventilating the other lung with oxygen to preserve normal systemic oxygentation. Scintigrams of the distribution of perfusion obtained with intravenous 13-N and the MGH positron camera revealed a 34 and 32 per cent decrease in perfusion to the hypoxic lung in the supine and erect positions and a 26 per cent decrease in the decubitus position with the hypoxic lung dependent (P equal to 0.94 from supine shift), indicating nearly equal vasoconstriction with shift of perfusion away from the hypoxic lung in all positions. Analysis of regional shifts in perfusion revealed an equal vasoconstrictor response from apex to base in the supine position but a greater response in the lower lung zones in the erect position where perfusion was also greatest.

Hypoxic vascular response of the lung: effect of aminophylline and epinephrine.

Regional alveolar hypoxia produces regional pulmonary vasoconstriction. Experiments were conducted to assess the influence of epinephrine and aminophylline infusion on the hypoxic vasoconstrictor r...