Reduction Of Hypoxic Pulmonary Vasoconstriction Research Articles

Attenuation of human hypoxic pulmonary vasoconstriction by acetazolamide and methazolamide.

Acetazolamide (AZ), a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide (MZ), an analog of acetazolamide, is more lipophilic, has a longer half-life, and activates a major antioxidant transcription factor. However, its influence on the hypoxic pulmonary response in humans is unknown. The aim of this study was to determine whether a clinically relevant dosing of MZ improves oxygenation, attenuates HPV, and augments plasma antioxidant capacity in men exposed to hypoxia compared with an established dosing of AZ known to suppress HPV. In this double-blind, placebo-controlled crossover trial, 11 participants were randomized to treatments with MZ (100 mg 2× daily) and AZ (250 mg 3× daily) for 2 days before 60 min of hypoxia (FIO2 ≈0.12). Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇A), blood gases, and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO2. AZ caused greater metabolic acidosis than MZ, but the augmented V̇A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with MZ (9.0 ± 0.9 mmHg) and AZ (8.0 ± 0.7 mmHg) vs. placebo (14.1 ± 1.3 mmHg, P < 0.05). Pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔPAO2) was reduced equally by both drugs. Only AZ improved the nonenzymatic plasma antioxidant capacity. Although AZ had only plasma antioxidant properties, MZ led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than AZ in humans.NEW & NOTEWORTHY Both acetazolamide and methazolamide are effective in the prevention of acute mountain sickness by inducing an increase in ventilation and oxygenation. Acetazolamide attenuates hypoxic pulmonary vasoconstriction; however, it was previously unknown whether methazolamide has the same effect in humans. This study shows that a dosing of methazolamide causing less metabolic acidosis improves oxygenation while attenuating hypoxic pulmonary vasoconstriction and pulmonary vascular sensitivity to hypoxia. Acetazolamide improved plasma antioxidant capacity better than methazolamide.

TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction.

Hypoxic pulmonary vasoconstriction (HPV) is critically important in regionally heterogeneous lung diseases by directing blood toward better-oxygenated lung units, yet the molecular mechanism of HPV remains unknown. Transient receptor potential (TRP) channels are a large cation channel family that has been implicated in HPV, specifically in the pulmonary artery smooth muscle cell (PASMC) Ca and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV. HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. In vitro experiments were performed in primary human PASMC. The hypoxia-induced pulmonary artery pressure increase seen in wild-type mice (5.6 ± 0.6 mmHg; mean ± SEM) was attenuated both by inhibition of TRPV4 (2.8 ± 0.5 mmHg), or in lungs from TRPV4-deficient mice (Trpv4) (3.4 ± 0.5 mmHg; n = 7 each). Functionally, Trpv4 mice displayed an exaggerated hypoxemia after regional airway occlusion (paO2 71% of baseline ± 2 vs. 85 ± 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in Trpv4 mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca influx and myosin light chain phosphorylation. TRPV4 may form a heteromeric channel with TRPC6 as the two channels coimmunoprecipitate from PASMC and as there is no additive effect of TRPC and TRPV4 inhibition on Ca influx in response to the agonist, 11,12-epoxyeicosatrienoic acid. TRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6.

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O(2) tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose-6-phosphate dehydrogenase (Glc-6-PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95% N(2), 5% CO(2)) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH, and HPV, substantiating the idea that glucose metabolism and Glc-6-PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD(+) and decrease in the ATP-to-ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated Glc-6-PD. Inhibition of Glc-6-PD decreased Ca(2+) sensitivity to the myofilaments and diminished Ca(2+)-independent and -dependent myosin light chain phosphorylation otherwise increased by hypoxia. Silencing Glc-6-PD expression in PA using a targeted small interfering RNA abolished HPV and decreased extracellular Ca(2+)-dependent PA contraction increased by hypoxia. Similarly, Glc-6-PD expression and activity were significantly reduced in lungs from Glc-6-PD(mut(-/-)) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating Glc-6-PD activity and the NADPH-to-NADP(+) ratio to the HPV response clearly indicated a positive linear relationship between Glc-6-PD activity and HPV. Based on these findings, we propose that Glc-6-PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension.

Activation of Glucose‐6‐Phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O2 tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose‐6‐phosphate dehydrogenase (G6PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95%N2‐5%CO2) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH and HPV, substantiating the idea that glucose metabolism and G6PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD+ and decrease in the ATP‐to‐ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated G6PD. Silencing G6PD expression in PA using a targeted siRNA abolished HPV and diminished Ca2+‐independent and Ca2+‐dependent myosin light chain phosphorylation otherwise increased by hypoxia. Similarly, G6PD expression and activity were significantly reduced in lungs from G6PDmut(−/−) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating G6PD activity and the NADPH‐to‐NADP+ ratio to the HPV response clearly indicated a positive linear relationship between G6PD activity and HPV. Based on these findings, we propose that G6PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension. (Supported by NIH grant RO1HL085352)

Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction

Acetazolamide and other related carbonic anhydrase (CA) inhibitors have had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS) and remain the standard of care for this indication. Despite many decades of CA inhibitor use for AMS, the possibility has never been seriously entertained that these drugs might also afford protection against high altitude pulmonary edema (HAPE). In this paper, I will present our evidence and supporting data of others, that acetazolamide has inhibitory effects on the hypoxic response of the pulmonary circulation that may be useful in HAPE. Data from pulmonary artery smooth muscle cells, isolated perfused lungs, and live unanethetized animals all point to a potent reduction in hypoxic pulmonary vasoconstriction (HPV) by acetazolamide that may have clinical utility in HAPE and possibly other pulmonary hypertensive disorders. Astonishingly, the efficacy of acetazolamide as a HPV inhibitor does not appear to be related to carbonic anhydrase inhibition, since other potent CA inhibitors have no effect on HPV either in the conscious dog or on hypoxic calcium (Ca(2+)) signalling in rat pulmonary artery smooth muscle cells, despite enzyme presence in these cells. Although we have not yet determined the mechanism of action for acetazolamide in HPV, we have ruled out actions on membrane L-type Ca(2+) channels, normoxic and hypoxic membrane potential and rho-kinase activation. Based upon these negative findings in isolated pulmonary artery smooth muscle cells and preliminary data in Ca(2+) free media we propose that acetazolamide may act at the level of Ca(2+) release from the sarcoplasmic reticulum, a process which initiates and amplifies cell membrane Ca(2+) channel opening. In further work, we have developed and will use a methylated analog of acetazolamide to yield a molecule lacking CA inhibiting activity, but which in most other respects (size, pK(a), heterocyclic ring structure, electrostatic charge distribution) is equivalent to acetazolamide.

Inhibition of Hypoxic Pulmonary Vasoconstriction in Isolated Rat Pulmonary Arteries by Diphenyleneiodonium (DPI)

The NADPH oxidase inhibitor, diphenyleneiodonium (DPI), is known to selectively inhibit hypoxic pulmonary vasoconstriction (HPV) in isolated rat and rabbit lungs. We have investigated whether DPI has similar effects in rat pulmonary arteries in vitro. Vessels (n=38, internal diameters 327±41 μm) were mounted in an automated myograph and preconstricted with prostaglandin F2α(PGF2α, 5 μm) before an acute hypoxic challenge. The effects of DPI (10 μm), or the vehicle DMSO, were studied on the first contractile phase of HPV. DPI (10 μm) was found to significantly inhibit HPV; 1.83±0.42 mN/mm (pre-DPI) compared to 0.11±0.22 mN/mm (post-DPI,P<0.01). However, the vehicle DMSO (0.2%) also resulted in a reduction of HPV, although this was significantly different from inhibition via DPI (P<0.05), implying a DPI-sensitive component. The effects of DPI (0.1–300 μm) were also studied on the second contractile phase of HPV. DPI (300 μm) caused a significant reversal of 45% (0.50–0.27 mN/mm) compared to 9% reversal (0.38–0.35 mN/mm) seen with DMSO (P<0.0001). The fact that an inhibitor of NADPH oxidase, the enzyme responsible for producing reactive oxygen species from oxygen, attenuated the pulmonary vascular response to hypoxia, may indicate that this, or a similar, enzyme is involved in oxygen sensing.

Effect of Intralipid on hypoxic and angiotensin-II induced pulmonary vasoconstriction in the isolated rat lung

Lipid infusions are reported to cause hypoxemia by increasing intrapulmonary shunt fraction. However, the mechanism by which they worsen gas exchange is unknown. We hypothesized that a reduction in hypoxic pulmonary vasoconstriction, caused by lipid infusion, could be the cause of increased shunt. A prospective, controlled laboratory study. A postgraduate teaching hospital laboratory. Male Wistar rats weighing 250 to 300 g. Four separate series of experiments were performed: a) The pulmonary vasopressor response to angiotensin-II was compared before and after adding either 0.9% sodium chloride (control n = 5) or 20 microL of Intralipid (n = 8). b) The pulmonary vasopressor response to hypoxia (FIO2 of 0.3) was compared before and after either 0.9% sodium chloride (control n = 5) or 20 microL of Intralipid (n = 8). c) 1 microM of indomethacin was added before either 0.9% sodium chloride (control n = 5) or Intralipid (n = 5) and the hypoxic pulmonary vasoconstriction response was compared. d) 10(-3) M L-monomethyl-n-arginine was added before 20 microL of Intralipid and the hypoxic pulmonary vasoconstriction response was compared (n = 5). Changes in pulmonary arterial pressure were measured before and after interventions. Intralipid reduced the angiotensin-II pressor response by 36 +/- 3% (p = .005) and the hypoxic pulmonary vasoconstriction response by 50 +/- 2% (p = .0003). This action was not blocked by pretreatment with either indomethacin or L-monomethyl-n-arginine. Intralipid reduces the hypoxic pulmonary vasoconstriction response in the isolated, blood perfused rat lung. This action is nonspecific, as shown by a similar reduction in the pulmonary pressor response to angiotensin-II. Pharmacologic blockade of prostaglandin release, by indomethacin, and nitric oxide release, by L-monomethyl-n-arginine did not prevent the reduction in hypoxic pulmonary vasoconstriction, thereby suggesting that neither agent mediates the lipid-induced change in pulmonary vasoreactivity.

Effect of Intralipid on hypoxic and angiotensin-II induced pulmonary vasoconstriction in the isolated rat lung

Objective: Lipid infusions are reported to cause hypoxemia by increasing intrapulmonary shunt fraction. However, the mechanism by which they worsen gas exchange is unknown. We hypothesized that a reduction in hypoxic pulmonary vasoconstriction, caused by lipid infusion, could be the cause of increased shunt. Design: A prospective, controlled laboratory study. Setting: A postgraduate teaching hospital laboratory. Subjects: Male Wistar rats weighing 250 to 300 g. Interventions: Four separate series of experiments were performed: a) The pulmonary vasopressor response to angiotensin-II was compared before and after adding either 0.9% sodium chloride (control n = 5) or 20 μL of Intralipid (n = 8). b) The pulmonary vasopressor response to hypoxia (Fio2 of 0.3) was compared before and after either 0.9% sodium chloride (control n = 5) or 20 μL of Intralipid (n = 8). c) 1 μM of indomethacin was added before either 0.9% sodium chloride (control n = 5) or Intralipid (n = 5) and the hypoxic pulmonary vasoconstriction response was compared. d) 10−3 M L-monomethyl-n-arginine was added before 20 μL of Intralipid and the hypoxic pulmonary vasoconstriction response was compared (n = 5). Measurements and Main Results: Changes in pulmonary arterial pressure were measured before and after interventions. Intralipid reduced the angiotensin-II pressor response by 36 ± 3% (p= .005) and the hypoxic pulmonary vasoconstriction response by 50 ± 2% (p= .0003). This action was not blocked by pretreatment with either indomethacin or L-monomethyl-n-arginine. Conclusions: Intralipid reduces the hypoxic pulmonary vasoconstriction response in the isolated, blood perfused rat lung. This action is nonspecific, as shown by a similar reduction in the pulmonary pressor response to angiotensin-II. Pharmacologic blockade of prostaglandin release, by indomethacin, and nitric oxide release, by L-monomethyl-n-arginine did not prevent the reduction in hypoxic pulmonary vasoconstriction, thereby suggesting that neither agent mediates the lipid-induced change in pulmonary vasoreactivity. (Crit Care Med 1994; 22:1964-1968)

Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation.

The effect of hypercapnia on pulmonary vascular tone is controversial with evidence for both a vasoconstrictor and vasodilator action. The objective of this study was to investigate the possibility that this dual response to CO2 could be explained by a direct constrictor action on smooth muscle and an indirect dilator action via the release of endothelium-derived relaxing factor. The effect of ventilation with hypercapnia (FICO2 0.15) on pulmonary pressor response to hypoxia (FIO2 0.3) was investigated. Prospective, randomized study. The National Heart and Lung Institute, UK. The isolated, blood-perfused rat lung. Angiotensin-II and a blocker of endothelium-derived relaxing factor synthesis, NG-monomethyl-L-arginine (L-NMMA). The vasomotor effect of hypercapnia depended on pulmonary arterial pressure. Under resting tone, CO2 acted as a mild constrictor (change in mean pulmonary arterial pressure from 14 +/- 2 to 15 +/- 2 mm Hg, n = 4; p < .05. At increased tone, induced either by hypoxia or Angiotensin-II, CO2 was a vasodilator. Thus, hypoxia increased mean pulmonary arterial pressure from 17 +/- 2 to 32 +/- 2 mm Hg (n = 8; p < .01), but simultaneous ventilation with hypoxia and hypercapnia reduced this by 16 +/- 1% (p < .01). Angiotensin-II (1 microgram) increased pulmonary arterial pressure from 14 +/- 2 to 39 +/- 5 mm Hg (n = 8; p < .01), but with hypercapnia, this angiotensin-induced pulmonary vasoconstriction was reduced by 18 +/- 6% (p < .001). The reduction in hypoxic pulmonary vasoconstriction induced by hypercapnia was not significantly different from that seen with Angiotensin-II hypercapnia. Blocking endothelium-derived relaxing factor synthesis using 30 microM NG-monomethyl-L-arginine did not significantly change either basal pulmonary arterial pressure or the response to hypercapnia, but increased hypoxic pulmonary vasoconstrictor by 24 +/- 4% (n = 4; p < .01). There was no significant difference between the change in hypoxic pulmonary vasoconstriction induced by hypercapnia after saline control (21 +/- 8% decrease) and the change in hypoxic pulmonary vasoconstriction caused by CO2 after 30 microM L-NMMA (25 +/- 10% decrease, p < .05, n = 8). Endothelium-derived relaxing factor seems unlikely to specifically modulate CO2-induced vasodilation in the rat pulmonary circulation.

Role of peptidoleukotrienes in hypoxic pulmonary vasoconstriction in rats

The role of leukotrienes in the mechanism of hypoxic pulmonary vasoconstriction (HPV) is controversial. To determine whether leukotriene C4 (LTC4) was produced during HPV, LTC4 levels were measured in individual samples of lung tissue, lung bronchoalveolar lavage fluid (BALF), and blood perfusate in isolated perfused lungs ventilated with normoxic or hypoxic gas mixtures. HPV was not associated with increased LTC4 in lung tissue or increased LTE4 in blood perfusate. Consistent with previous studies demonstrating elevated levels of LTC4 in pooled BALF fluid from hypoxic lungs, individual lung BALF samples demonstrated an elevation of LTC4 during hypoxia. However, the process of lung lavage alone stimulated eicosanoid production, with LTC4, 6-ketoprostaglandin F1 alpha, and thromboxane B2 levels being higher in lavaged compared to non-lavaged lungs. In lungs to which the lipoxygenase inhibitor AA 861 was added to the perfusate, a reduction in the lung tissue LTC4 levels was observed without any or only a slight reduction in HPV. To evaluate the physiological effects of LTC4 in the airways, exogenous LTC4 (1-1,000 ng) was added to the airways of both blood- and physiological salt solution-perfused lungs without any effect on the pulmonary artery pressure or a response to hypoxia. These results do not support the hypothesis that leukotrienes mediate HPV in the rat.

The Contrasting Influence of Two Lipoxygenase Inhibitors on Hypoxic Pulmonary Vasoconstriction in Anesthetized Pigs

Because leukotrienes may mediate hypoxic pulmonary vasoconstriction (HPV), we examined the influence of two lipoxygenase inhibitors on HPV in anesthetized pigs. HPV was induced by ventilation with a hypoxic gas mixture (FIO2 at 0.095), resulting in a fall in PaO2 to 23 +/- 2 mm Hg and a rise in pulmonary vascular resistance from 285 +/- 15 to 595 +/- 30 dyne/s/cm-5. After infusion of either U-60,257B (50 mg/kg, n = 13) or BW 755c (20 mg/kg, n = 8), the responses to repeated hypoxic challenges were recorded. After U-60,257B infusion the hypoxic pressor response was eliminated at 10 and 30 min and remained significantly (p less than 0.01) attenuated at 50 min. The pulmonary pressor response to angiotensin II infusion (0.2 micrograms/kg/min) was also ablated, whereas the systemic response was unchanged. In contrast, after BW 755c infusion there was a modest but sustained augmentation of HPV, maximum at 30 min (pulmonary vascular resistance, 158 +/- 23% control, p less than 0.01), and no alteration of the responses to angiotensin II. BW 755c inhibited the A23187-induced release of leukotrienes, but not histamine, from isolated porcine lung cells (IC50, 6.3 x 10(-5) M), whereas U-60,257B inhibited the release of both leukotriene (IC50, 1.1 x 10(-4) M) and histamine. These findings indicate that reduction of HPV by lipoxygenase inhibitors is not necessarily a consequence of inhibition of leukotriene synthesis.

Restoration of Hypoxic Pulmonary Vasoconstriction following Normoxia in Isolated Dog Lungs Occurs in the Presence but Not in the Absence of Prostaglandin Synthesis Inhibitors

We examined the possibility that eucapnic (6% CO2) alveolar hypoxia (3% O2) in isolated dog lungs not only produces an increase in pulmonary vascular resistance but also initiates the subsequent prostaglandin (PG) dependent reduction in this hypoxic pulmonary vasoconstriction (HPV). We determined that a reduction in HPV occurred after 45 min including a 35-min period of hypoxia (prolonged hypoxia), after 45 min of intermittent hypoxia, and after 45 min of normoxia (14% O2). These reductions were PG dependent, since they were reversed or prevented by PG synthesis inhibitors in the autologous blood perfusate. In addition to the PG-dependent reduction that required 45 min to develop, a separate reduction in HPV also occurred. This reduction occurred during prolonged hypoxia, was not prevented by PG synthesis inhibitors, was reversed after 6 min of normoxia, and was reproduced in a second period of prolonged hypoxia. We conclude that alveolar hypoxia did not initiate the PG-dependent reduction in HPV, since it occurred after normoxia as well as after hypoxia. However, hypoxia appeared to contribute to a separate PG-independent reduction in HPV, since this reduction was initiated and maintained exclusively during prolonged hypoxia and was unaffected by PG synthesis inhibitors.

Inhibition of hypoxic pulmonary vasoconstriction by nifedipine

Nifedipine is a potent slow channel calcium antagonist and systemic vasodilator recently reported to attenuate hypoxic pulmonary vasoconstriction in man. Other systemic vasodilators have also been shown to attenuate hypoxic pulmonary vasoconstriction, but their effects in some species may be mediated by reflex beta-adrenergic discharge. We evaluated the effect of nifedipine on the relation between pulmonary arterial pressure and blood flow during hyperoxia (inspired partial pressure of oxygen [PO 2] 200 mm Hg) and hypoxia (inspired PO 2 50 mm Hg) in denervated ventilated pig lungs perfused in situ with the animal's own blood. Ten lungs were ventilated with alternating 15 minute periods of hyperoxia and hypoxia. Hypoxia shifted the pulmonary artery pressure (x axis)-blood flow (y axis) relationship to the right and decreased its slope, indicating vasoconstriction. Nifedipine, given as a 0.1, 1, or 10 μg/kg bolus into the pulmonary artery, caused a dose-dependent reduction of hypoxic pulmonary vasoconstriction. It is concluded that nifedipine is a potent pulmonary vasodilator acting locally within the lung and that it might be useful in the therapy of hypoxic pulmonary hypertension from chronic lung disease in man.

Reduction of hypoxic pulmonary vasoconstriction by nitrous oxide administration in the isolated perfused cat lung.

Local pulmonary vasconstriction in response to alveolar hypoxia is a protective mechanism reducing blood flow to poorly oxygenated areas of lung. Pulmonary blood flow is thereby directed to better oxygenated lung units and venous admixture and the resulting arterial hypoxaemia is reduced. The effect of nitrous oxide on the pulmonary pressor response to alveolar hypoxia was assessed in the isolated perfused cat lung preparation under conditions of constant flow and constant left atrial and airway pressures. Nitrous oxide, in concentrations of 50 per cent and 75 per cent, was found to produce a reversible depression of the hypoxic pulmonary pressor response. The importance of hypoxia pulmonary vasconstriction and the possible implications of its reduction by anaesthetic agents are discussed.

Reduction of hypoxic pulmonary vasoconstriction by diethyl ether in the isolated perfused cat lung: the effect of acidosis and alkalosis.

Hypoxic pulmonary vasoconstriction is a protective mechanism diverting pulmonary blood flow away from hypoxic areas toward more optimally oxygenated lung units. Venous admixture is reduced and arterial oxygenation improved. Hypoxic pulmonary vasoconstriction was demonstrated during acidosis, alkalosis and normal pH in the isolated perfused cat lung under conditions of constant flow and constant left atrial and airway pressures. Two per cent diethyl ether markedly reduced hypoxic vasoconstriction under all acid-base conditions, the hypoxic pressor response returning after wash-out of diethyl ether. Modification of hypoxic pulmonary vasoconstriction during acid-base disturbances and possible implications of concurrent anaesthetic administration are discussed.

Reduction of hypoxic pulmonary vasoconstriction during trichloroethylene anesthesia.

A double-lumen tube was inserted into the trachea of dogs anesthetized with intravenous pentobarbital (30-40 mg/kg). Blood flow/unit lung volume in each lung was measured with 133Xe. Both lungs were initially ventilated with oxygen and measurements of pulmonary blood flow, CO2 output, cardiac output, and blood gases were made. When nitrogen was administered to one lung blood flow was diverted to the opposite lung. The diversion of flow was reduced by the inhalation of 1% trichloroethylene but returned after withdrawal of the anesthetic. There were no significant changes in cardiac output. Changes in CO2 output and arterial Po2 were compatible with the xenon results. It is concluded that trichloroethylene may increase arterial hypoxemia by reducing vasoconstriction in hypoxic areas of lung.

Reduction of hypoxic pulmonary vasoconstriction by magnesium chloride.

Reduction of hypoxic pulmonary vasoconstriction by magnesium chloride.