G. H. Gurtner

Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofens action.

Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean ± SEM) (from 13.6 ± 1.2 to 40.6 ± 9.5 mm Hg, p < 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 μM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (ΔW) of 5.7 ± 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (AW = 0.7 ± 0.3 g/min, p < 0.05). pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., ΔW = 0.05 ± 0.02 g/min, p < 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, ΔW = 0.6 ± 0.2 g/min, p < 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, ΔW = 0.1 ± 0.08 g/min, p < 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2−), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.

Barbiturate anesthetics inhibit thromboxane-, potassium-, but not angiotensin-induced pulmonary vasoconstriction.

Administration of the oxidant lipid peroxide tertiary butyl hydroperoxide (t-bu-OOH) in the isolated rabbit lung leads to acute pulmonary vasoconstriction, which is caused by the synthesis of thromboxane. The inhalational anesthetics, halothane, nitrous oxide, and cyclopropane, markedly enhance t-bu-OOH-induced pulmonary vasoconstriction and thromboxane production. The effects of the intravenous (iv) barbiturates thiopental and pentobarbital on t-bu-OOH-induced vasoconstriction were studied. Thiopental completely and pentobarbital partially blocked t-bu-OOH-induced vasoconstriction. Thiopental inhibited t-bu-OOH-induced synthesis of thromboxane and prostacyclin but pentobarbital did not. This inhibitory action of thiopental may be due to its antioxidant properties because similar inhibition has been observed of t-bu-OOH-induced thromboxane production with the antioxidants, vitamin E, or butylated hydroxylanisole. Thiopental and pentobarbital also inhibited the vasoconstriction induced by a thromboxane analog, epoxymethano prostaglandin H2 (U46619). Finally, both barbiturates partially inhibited the pulmonary vasoconstriction caused by potassium chloride, which requires calcium entry, but they did not inhibit the constriction caused by angiotensin II, which does not require calcium entry. These results suggest that pentobarbital and thiopental may block pulmonary vasoconstriction by inhibiting calcium entry.

Inhalation anesthetics augment oxidant-induced pulmonary vasoconstriction: Evidence for a membrane effect

Inhalational anesthetics “fluidize” biologic membranes. Since arachidonate metabolism also occurs in cell membranes, anesthetic agents may modify arachidonic acid mediator production. The authors used the isolated perfused rabbit lung preparation to examine the effects of inhalational anesthetics on the production of arachi-donate mediators. The oxidant tert-butyl-hydroperoxide (t-bu-OOH) is known to cause pulmonary vasoconstriction by causing increased production of thromboxane A2 (TxA2). The authors administered three anesthetics (halothane, cyclopropane, and nitrous oxide) of widely different potencies, at different dosages, each to three different groups of preparations and challenged the lungs at each anesthetic dose with t-bu-OOH. They found a dose-related augmentation of the pulmonary vasopressor response to t-bu-OOH. Preparations given t-bu-OOH alone showed no change in response over time. Lungs perfused with indomethacin (5 μg.ml-1 in Krebs-Henseleit buffer), ventilated with cyclopropane (2 MAC), and challenged with t-bu-OOH showed almost complete inhibition of the response to t-bu-OOH. Indomethacin at this concentration is a specific inhibitor of cyclooxygenase. The authors also have demonstrated significantly increased perfusate levels of thromboxane B2 (TxB2), the inactive metabolite of TxA2, after oxidant challenge during exposure to 2% halothane compared with TxB2 levels before halothane exposure. The authors believe that the augmented pressor response and mediator production occur because of increased substrate (arachidonic acid) availability induced by anesthetic agent.

A POSSIBLE ROLE OF OXYGENASES IN THE REGULATION OF CEREBRAL BLOOD FLOW

Publisher Summary This chapter discusses the effect of arterial hypoxemia on cerebral blood vessels. Hypoxemia produces cerebral vasodilation and an increase in cerebral blood flow (CBF). However, the precise mechanism by which hypoxemia produces vasodilation is unclear. There is evidence that low PO2 act directly on cerebral vascular smooth muscle, resulting in vasodilation. It has also been suggested that other local factors such as cerebral parenchymal acidosis secondary to anaerobic metabolism and adenosine release caused by hypoxemia are responsible for cerebral dilation. Neurogenic mechanisms are involved in the cerebral vasodilator response to hypoxemia, and it has been suggested that the carotid chemoreceptor is responsible for all, or at least a major part, of the cerebral vasodilation in response to hypoxemia. The the cerebral vasodilation to hypoxemia is not affected by denervation of the carotid or aortic chemoreceptor and is not modified by the denervation of the carotid or aortic baroreceptor. Data suggests that arterial oxygen content is important than arterial oxygen tension in the mechanism of cerebral vasodilation. This chapter presents a study to test the hypothesis that oxygen substrates such as metyrapone and imipramine could alter the responses of the cerebral vasculature to hypoxemia.

O2 Sensitive, Local Regulation of CSF H+ Activity

It has been known for many years that the H+ activity of the CSF was somehow protected from acidosis occurring in the blood and that this protection was partially achieved by a mechanism which could cause HCO 3 - differences between CSF and blood.

Relationships between Blood and Extravascular Pco2, [H+] and [HCO3−] in Lung, Cerebrospinal Fluid, and Brain

Several investigators have observed, under conditions of little or no gas exchange, that large differences in Pco2 (APco2) occur between mixed venous blood and alveolar gas (JONES, et al. [1969]; GURTNER, SONG, and FARHI [1969]; DENNISON, et al. [1969]; GUYATT, et al. [1971]. Gurtner and his colleagues have found that ∆Pco2 was related to both [H+] and [HCO3 −] activity by the mixed venous blood. They developed a model explaining their results that involves a coupling of bulk flow, diffusion, and chemical reaction near a negatively charged capillary wall. This model was considered in their article that appeared in Respiration Physiology and will be considered only briefly at the present time. The model postulates an intracapillary H+ difference due to a negatively charged capillary wall. There is a large amount of evidence that walls of blood vessels carry fixed negative charges. This evidence is reviewed in the 1969 paper.

The Effect of Treatment with Nitrendipine and Other Calcium Channel Blockers on the Physiologic and Pathologic Changes Caused by Hypoxia in Rats

Nitrendipine and other calcium channel blokers acutely inhibit hypoxic pulmonary vasoconstriction and show promise in the prevention of the pulmonary vascular and cardiac changes produced by chronic alveolar hypoxia. This paper reviews the current information available from animal and clinical studies.

OXIDANT AND LIPID INDUCED PULMONARY VASOCONSTRICTION MEDIATED BY ARACHIDONIC ACID METABLITES

In experiments using isolated rabbit lungs perfused with Krebs-Henseleit buffer in a nonrecirculating manner, we found that administration of an organic peroxide, tert-butyl hydroperoxide (t-bu-OOH), or Intralipid, an esterified mixture of unsaturated fatty acids, caused a marked vasopressor response which was associated with increased levels of thromboxane in the effluent perfusate. The vasopressor response to t-bu-OOH was greater in the lungs of vitamin E-deficient animals, and this could be correlated with an attenuated ability to increase prostacyclin production in these lungs. Conversely, administration of Intralipid to normal lungs caused marked increases in prostacyclin and a smaller pressor response. The magnitude of the pressor response was strongly correlated with the ratio of thromboxane B2 to the prostacyclin metabolite. No release of these mediators was associated with pulmonary vasoconstriction caused by administration of angiotensin II. The pressor response could be completely blocked by administration of indomethacin. We propose that this activation of the cyclooxygenase pathway of arachidonic acid metabolism may be important in the pathophysiology of oxidant lung damage.