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 ibuprofen's action.

Pharmacological modification of pulmonary vascular injury: possible role of cAMP.

Experiments were designed to test the hypothesis that drugs which increase adenosine 3',5'-cyclic monophosphate (cAMP) in the lung would prevent the pulmonary hypertension and the increase in vascular permeability caused by the infusion of the oxidant lipid peroxide, tert-butyl hydroperoxide (t-bu-OOH), in isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pretreatment with indomethacin or verapamil was also studied, since these drugs block the increase in pulmonary arterial pressure caused by t-bu-OOH. Indomethacin or verapamil prevented the pulmonary hypertension but did not prevent the increase in permeability caused by t-bu-OOH. Consequently, indomethacin or verapamil treatment partially reduced the gain in lung weight caused by t-bu-OOH. In contrast, pretreatment with isoproterenol, prostaglandin E1, or a cAMP analogue not only prevented the pulmonary hypertension but also inhibited the increase in vascular permeability caused by t-bu-OOH. Consequently, these drugs completely blocked the gain in lung weight caused by t-bu-OOH. Posttreatment with aminophylline or the cAMP analogue also significantly reduced the gain in lung weight caused by t-bu-OOH. These results indicate that pharmacological therapy can reduce the pulmonary hypertension and the increase in vascular permeability caused by the infusion of a lipid hydroperoxide. Since isoproterenol, aminophylline, prostaglandin E1, and a cAMP analogue all had similar effects, the results suggest that the likely common mechanism for their protective effect is an increase in cAMP.

Protein kinase C-mediated pulmonary vasoconstriction in rabbit: role of Ca2+, AA metabolites, and vasodilators.

We studied the effects of three chemically distinct protein kinase C activators on pulmonary vascular tone in the buffer-perfused isolated rabbit lung. The three activators, 12-deoxyphorbol 13-isobutyrate (12,13-phorbol), mezerein, and 1-oleoyl-2-acetyl-sn-glycerol, produce concentration-dependent increases in pulmonary arterial pressure, whereas the inactive compound 4 alpha-phorbol 12,13-dibutyrate does not affect pulmonary arterial pressure. Reducing calcium availability with verapamil, a calcium-free buffer, or a chelator of intracellular calcium significantly decreases the response to 12,13-phorbol or mezerein. Pretreatment with phloretin, an inhibitor of protein kinase C, has no affect on the vasoconstriction caused by infusion of a KCl bolus, but it does inhibit in a dose-dependent manner the response to 12,13-phorbol and mezerein. 12,13-Phorbol at a concentration of 2.5 microM, but not of 1 microM, stimulates prostacyclin and thromboxane synthesis by the isolated lung. Because inhibitors of thromboxane synthesis significantly decrease the response, thromboxane likely contributes to the vasoconstriction produced by higher concentrations of 12,13-phorbol and mezerein. Pretreatment with isoproterenol or nitroprusside reduces the increase in pulmonary arterial pressure caused by the protein kinase C activators but does not reverse vasoconstriction, even though subsequent treatment with verapamil does. In summary, activating protein kinase C in the isolated rabbit lung causes long-lasting pulmonary vasoconstriction, reducing calcium availability decreases the response, part of the increase in pulmonary arterial pressure appears secondary to thromboxane generation, and pretreatment with isoproterenol or nitroprusside prevents the vasoconstriction, but posttreatment with these vasodilators is ineffective.

O2 radicals mediate reperfusion lung injury in ischemic O2-ventilated canine pulmonary lobe.

This study was undertaken to determine whether lung injury after a period of ischemia reperfusion is caused by O2 ventilation during ischemia and whether this injury is mediated by reactive O2 metabolites. Isolated canine left lower pulmonary lobes were subjected to room temperature ischemia for 6 h while being ventilated with either 100% O2, room air, or 100% N2. After the ischemic period, all lobes were perfused with autologous blood and ventilated with 100% O2 for an additional 4 h. In lobes ventilated with 100% O2 during the ischemic period, massive weight gain (228%) occurred 4 h after reperfusion. A marked increase in pulmonary shunt was noted. Lobes ventilated with room air behaved similarly. In contrast, lobes ventilated with 100% N2 gained significantly less weight (54%) and did not manifest any increase in pulmonary shunt. When lobes ventilated with 100% O2 or room air were pretreated with superoxide dismutase (SOD), the injury was significantly reduced. Pressure-volume deflation study of lobes, after ischemia only, demonstrated that ventilation with 100% O2 and with 100% N2 both equally decreased pulmonary compliance. We conclude that lung ischemia-reperfusion injury is related to O2 ventilation during ischemia and that injury can be prevented by administration of SOD or ventilation with 100% N2. This suggests that the injury is related to O2 metabolites produced during O2 ventilation in the absence of the circulation.

Mepacrine attenuates pulmonary vasoreactivity in rabbits.

The organic peroxide tert-butyl hydroperoxide (t-bu-OOH) induces pulmonary vasoconstriction by stimulating production of thromboxane in the rabbit lung, possibly by activating phospholipase A2. t-bu-OOH-induced vasoconstriction and thromboxane production is augmented by inhalational anesthetic agents, perhaps due to an effect of anesthetic agents on membrane lipids. To further investigate the mechanism of thromboxane generation, we studied the influence of the phospholipase A2 inhibitor, mepacrine, in a dose known to inhibit the enzyme in other systems, on t-bu-OOH-induced pulmonary arterial vasoconstriction. We found that 10(-4) M mepacrine completely inhibited t-bu-OOH-induced vasoconstriction. We also found that mepacrine inhibited arachidonic acid-induced pulmonary vasoconstriction but did not inhibit thromboxane productions. We also investigated the effect of mepacrine on two other pulmonary vasoconstrictors, angiotensin II (ANG II) and KCl, which do not act through arachidonic acid metabolites in the rabbit lung. Mepacrine inhibited both ANG-II and KCl-induced vasoconstriction. The inhibition by mepacrine of pulmonary vasoconstriction is reversible if the drug is washed out of the lung. This effect of mepacrine cannot be explained by phospholipase inhibition alone and is consistent with prevention of smooth muscle contraction.

Antioxidants and antioxidant enzymes protect against pulmonary oxygen toxicity in the rabbit.

Two major lines of defense exist against oxidant lung injury: tissue antioxidants and antioxidant enzymes. We studied pretreatment with the antioxidants, vitamin E and butylated hydroxyanisole (BHA), and the antioxidant enzymes, superoxide dismutase (SOD) and catalase, in rabbits exposed to 100% O2 for 48 h. BHA (200 mg/kg ip) or vitamin E (50-100 mg/kg po) were given for 2 or 3 days, respectively, before O2 exposure. Combined therapy with polyethylene glycol- (PEG) conjugated SOD (12 mg/kg) and catalase (200,000 U/kg) was given intraperitoneally 1 h before and 24 h after beginning 100% O2. Hyperoxia significantly increased the pulmonary content of malondialdehyde, indicating enhanced lipid peroxidation. One hundred percent O2 also increased lung weight gain and alveolar-capillary permeability to aerosolized 99mTc-labeled diethylenetriaminepentaacetate (99mTc-DTPA, 500 mol wt) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt). Pretreatment with vitamin E, BHA, or the combination of PEG-SOD and PEG-catalase prevented the increase in malondialdehyde, lung weight gain, and alveolar-capillary permeability caused by hyperoxia. These results indicate that augmenting either tissue antioxidants or antioxidant enzymes can prevent the pulmonary injury caused by 48 h of 100% O2 in rabbits.

Thromboxane-induced pulmonary vasoconstriction: involvement of calcium.

Infusion of tert-butyl hydroperoxide (t-bu-OOH) or arachidonic acid into rabbit pulmonary arteries stimulated thromboxane B2 (TxB2) production and caused pulmonary vasoconstriction. Both phenomena were blocked by cyclooxygenase inhibitors or a thromboxane synthase inhibitor. The increase in pulmonary arterial pressure caused by either t-bu-OOH or arachidonic acid infusion correlated with the concentration of TxB2 in the effluent perfusate. The concentration of TxB2 in the effluent perfusate, however, was always 10-fold greater after arachidonic acid infusion. In the rabbit pulmonary vascular bed lipoxygenase products did not appear involved in the vasoactive response to t-bu-OOH or exogenous arachidonic acid infusion. Calcium entry blockers or a calcium-free perfusate prevented the thromboxane-induced pulmonary vasoconstriction. Calmodulin inhibitors also blocked the pulmonary vasoconstriction induced by t-bu-OOH without affecting the production of TxB2 or prostacyclin. These results suggest that thromboxane causes pulmonary vasoconstriction by increasing cytosol calcium concentration.

Mechanism of hyperoxia-induced pulmonary vascular paralysis: effect of antioxidant pretreatment.

We designed experiments using isolated rabbit lungs to determine the effect of hyperoxia on the pulmonary vasoconstriction caused by the infusion of the lipid peroxide tert-butyl hydroperoxide (t-bu-OOH), which produces vasoconstriction by stimulating the pulmonary synthesis of thromboxane. Exposure to 48-60 h of 100% O2 at 1 ATA markedly reduced the increase in pulmonary artery pressure caused by t-bu-OOH infusion. We also investigated whether the mechanism for the attenuated vasoconstriction was due to altered production of arachidonate mediators or oxidant-induced damage to the contractile mechanism. In addition to infusing t-bu-OOH, which selectively stimulates thromboxane production, we also infused Intralipid, an esterified fatty acid emulsion that stimulates production of both thromboxane and prostacyclin. These experiments were done to study the effect of hyperoxia on prostacyclin synthesis. To determine if antioxidant therapy would prevent the changes in mediator production and vascular reactivity caused by hyperoxia, we pretreated animals with the antioxidants butylated hydroxyanisole (BHA) or vitamin E. The lack of vascular reactivity to t-bu-OOH was not due to a decrease in thromboxane synthesis or an increase in prostacyclin synthesis. Hyperoxia did not affect thromboxane synthesis during basal conditions or after stimulation of synthesis by t-bu-OOH. 100% O2 also did not effect the basal synthesis of prostacyclin by the lung. Hyperoxia did, however, markedly reduce prostacyclin synthesis when it was stimulated by Intralipid infusion. Antioxidant pretreatment did not reverse the inhibition of prostacyclin synthesis but did prevent the loss of vascular reactivity caused by hyperoxia. Thus hyperoxia causes vascular paralysis through oxidant-induced injury to the pulmonary vasculature.

Intratracheal administration of DBcAMP attenuates edema formation in phosgene-induced acute lung injury.

Phosgene, a toxic gas widely used as an industrial chemical intermediate, is known to cause life-threatening latent noncardiogenic pulmonary edema. Mechanisms related to its toxicity appear to involve lipoxygenase mediators of arachidonic acid (AA) and can be inhibited by pretreatment with drugs that increase adenosine 3',5'-cyclic monophosphate (cAMP). In the present study, we used the isolated buffer-perfused rabbit lung model to investigate the mechanisms by which cAMP protects against phosgene-induced lung injury. Posttreatment with dibutyryl cAMP (DBcAMP) was given 60-85 min after exposure by an intravascular or intratracheal route. Lung weight gain (LWG) was measured continuously. AA metabolites leukotriene (LT) C4, LTD4, and LTE4 and 6-ketoprostaglandin F1 alpha were measured in the perfusate at 70, 90, 110, 130, and 150 min after exposure. Tissue malondialdehyde and reduced and oxidized glutathione were analyzed 150 min postexposure. Compared with measurements in the lungs of rabbits exposed to phosgene alone, posttreatment with DBcAMP significantly reduced LWG, pulmonary arterial pressure, and inhibited the release of LTC4, LTD4, and LTE4. Intratracheal administration of DBcAMP was more effective than intravascular administration in reducing LWG. Posttreatment also decreased MDA and protected against glutathione oxidation observed with phosgene exposure. We conclude that phosgene causes marked glutathione oxidation, lipid peroxidation, release of AA mediators, and increases LWG. Posttreatment with DBcAMP attenuates these effects, not only by previously described inhibition of pulmonary endothelial or epithelial cell contraction but also by inhibition of AA-mediator production and a novel antioxidant effect.

Endogenous production of superoxide by rabbit lungs: effects of hypoxia or metabolic inhibitors.

We find spontaneous light emission from isolated Krebs-Henseleit-perfused rabbit lungs when the light-emitting super-oxide trap lucigenin is added to the perfusate. Lucigenin light emission appears to be specific for superoxide anion, because light emission from the lung caused by a superoxide-generating system is abolished by superoxide dismutase but not by catalase or dimethylthiourea. We also studied the relative sensitivity of lucigenin photoemission to superoxide and to H2O2 in vitro. Lucigenin photoemission is three to four orders of magnitude more sensitive to superoxide than to H2O2 and probably cannot detect H2O2 in concentrations thought to occur in biological systems. Basal lucigenin photoemission by the lung is oxygen dependent, because severe hypoxia completely inhibits light emission. Superoxide dismutase reduces basal photoemission by 50%, and administration of the low-molecular-weight superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (tiron) inhibits basal photoemission by approximately 90%. These observations suggest that endogenous superoxide production is primarily intracellular and that approximately half of the superoxide reaches the extracellular space. Superoxide transport may involve anion channels, because the anion channel blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid increases photoemission, suggesting intracellular accumulation of superoxide. A cytochrome P-450 inhibitor, SKF 525A, or the mitochondrial transport inhibitor antimycin decreased basal photoemission by approximately 50%, suggesting that cytochrome P-450-mediated reactions and perhaps mitochondrial function contribute to basal superoxide production in the isolated perfused lung. Endogenous superoxide production may be important in regulation of pulmonary vascular reactivity and may contribute to the pathogenesis of lung reperfusion injury.

Hydroperoxide-induced chemiluminescence in rabbit lungs: role of arachidonic acid enzymes.

Low-level chemiluminescence (C) is thought to be an index of oxidant stress. We measured the relationship between low-level C, pulmonary arterial pressure, and perfusate concentration of thromboxane B2 (TxB2) in isolated perfused rabbit lungs during challenge with tert-butyl hydroperoxide (t-bu-OOH). We also measured glutathione release as another index of oxidant stress. We found that C was correlated with each variable, suggesting that oxidant stress measured by C and by glutathione release stimulated TxB2 production and pulmonary vasoconstriction. We also investigated the contribution of active O2 metabolites produced by prostaglandin (PG) peroxidase to oxidant stress by studying the effects of t-bu-OOH before and after the use of cyclooxygenase and lipoxygenase inhibitors. We found that C was augmented after inhibition, perhaps due to metabolism of t-bu-OOH by peroxidases of both arachidonic acid (AA) metabolic pathways in the absence of their normal substrates. We studied phenylbutazone, thought to inhibit peroxidases, and AA. C during t-bu-OOH administration was not augmented after phenylbutazone and was markedly inhibited after AA administration perhaps because AA competes with t-bu-OOH. To further study the role of peroxidases we pretreated the lungs with the antioxidant dithiothreitol, which inhibits peroxidases involved in both the cyclooxygenase and lipoxygenase pathways. Dithiothreitol nearly abolished C produced by t-bu-OOH and also prevented the increased light caused by eicosatetrynoic acid. We directly tested the hypothesis that C occurred as a result of the interaction of t-bu-OOH and the cyclooxygenase and lipoxygenase enzymes; we measured C when t-bu-OOH was added to purified PGH2 synthase or soybean lipoxygenase. The combination of t-bu-OOH with PGH2 synthase or lipoxygenase led to C that was inhibited by dithiothreitol and by the antioxidant phenol. These results suggest that enzymes involved in AA metabolism can interact with t-bu-OOH and that the action of these enzymes on t-bu-OOH leads to C. The results may mean that lipid peroxides can indirectly contribute to tissue oxidant stress due to production of active O2 metabolites as by-products of their metabolism by AA peroxidases.

Effect of pH on pulmonary vascular tone, reactivity, and arachidonate metabolism.

We studied the effects of perfusate pH on pulmonary vascular tone, reactivity, and thromboxane and prostacyclin synthesis in isolated buffer-perfused rabbit lungs. Extracellular acidosis did not affect base-line vascular tone, but alkalosis had a biphasic effect. Increasing the perfusate pH from 7.40 to 7.65 caused vasodilation, whereas raising pH to 7.70-8.10 caused vasoconstriction. Removing calcium (Ca2+) from the perfusate completely prevented the vasoconstriction caused by alkalosis. Perfusate pH strikingly affected pulmonary vascular reactivity. Acidosis inhibited the vasoconstriction caused by thromboxane and potassium chloride (KCl) but did not affect the response to angiotensin II. Alkalosis, in contrast, augmented the vasoconstriction caused by thromboxane and angiotensin II but reduced the vasoconstriction caused by KCl. Changes in pH also altered thromboxane and prostacyclin synthesis after the infusion of exogenous arachidonic acid (AA) or the endogenous release of AA by the lipid peroxide tert-butyl hydroperoxide.

Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators.

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotension II and KCl.

Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists protect against pulmonary edema caused by phosgene.

Phosgene is a toxic oxidant gas that causes the adult respiratory distress syndrome in exposed workers. Phosgene exposure markedly increased lung weight gain in buffer-perfused isolated rabbit lungs (31 +/- 5 g over 60 min after phosgene vs. 7.7 +/- 1.2 in control lungs, P less than 0.01) and markedly increased the lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.02 +/- 0.01 in control lungs, P less than 0.01). Pretreatment with dibutyryl adenosine 3',5' -cyclic monophosphate (DBcAMP), aminophylline, or terbutaline plus isoproterenol prevented the increase in lung weight caused by phosgene (31 +/- 5 g phosgene, 11.7 +/- 2.8 DBcAMP, 7.5 +/- 2.5 aminophylline, 6.1 +/- 1 terbutaline and isoproterenol, 6.1 +/- 1.2 control + aminophylline, and 7.7 +/- 1.2 control; all treatments were P less than 0.01 vs. the untreated phosgene group and not significantly different from control lungs). Pretreatment with aminophylline prevented the increase in lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.06 +/- 0.02 in aminophylline-treated lungs, P less than 0.01). Posttreatment with aminophylline and terbutaline also prevented the increase in lung weight caused by phosgene. These results indicate that phosgene dramatically increases the movement of fluid and protein across the pulmonary vasculature and that treatment with DBcAMP, aminophylline, terbutaline, or isoproterenol markedly reduces the pulmonary edema caused by phosgene.

Nitric oxide and prostaglandins mediate vasodilation to 5,6-EET in rabbit lung.

We have previously found that 5,6-EET (epoxyeicosatrienoic acid)(50 nM) significantly dilates the vascular bed(42%) of the isolated, constantly perfused rabbit lung, which has been constricted with U46619(5-8 pM). We studied the role of EDRF-NO and prostaglandins in the 5,6-EET-induced vascular relaxation. Dilation to 5,6-EET was evident only when the pulmonary vascular tone was increased. L-NNA (N omega-nitro-L-arginine, 10(-4) M), an inhibitor of NO synthase(NOS); U46619(5-10 pM), a thromboxane mimetic; and L-NNA + INDO(indomethacin, 10(-5) M), a cyclooxygenase inhibitor, all increased the pressure of pulmonary artery(PPa) from baseline, to a peak range of 28-38mmHg(32.75 [symbol: see text] 2.2), whereas INDO alone increased Ppa only by 10mmHg. L-NNA + INDO,L-NNA alone, and INDO + U46619 attenuated the 5,6-EET relaxing effect by 100%, 88% and 64.5%, respectively. In the presence of L-NNA and 5,6-EET, SNAP(S-nitroso-N-acetyl-D,L-penicillamine, 10(-6) M), a NO donor, reduced Ppa by 75%. We conclude that the mechanism of vasodilation to 5,6-EET in the rabbit pulmonary circulation is via both EDRF-NO and PG pathways and that the vasodilation is largely EDRF-NO dependent.

Interaction of carbon monoxide and cyanide on cerebral circulation and metabolism.

Significant elevations of carboxyhemoglobin and blood cyanide have been found in fire victims. The nature of the interaction of acute exposures to these agents is unclear. This study was undertaken to describe the of cyanide and carbon monoxide--alone and in combination--on the circulation and metabolism of the brain in anesthetized dogs. Cerebral blood flow increased to 130 and 200% of control with elevations in carboxyhemoglobin to 30 and 51% or with elevations in blood cyanide to 1.0 and 1.5 microgram/ml, respectively. Cerebral oxygen consumption remained unchanged until the higher level of carbon monoxide or cyanide was reached. When carbon monoxide and cyanide were administered simultaneously, cerebral blood flow increased in an additive manner, but significant decreases in cerebral oxygen consumption occurred at the combination of the lower concentrations. These data suggest that carbon monoxide and cyanide are physiologically additive on producing changes in cerebral blood flow, but may act synergistically on cerebral metabolism.

Can alveolar pCO2 exceed pulmonary end-capillary CO2? Yes.

In 1891 Christian Bohr observed that alveolar PCO2 could exceed arterial PCO2 when high levels of CO2 were present in the inspired air. He proposed that CO2 could be secreted by the lung. His hypothesis was dismissed as being due to experimental error; however, recently the same phenomenon was rediscovered using modern techniques. A possible explanation for the phenomenon may involve coupling between diffusion and chemical reaction of H+, HCO3-, and CO2 in the vicinity of a negatively charged capillary wall, causing the PCO2 to be higher near the wall that in the bulk phase of capillary blood. Alveolar PCO2 is related to the PCO2 near the wall rather than the bulk phase PCO2. The Charged Membrane Hypotheses can explain the phenomenon of CO2 secretion not by a cellular mechanism, but a physical chemical disequilibrium within the capillary which is maintained by blood flow through the capillary.