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Biomedical subjects

G H Gurtner

Publications and source records attributed to G H Gurtner.

At least 37 records · Page 2Linked to original sources
PubMed1988

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 less than 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 microM 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 (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 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.

Amiodarone↗
PubMed1988

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.

Animals↗
PubMed1988

The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury.

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1987

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.

Alprostadil↗
PubMed1987

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.

Animals↗
PubMed1986

Leukotriene D4 increases pulmonary vascular permeability and pressure by different mechanisms in the rabbit.

We designed experiments to define the effects of leukotriene D4 (LTD4) in the rabbit lung and to determine whether or not these effects were due to the synthesis of cyclooxygenase products. Infusion of LTD4 (0.01, 0.03, and 0.10 microgram) into the rabbit pulmonary vasculature caused a dose-related increase in pulmonary arterial pressure and tracheal pressure. Pretreatment with FPL 55712 (38 microM), a leukotriene receptor antagonist, or indomethacin (10 micrograms/ml of perfusate) completely prevented the increase in tracheal and pulmonary arterial pressure. We also studied the effect of LTD4 on pulmonary vascular permeability by measuring lung weight gain at 4 levels of left atrial pressures (0, 5, 10, and 15 mmHg). Leukotriene D4 increased lung weight gain at all levels of left atrial pressure compared with that in the control group. Pretreatment with FPL 55712 completely inhibited the increase in vascular permeability caused by LTD4. Although pretreatment with indomethacin blocked the increase in tracheal and vascular pressure caused by LTD4, it did not prevent the increase in vascular permeability. We conclude that in the rabbit, LTD4 increases tracheal pressure, pulmonary arterial pressure, and pulmonary vascular permeability. Leukotriene D4 increases tracheal and pulmonary arterial pressure by stimulating the synthesis of cyclooxygenase products, and it increases vascular permeability through a mechanism that does not require the synthesis of cyclooxygenase products.

Animals↗
PubMed1985

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 arachidonate 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 micrograms . 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.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

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.

Angiotensin II↗
PubMed1985

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.

Animals↗
PubMed1985

Isoproterenol or aminophylline attenuate pulmonary edema after acid lung injury.

We tested the hypothesis that isoproterenol and aminophylline would reduce both the pulmonary hypertension and increased pulmonary vascular permeability caused by the intratracheal instillation of hydrochloric acid. The lungs of New Zealand white rabbits were studied using a blood-perfused isolated lung preparation. Changes in pulmonary artery pressure and lung weight were measured for 30 min after acid injury (2 ml/kg 0.1 N HCl). In a control group without acid injury, pulmonary artery pressure and lung weight did not change throughout 1 h of perfusion. In an acid control group, pulmonary artery pressure increased 11 +/- 3 mmHg (p less than 0.01), and lung weight increased 19.2 +/- 5.1 g during the 30 min after acid injury (p less than 0.001). Pretreatment with aminophylline (p less than 0.01) or isoproterenol (p less than 0.001) completely prevented the increase in pulmonary artery pressure after acid instillation. Pretreatment with aminophylline strikingly reduced the increase in lung weight caused by acid injury to 3.6 +/- 1.0 g over 30 min (p less than 0.01). Pretreatment with isoproterenol prevented any increase in lung weight (0.5 +/- 0.5 g over 30 min, p less than 0.01). Post-treatment with isoproterenol beginning 3 min after acid instillation also prevented the increase in pulmonary artery pressure (p less than 0.01) and markedly reduced the increase in lung weight to 5.8 +/- 2.4 g over 30 min (p less than 0.01). The beneficial effect of isoproterenol is mediated through activation of beta-adrenergic receptors because propranolol reverses its effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline↗
PubMed1984

Effect of carbonic anhydrase inhibition on the DC potential difference between cerebrospinal fluid and blood.

The effect of cerebral carbonic anhydrase inhibition on the DC potential difference between cerebrospinal fluid (CSF) and blood (PD) was studied in anesthetized dogs by perfusing the ventriculocisternal system with artificial CSF containing the carbonic anhydrase inhibitor, acetazolamide. The slope of the PD vs. arterial blood pH (delta PD/delta pHa) was calculated from PD and pHa values obtained during room-air breathing, respiratory acidosis, and respiratory alkalosis. delta PD/delta pHa decreased from -26.3 +/- 1.9 millivolts per pH unit (mV/U) before acetazolamide administration to 17.6 +/- 2.1 after acetazolamide (P less than 0.02). The PD at pH 7.4 (PD7.4) increased slightly from 2.9 +/- 0.5 mV before acetazolamide treatment to 3.9 +/- 0.6 after acetazolamide (P less than 0.02). The results suggest that carbonic anhydrase could be involved in generating the PD between CSF and blood.

Acetazolamide↗
PubMed1983

beta-Adrenergic activity and cardiovascular response to severe respiratory acidosis.

The mechanism responsible for the depressive myocardial effects of severe respiratory acidosis is unclear; however, sympathetic stimulation and catecholamines are known to be involved. The influence of beta-adrenergic receptor activity on the myocardial response to severe respiratory acidosis was studied in 18 anesthetized, mechanically ventilated dogs. Arterial CO2 tension (PaCO2) was raised by increasing the inspired CO2 fraction in O2. In control animals, as PaCO2 increased, heart rate (HR) decreased (PaCO2 approximately 110 mmHg), then returned to control (PaCO2 approximately 220 mmHg), whereas arterial blood pressure (Pa) and cardiac output (Q) remained unchanged from prehypercapnia levels. At PaCO2 greater than 350 mmHg, Pa, HR, and Q decreased and left ventricular function (LVF) curves were depressed. Death occurred at a PaCO2 of 404 +/- 25 mmHg (pH 6.48 +/- 0.02). In a second group of animals, administration of isoproterenol during the increase in PaCO2 did not result in depression of myocardial function, and death did not occur even at a significantly higher PaCO2 (PaCO2 496 +/- 12 mmHg; pH 6.39 +/- 0.02) than in the control group. Administration of propranolol to a third group of animals as PaCO2 increased did not change Pa, HR, and Q; however, LVF curves indicated a more rapid and severe depression of myocardial performance than in control, and death occurred at a significantly lower PaCO2 (PaCO2 220 +/- 25 mmHg; pH 6.65 +/- 0.02). We conclude that beta-adrenergic receptor stimulation can prevent hypercapnic heart failure and that beta-adrenergic receptor activity is involved in the mechanism responsible for this failure.

Acidosis, Respiratory↗
PubMed1983

Oxidant- and lipid-induced pulmonary vasoconstriction mediated by arachidonic acid metabolites.

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.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Interactions between placental O2 and CO transfer.

In 14 pregnant ewes the fetal side of the placenta was artificially perfused with adult sheep blood or with an emulsion of the fluorocarbon FC-47 containing varying amounts of CO. We measured diffusing capacities for O2 and Ar and permeability for urea and tritiated water (3H2O). We found that O2 diffusing capacity fell markedly in the presence of low levels of CO but that AR diffusing capacity and the permeability of urea and 3H2O remained constant at different levels of exposure to CO. We interpret the results as being consistent with the hypothesis that placental O2 transport is partially carrier mediated and that O2 and CO compete for the same carrier.

Animals↗
PubMed1982

CO concentration-dependent changes in pulmonary diffusing capacity in humans.

Steady-state CO pulmonary diffusing capacity (DLCO) was measured at different inspired CO concentrations in seven males and one female during light treadmill exercise. As the CO level is increased. DLCO increases, reaches a maximum at an end-tidal CO concentration of approximately 100 ppm, and then decreases. The maximum DLCO is up to twice as large as the DLCO measured at an inspired CO concentration of approximately 1,780 ppm. These results are consistent with the presence of saturation kinetics, one of the basic properties of carrier-mediated transport systems. A similar relationship between DLCO and CO concentration was found in previous studies of mechanically ventilated dogs. Thus there is evidence for carrier-mediated transport of CO in the lungs of both humans and dogs.

Adult↗
PubMed1981

Effect of hypoxia and CO on a cytochrome P-450-mediated reaction in rabbit lungs.

Evidence indicates that the diffusion of O2 and CO in tissue may be facilitated by a carrier molecule having a P50 that approximates tissue O2 partial pressure (PO2; 1-15 Torr) and a much higher affinity for CO than for O2. To determine whether cytochrome P-450 in lung satisfies these criteria, we measured the effect of hypoxia and of CO on the rate of metabolism of the cytochrome P-450 mediated O-demethylation of p-nitroanisole in isolated perfused rabbit lungs. Metabolism was inhibited by 50% of a control at an estimated tissue PO2 fo 4 Torr (5.5 microM). When inspired CO2 was kept at 200 Torr and inspired CO partial pressure (PCO) varied an estimated tissue PCO/PO2 ratio of 0.025 reduced the reaction rate by 50% of control, but some metabolism persisted at PCO/PO2 ratios larger than one. The relationship between reaction rate and PCO/PO2 ratio could not be fit by a single value for Haldane constant for M (CO affinity/O2 affinity) but could be described with a two-component model in which metabolism was equally divided between a high-affinity cytochrome (M = 200) and a low-affinity cytochrome (M = 2). These findings suggest that cytochrome P-450 could act as a carrier for O2 and CO in tissue with low PO2's.

Animals↗
PubMed1979

Gas-to-blood PCO2 differences during severe hypercapnia.

Five anesthetized dogs were made severely hypercapnic by stepwise addition of CO2 to their inspired air. Blood PCO2 levels greater than 400 Torr were reached. During hypercapnia, the steady-state end-tidal PCO2 (PaCO2) was always higher than the simultaneous measured arterial PCO2 (PaCO2). The mean ratio PaCO2/PACO2 was 0.861 +/- 0.01. These results are consistent with the predictions of the Charged Membrane Hypothesis, that gas-to-blood PCO2 differences should be directly proportional to the blood H+ activity. The results cannot be explained by delayed equilibration of CO2 between plasma and red blood cells. The latter hypothesis predicts that, under the conditions of these experiments, the PCO2 of arterial blood should be higher than the PCO2 of end-tibal gas. The blood HCO3- during hypercapnia did not increase as much as would be predicted if the blood were exposed to CO2 in vitro. This may reflect movement of blood HCO3- generated by the buffering of carbonic acid into intracellular compartments during hypercapnia.

Acid-Base Equilibrium↗