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Biomedical subjects

N A Paterson

Publications and source records attributed to N A Paterson.

At least 37 records · Page 2Linked to original sources
PubMed1989

Role of lipoxygenase, cyclooxygenase and cytochrome P-450 metabolites in contractions of isolated guinea pig pulmonary venules induced by hypoxia and anoxia.

Arachidonic acid metabolites, notably leukotrienes (LTs), have been postulated to play a role in hypoxic pulmonary vasoconstriction. In the present study, we examined the contribution of arachidonic acid metabolites, via the cyclooxygenase, 5-lipoxygenase and cytochrome P-450 monooxygenase pathways, to the hypoxia (25 +/- 3 torr)- and anoxia (0 +/- 2 torr)-induced contractions of isolated pulmonary venules. Neither the cyclooxygenase inhibitors indomethacin (5 microM) or ibuprofen (10 microM) nor the 5-lipoxygenase inhibitors nordihydroguaiaretic acid (5 microM) or U 60257B (10 microM) affected the contractile responses. Similarly, the LT receptor antagonists FPL 57231 (3 microM) or LY 163443 (1 microM), at concentrations that inhibited LT-induced venular contractions, did not significantly affect the responses to hypoxia or anoxia. In fact, anoxia suppressed spontaneous LT release from the venules. The cytochrome P-450 inhibitor SKF-525A (500 microM) nonselectively depressed venular contractions induced by decreased PO2 and pharmacological agents. Induction of the cytochrome P-450 monooxygenase system with beta-naphthoflavone did not alter venular contractions induced by hypoxia or anoxia. Contractions of isolated guinea pig pulmonary venules elicited by decreased PO2 are not mediated by 5-lipoxygenase or cyclooxygenase metabolites. Furthermore, the data do not support a role for cytochrome P-450 metabolites of endogenous substrates in these contractions.

Acetophenones↗
PubMed1988

Effect of hypoxia on responses of respiratory smooth muscle to histamine and LTD4.

The aim of the present study was to compare the effect of reduced oxygenation on the contractions of pulmonary vascular and airway smooth muscle induced by leukotriene D4 (LTD4) with those induced by histamine (an agonist with similar mechanisms of smooth muscle contraction) and KCl (a voltage-dependent stimulus). During hypoxia (PO2: 40 +/- 4 Torr) the responses of isolated porcine pulmonary artery and vein spiral strips to LTD4 increased approximately three- and two-fold, respectively, and the vein also exhibited an augmented response to histamine. The augmentation was blunted (LTD4) or reversed (histamine) during anoxia (PO2: 0 +/- 2 Torr). Responses to KCl were not systematically altered by reduced oxygenation. In contrast, the contractions of the guinea pig parenchymal lung strip by all three agonists were generally suppressed by reduced oxygenation. After reoxygenation, the contractile responses of each of the three smooth muscle preparations were generally increased compared with previous and concurrent base-line observations, particularly the LTD4-induced pulmonary vein contraction that increased approximately sevenfold after reoxygenation after anoxia. The contribution (if any) of leukotrienes to hypoxic pulmonary vasoconstriction may reflect increased vascular responsiveness to leukotrienes during hypoxia as well as (or instead of) increased leukotriene release.

Animals↗
PubMed1986

The effect of leukotrienes on porcine alveolar macrophage function.

The ability of the synthetic leukotrienes LTB4, LTC4, LTD4 and LTE4 to stimulate porcine AM was compared with that of two known AM stimuli: zymosan, a particulate stimulus and phorbol myristate acetate (PMA), a soluble stimulus. The criteria for AM stimulation were: increased generation of superoxide anion (O2-), the release of the lysosomal enzymes N-acetyl-beta-D-glucosaminidase (NABG) and arylsulfatase and an increase in surface free energy. Whereas zymosan and PMA both stimulated AM according to each of the three criteria, the effect of leukotrienes was relatively minor. LTB4 (10(-6) M) and LTD4 (10(-6) M) caused a modest reduction in spontaneous O2- release by AM. LTD4 (10(-6) M) also caused a small (18%), but significant (p less than 0.05), reduction in the additional O2- release induced by PMA. LTC4 and LTE4 did not alter spontaneous O2- release. Neither spontaneous nor stimulated enzyme release was systematically altered by any of the leukotrienes. LTD4 caused a cysteine-inhibitable, dose-dependent increase in surface free energy with a plateau at concentrations above 10(-8) M. The increased surface free energy induced by LTD4 may be a consequence of binding to a surface dipeptidase.

Acetylglucosaminidase↗
PubMed1986

Influence of hypoxia on histamine and leukotriene release from dispersed porcine lung cells.

The ability of hypoxia (PO2 57 Torr) and anoxia (PO2 0 Torr) to induce the release of histamine or sulfidopeptide leukotrienes from dispersed porcine parenchymal lung cells was examined. Spontaneous release of histamine (9.2 +/- 1.3%) was not significantly increased during hypoxia or anoxia, and spontaneous leukotriene release was not detected under any conditions. The release of leukotriene induced by A23187 (78 +/- 11 pmol leukotriene D4 equivalent/10(7) parenchymal lung cells) was unchanged during hypoxia and was significantly reduced (55.4 +/- 7.7% control leukotriene release) during anoxia, whereas A23187-induced histamine release (63.2 +/- 4.2% total cell histamine) was unaffected by reduced oxygenation. Reduction of final buffer pH from 7.4 to 7.0 did not affect mediator release. High-pressure liquid chromatographic analysis of the released leukotrienes revealed a mixture of leukotrienes C4 and D4, with a symmetrical reduction in product during anoxia. Although leukotriene release in response to hypoxia was not demonstrated, the findings do not preclude limited local release of leukotrienes, perhaps in association with increased smooth muscle responsiveness.

Animals↗
PubMed1985

Zymosan enhances leukotriene D4 metabolism by porcine alveolar macrophages.

Porcine alveolar macrophages (AM) metabolize leukotriene D4 (LTD4) to leukotriene E4 (LTE4). In the present study, the ability of a fluid-phase AM stimulus (A23187) and a phagocytic stimulus (opsonized zymosan) to augment LTD4 metabolism was examined. Both stimuli increased the release of superoxide (O-2) anions. However, whereas zymosan caused a consistent reduction in surface free energy, the effect of A23187 was variable. Similarly, zymosan induced release of the lysosomal enzymes N-acetyl-beta-D-glucosaminidase and arylsulphatase (mean net release, 14.9% and 12.0%, respectively), whereas release induced by A23187 was smaller (mean net release 1.42% and 1.31%, respectively) and of marginal statistical significance. Zymosan, but not A23187, caused a significant (P less than 0.005) augmentation of LTD4 inactivation: from 93 +/- 7 pM/10(7) cells (69 +/- 5% of added LTD4) at 60 min by control AM, to 117 +/- 3 pM/10(7) cells (88 +/- 2% of added LTD4) at 60 min by zymosan-treated AM. Zymosan also induced the release of LTD4 inactivating capacity (128 +/- 21 pM LTD4/10(7) AM/60 min) into the supernatant. Conversion of LTD4 to LTE4 by zymosan-treated AM and their supernatants was confirmed chromatographically. In addition, LTD4 inactivation by AM and their supernatants was inhibited by 10 mM L-cysteine. These data suggest that zymosan released a dipeptidase, possibly of lysosomal origin, which catalysed the conversion of LTD4 to LTE4.

Animals↗
PubMed1984

Metabolism of leukotriene D4 by porcine alveolar macrophages.

Porcine alveolar macrophages (AM), as we reported in 1981, inactivate slow-reacting substance of anaphylaxis (SRS-A) in a time- and cell-number-dependent fashion. In the present study, metabolism of synthetic leukotriene D4 (LTD4) to leukotriene E4 (LTE4) by AM was demonstrated (mean conversion, 216 pmoles LTD/10(7) AM/60 min). The metabolism was inhibited by cooling or by removal of calcium ions plus addition of EDTA but not by dinitrophenol or puromycin, lipoxygenase inhibitors, the peroxidase inhibitor aminotriazole, or the hydroxyl ion scavenger benzoic acid. Similarly, although the addition of catalase plus superoxide dismutase significantly augmented (169 +/- 25% control) SRS release from dispersed porcine lung cells, the presence of these enzymes did not prevent LTD4 metabolism by AM. Inhibitors of gamma-glutamyl transpeptidase were also without effect but the dipeptidase inhibitors L-cysteine and dithiothreitol significantly reduced the conversion, as did pretreatment of AM with thermolysin (100 micrograms/ml). These data indicate that an AM dipeptidase, which may at least partly be located on the cell surface, converts LTD4 to the less bioactive LTE4.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1984

Interstitial pneumonitis in myasthenia gravis.

Both myasthenia gravis and interstitial pneumonitis are associated with various autoimmune phenomena and can coexist with other immune disorders, but the two have not been described together. We present a woman with such a concurrence whose clinical picture improved following plasmapheresis and thymectomy.

Female↗
PubMed1982

The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A double-blind single dose study.

In two groups of patients, 15 with asthma and 15 with chronic bronchitis, the bronchodilator effects of ipratropium bromide, of fenoterol plus theophylline, and of the combination of the three drugs, were compared using a double-blind, single-dose, placebo-controlled format. Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis (delta FEV1 = .29 L in one hour in asthmatic patients, .18 L in patients with bronchitis). In contrast, fenoterol plus theophylline induced a considerably greater effect in asthmatic patients (delta FEV1 = .41 L in one hour) than in those with bronchitis (delta FEV1 = .07 in one hour). The use of the three drugs in combination compared with ipratropium bromide alone, or fenoterol plus theophylline alone, resulted in a significant additional bronchodilatation in asthmatic patients. In the patients with bronchitis, the triple combination was clearly superior to fenoterol plus theophylline. A similar trend was present in comparing the triple combination to ipratropium bromide, but the difference did not reach statistical significance. There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive. Asthmatic patients and the physician were able to distinguish the triple combination from placebo. No such ability was demonstrated with respect to those with bronchitis. All three drugs were well tolerated. Side effects were mostly mild, and none was related to the use of ipratropium.

Administration, Oral↗
PubMed1981

The effects of SRS-A and histamine antagonists on antigen-induced contraction of guinea pig trachea.

Spirally cut tracheae from actively sensitized guinea pigs were challenged with antigen in the presence and absence of indomethacin. In the absence of indomethacin, the SRS-A antagonist FPL55712, added 30 min before challenge had no effect on antigen-induced contraction (ATC) when added in concentrations less than or equal to 1.7 X 10(-6) M. However with the highest concentration employed (5.2 X 10(-6) M) the duration of ATC was reduced by 45%. Furthermore the enhancement by indomethacin of the peak height of ATC was reduced even by lower (5.2 X 10(-7) M) concentrations of FPL55712. The inhibition of FPL55712 was time-dependent, suggesting that its action was not confined to competitive receptor antagonism. Hence, although our previous data indicate that a lipoxygenase product is involved in ATC, the current findings suggest that lipoxygenase products in addition to SRS-A contribute to the response. THe H1-antagonists mepyramine, chlorpheniramine and diphenhydramine inhibited ATC only in the first minute, and the peak height was reduced only by diphenhydramine. The H2-antagonist cimetidine had no effect on ATC. These data suggest that the contribution of histamine to ATC is small, confined to the first minute following antigen challenge and mediated via H1-receptors. Reduction of the peak height by diphenhydramine may be unrelated to its H1-antagonist properties.

Airway Resistance↗
PubMed1981

Immunological and non-immunological synthesis and release of prostaglandins and thromboxanes from isolated guinea pig trachea.

Specific radioimmunoassays were used to demonstrate the synthesis by the guinea pig trachea of 6-keto PGF1 alpha, TxB2, and PGF2 alpha in addition to PGE2. The rank order of both spontaneous and stimulated release was PGE2 greater than PGF2 alpha greater than 6-keto PGF1 alpha = TxB2. Ovalbumin-induced prostanoid release from sensitized tissue was antigen-specific. The release was unlikely to be secondary consequence of tracheal contraction since incubations with calcium ionophore A23187, at a concentration which produces an equivalent magnitude of contraction of sensitized trachea, did not induce a significant PG or Tx production. In contrast, significantly higher prostanoid synthesis was induced by A23187 in unsensitized than sensitized trachea. Thus sensitization altered the profile of arachidonic acid metabolism evoked by the ionophore.

Animals↗
PubMed1981

Release of slow-reacting substance of anaphylaxis from dispersed pig lung cells: effect of cyclo-oxygenase and lipoxygenase inhibitors.

Study of the release of slow-reacting substance of anaphylaxis (SRS-A) from lung cells has been hampered by the lack of suitable animal model. Using both immunologic and pharmacologic stimuli, we have obtained histamine and SRS-A release from dispersed pig lung cells containing 6% mast cells (with a histamine content of 1.9 pg/cell). Lung cells dispersed from actively sensitized (with intratracheal Ascaris antigen) but not unsensitized pigs released both histamine (mean net release 33%) and SRS-A (mean release, 47 units/10(7) cells) when challenged with Ascaris antigen. Greater release of histamine (mean net release 52%) and of slow-reacting substance (SRS) (mean release 701 units/10(7) cells) was induced by challenge with the calcium ionophore A23187. The pharmacologic and physicochemical characteristics of the SRS together with its profile of enzymatic inactivation resembled those described for SRA-A released from human lung. Both antigen-induced and A23187-induced SRS(-A) release were enhanced by indomethacin, a cyclo-oxygenase inhibitor, but inhibited by both phenidone (IC50 35 microM) and eicosatetraenoic acid (IC50 15 microM), inhibitors of both cyclo-oxygenase and lipoxygenase, confirming that generation of SRS(-A) by either stimulus required an intact lipoxygenase pathway of arachidonic acid metabolism.

Animals↗
PubMed1981

Inactivation by alveolar macrophages of slow-reacting substance of anaphylaxis released from pig lung cells.

The influence of alveolar macrophages on the release of slow-reacting substance of anaphylaxis (SRA-A) and histamine from dispersed pig lung cells was studied. The addition of alveolar macrophages to lung cells (1:3) decreased SRS-A release by 62% +/- 7% without a significant decrease in histamine release. Increased numbers of alveolar macrophages (1:1) decreased both SRS-A release (by 90% +/- 5%) and to a lesser extent histamine release (by 59% +/- 18%). The decrease in released SRS-A was not caused by prostaglandin release from macrophages, and kinetic data indicated that in contrast to histamine the decrease was predominantly the result of SRS-A inactivation rather than inhibition of its release. When alveolar macrophages were incubated with SRS-A, inactivation (191 units/10(7) cells/30 min) was confirmed. SRS inactivation was not reproduced by glutaraldehyde-treated macrophages or by granulocyte and mononuclear populations obtained from peripheral blood. Alveolar macrophages may limit the consequences of SRS-A release in the peripheral air spaces.

Lung↗
PubMed1981

A comparison of antigen-induced and calcium ionophore A23187 induced contraction of isolated guinea pig trachea.

Ovalbumin (OA) and the calcium ionophore A23187 induced a dose-dependent contraction of guinea pig tracheal strips. The OA-induced contraction (of sensitized trachea) consisted of an initial peak concentration, maximal between 5 and 10 min, followed by a very gradual decline from the peak. On the other hand, A23187 induced a sustained contraction of the trachea with a more gradual onset. Both antigen- and A23187-induced contractions required the presence of extracellular calcium. The response was not reduced by delaying (up to 10 min) the addition of calcium, suggesting that the mechanism of antigen-induced contraction differs from that of antigen-induced histamine secretion from rat mast cells and human basophils. The 1st min of the OA-induced contraction was inhibited significantly by mepyramine (10(-5) M) suggesting that histamine contributed to the contraction at this time point. In contrast, A23187-induced contraction was unaffected by mepyramine. On the other hand, both the A23187-induced contraction and the prolonged phase of the OA-induced contraction were enhanced by indomethacin, a cyclooxygenase inhibitor, and inhibited by phenidone, a cyclooxygenase-lipoxygenase inhibitor. This suggests that a product of the lipoxygenase pathway of arachidonic acid metabolism contributes to OA- and A23187-induced contraction of the guinea pig trachea.

Animals↗
PubMed1980

Evidence for lipoxygenase pathway involvement in allergic tracheal contraction.

Challenge of actively sensitized guinea-pig trachea in vitro led to a contraction which was enhanced by the cyclo-oxygenase inhibitors, indomethacin and sodium meclofenamate. Cyclo-oxygenase inhibitors eliminated the release of PGE-like material induced by arachidonic acid (AA), histamine, and antigen challenge. AA (10 microgram./ml.) and PGE2 (100 ng./ml.) usually relaxed the trachea, whereas in the presence of cyclo-oxygenase inhibitors a contraction occurred. Phenidone and ETYA, which also blocked the lipoxygenase pathway of AA metabolism inhibited the enhancement of allergic tracheal contraction induced by cyclo-oxygenase inhibitors, decreased the time that the trachea remained contracted, and also eliminated the contraction induced by AA and PGE2. Thus, cyclo-oxygenase inhibitors may enhance allergic tracheal contraction by diverting AA metabolism into the lipoxygenase pathway and product of the latter pathway, possibly SRS-A, may be responsible for the enhancement and for the prolonged phase of allergic tracheal contraction. An analogous mechanism may account for aspirin-induced asthma in man.

Animals↗
PubMed1979

The Trendelenburg position: hemodynamic effects in hypotensive and normotensive patients.

The effect of the Trendelenburg position on systemic and pulmonary hemodynamics in critically ill patients is not generally appreciated. This study examined the hemodynamoc effect of 15-20 degrees head-down tilt in 61 normotensive and 15 hypotensive patients with acute cardiac illness or sepsis. In normotensive patients, the head-down tilt increased the preload of both right and left ventricles, increased cardiac output slightly, decreased systemic vascular resistance, and did not change the mean arterial pressure. This effect was probably mediated by baroreceptor stimulation. In hypotensive patients, the Trendelenburg position did not increase preload, slightly increased afterload, and decreased cardiac output. This study failed to document any beneficial hemodynamic effect of the Trendelenburg position in critically ill normo- or hypotensive patients.

Adult↗
PubMed1978

Pulmonary hypertension in sepsis: measurement by the pulmonary arterial diastolic-pulmonary wedge pressure gradient and the influence of passive and active factors.

To examine the relative roles of passive factors (flow; filling pressures of left side of heart) and active factors (acidosis; arterial unsaturation) in the genesis of pulmonary hypertension when associated with sepsis, 37 patients with sepsis and 24 patients without sepsis were examined. Pulmonary hypertension was measured by the pulmonary arterial diastolic-pulmonary wedge pressure gradient (PAd-PWP gradient) and correlated reasonably with a standard formula for calculated resistance ([PA--PWP]/CI, where PA is mean pulmonary artery pressure and CI is cardiac index). In 22 of 37 patients, sepsis was associated with a significant degree of resistance to flow in the pulmonary circulation, as measured by the PAd-PWP gradient: and the higher the PAd--PWP gradient, the greater the likelihood of early death. None of the examined passive or active factors appeared to be adequate to explain pulmonary hypertension when present. By the use of previously derived formulae to estimate the compliance of the elastic pulmonary arteries, factors affecting this part of the pulmonary microcirculation could not be held accountable for apparent pulmonary hypertension. Therefore, the presence of pulmonary hypertension in sepis appears to be an active, rather than a passive, phenomenon and unrelated to arterial oxygen saturation or acid-base imbalance. Although the exact cause is unknown, pulmonary hypertension in sepis is associated with a high mortality and may be clinically followed by measurement of the PAd-PWP gradient.

Bacterial Infections↗