Adenosine as a bronchoconstrictor mediator in asthma and its antagonism by methylxanthines

Holgate, S. T.; Mann, J. S.; Cushley, M. J.

doi:10.1016/0091-6749(84)90262-8

Cited by 54 publications

(23 citation statements)

References 23 publications

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“…Therefore, if stimulation of the A 2 receptor results in inhibition of PMN function, then competitive antagonism of the receptor would, potentially, have the opposite (stimulatory) effect. The accepted therapeutic levels of aminophylline and theophylline are comparable to the concentrations associated with adenosine receptor antagonism [21]. Thus, the results with therapeutic levels of aminophylline presented here may be due to A 2 receptor antagonism, whilst at higher concentrations the mechanism of inhibition of cell function is probably due to phosphodiesterase inhibition and elevation of cAMP.…”

Section: Discussionsupporting

confidence: 64%

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

Llewellyn-Jones

Stockley²

1994

Eur Respir J

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We have assessed the effects of the β 2 -agonist, terbutaline, and the methylxanthine, aminophylline, on PMN functions in vitro at both therapeutic and higher concentrations.At therapeutic levels, both agents increased PMN chemotaxis to formyl-methionylleucyl-phenylalanine (FMLP) in a dose-dependent manner from a control value of 22.5±3.58 cells·field -1 to 26.1±4.73 cells·field -1 with 4 mg·l -1 terbutaline, and to 26.3±4.49 cells·field -1 with 20 mg·l -1 aminophylline. When the cells were preincubated with higher doses of the agents in separate experiments there was inhibition of chemotaxis from a control value of 31.1±2.06 cells·field -1 to 18.3±0.82 cells·field -1 at 160 mg·l -1 terbutaline, and to 16.1±0.77 cells·field -1 at 400 mg·l -1 aminophylline. A similar effect was seen when the PMNs were preincubated with terbutaline and aminophylline prior to assessment of superoxide anion generation, with stimulation of superoxide release at therapeutic levels of the drugs and inhibition at higher doses (19% increase from resting control cells at terbutaline 4 mg·l -1 and 53% reduction at 160 mg·l -1 ; 28% increase with aminophylline 20 mg·l -1 and 22% reduction at 400 mg·l -1 ). Both terbutaline and aminophylline had no effect on PMN degranulation, as assessed by the degradation of fibronectin.These data suggest that terbutaline and aminophylline exert a biphasic effect on PMN functions in vitro, and may have detrimental effects on lung tissues at therapeutic levels through potentiation of PMN recruitment and activation. However, the observed effects of therapeutic doses of these agents on in vitro PMN functions were relatively small and, therefore, the clinical relevance of these results is, as yet, uncertain.

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Section: Discussionsupporting

confidence: 64%

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

Llewellyn-Jones

Stockley²

1994

Eur Respir J

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“…The effect may be dependent upon not only a decrease in bronchoconstriction and/or mucosal edema but also antiinflammatory actions, such as the non-selective inhibition of phosphodiesterase, 20) antagonism of adenosine receptor 22,23) and/or activation of histone deacetylate, 24,25) which can lead to reduced levels of cytokines that contribute to the development of LAR and AHR. Furthermore, pranlukast inhibited the LAR and AHR, suggesting that CysLTs are important mediators in the development of these responses.…”

Section: Discussionmentioning

confidence: 99%

Intratracheal Sensitization/Challenge-Induced Biphasic Asthmatic Response and Airway Hyperresponsiveness in Guinea Pigs

Mizutani

Inui²,

Yoshino

et al. 2010

Biological & Pharmaceutical Bulletin

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In most experimental model of asthma using guinea pigs, the animals are made to inhale an aerosolized antigen which passes through the nasal cavity. In the present study, we attempted to create an animal model of asthma showing a biphasic asthmatic response and airway hyperresponsiveness, in which the allergic responses are restricted to the lung. Guinea pigs were sensitized by the intratracheal instillation of ovalbumin (OVA)؉Al(OH) 3 once a day for 7 d, and then intratracheally challenged with OVA 12 d after the last sensitization. The change in specific airway resistance (sRaw) and airway responsiveness to histamine were measured. Pranlukast (100 mg/kg), theophylline (50 mg/kg), and dexamethasone (10 mg/kg) were orally administered 18 and 2 h before the antigen challenge. The challenge caused a marked biphasic elevation of sRaw with peaks at 5 min and 4 h. At 24 h, airway hyperresponsiveness to histamine was observed. Pranlukast, theophylline, and dexamethasone suppressed the late asthmatic response and airway hyperresponsiveness. The early asthmatic response was inhibited by theophylline and dexamethasone. In conclusion, the intratracheal sensitization and challenge caused a biphasic asthmatic response and airway hyperresponsiveness in guinea pigs. This model may be useful for the evaluation of anti-asthma drugs.

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“…This nucleoside inhibits respiratory burst activation in human PMNs, an effect which is mediated via binding to external cell membrane regulatory nucleoside receptors (7,8,42). Pentoxifylline is a methylxanthine derivative, and methylxanthines are known inhibitors of nucleoside receptor binding (4,10,11,22) and nucleoside transport (14,30,46). Methylxanthines can also block adenosine activity mediated by regulatory receptors.…”

mentioning

confidence: 99%

Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells

Hand

1995

Antimicrob Agents Chemother

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Pentoxifylline modulates multiple activities of stimulated polymorphonuclear neutrophils (PMNs), including the respiratory burst response and membrane transport of certain substances (e.g., nucleosides). We found that several weakly basic antibiotics are highly concentrated by human PMNs and that these drugs also inhibit the respiratory burst response (by a mechanism different from that of pentoxifylline). Since both pentoxifylline and antibiotics will be administered to some patients with serious infections, we have evaluated several types of interactions between these drugs and human PMNs and have attempted to identify the mechanisms that produce alterations in cellular function. Roxithromycin, dirithromycin, and clindamycin were avidly concentrated by PMNs. Pentoxifylline and two derivatives (HWA-448 [torbafylline] and HWA-138 [albifylline]) increased the uptake of these antibiotics by PMNs, both in the resting state and during phagocytosis. Pentoxifylline, HWA-448, HWA-138, and the highly concentrated antibiotics each exerted an inhibitory effect on the stimulated respiratory burst response in PMNs. The combination of both pentoxifylline and a modulatory antibiotic (roxithromycin or clindamycin) inhibited superoxide production to a greater extent than either agent alone. This additive effect might be expected, since pentoxifylline and the modulatory antibiotics influence the respiratory burst activation pathway at different sites. The ability of pentoxifylline to augment the entry of antibiotics into neutrophils has important therapeutic implications. The consequences of this phenomenon might include improved intracellular bactericidal activity as well as efficient antibiotic delivery and release at sites of infection.

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Adenosine as a bronchoconstrictor mediator in asthma and its antagonism by methylxanthines

Cited by 54 publications

References 23 publications

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

Intratracheal Sensitization/Challenge-Induced Biphasic Asthmatic Response and Airway Hyperresponsiveness in Guinea Pigs

Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells

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