Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline

Kolbeck, Ralph C.; Speir, William A.; Carrier, Gerald O.; Bransome, Edwin D.

doi:10.1007/bf02714008

Cited by 101 publications

(19 citation statements)

References 44 publications

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“…The relaxant effect of,-receptor agonists is generally believed to be due to intracellular Ca sequestration and/or Ca extrusion from the cell, effected by an increase in cyclic AMP (Hardman, 1981;Hisayama & Takayanagi, 1983). The fact that forskolin which activates adenylate cyclase and theophylline which inhibits phosphodiesterase produce relaxation also suggests an important role ofcyclic AMP in relaxation (Seamon & Daly, 1981;Muller & Baer, 1983), although the degree of relaxation is not quantitatively correlated with an increase in cyclic AMP concentrations (Fredholm et al, 1979;Kolbeck et al, 1979;Vegesna & Diamond, 1983;1984).…”

Section: Discussionmentioning

confidence: 99%

Effects of relaxants on electrical and mechanical activities in the guinea‐pig tracheal muscle

Honda

Satake

Takagi

et al. 1986

British J Pharmacology

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1 In isolated tracheal musces of the guinea-pig, effects of several relaxants were studied by simultaneously recording the membrane potential and mechanical response. 2 Intracellular recordings showed regular slow waves in most preparations. There was a close correlation between membrane potential and slow wave amplitude. The linear regression line of the slow wave amplitude (Y mV) on the membrane potential (X mV) could be expressed by Y = -0.35X -5.9. The mean values of resting potential and slow wave amplitude were -50.6 ± 0.6 m.V a-nd 11.9 ± 0.5 mV, respectively. 3 Relaxant drugs used (isoprenaline, terbutaline, adrenaline, noradrenaline, theophylline, forskolin and dibutyryl cyclic AMP) all produced hyperpolarization of the membrane and abolished the slow wave. The degree of relaxation was closely related to these electrical responses, although the recovery of electrical responses was faster than the mechanical response. 4 It was concluded that the relaxation caused by the agents, which are known to increase the intracellular cyclic AMP level, was accompanied by a clear hyperpolarization and suppression of slow waves.

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Section: Discussionmentioning

confidence: 99%

Effects of relaxants on electrical and mechanical activities in the guinea‐pig tracheal muscle

Honda

Satake

Takagi

et al. 1986

British J Pharmacology

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“…There is no direct evidence in favour of this, other than an effect on intracellular cAMP concentration due to its PDE inhibitory action. An early study suggesting that theophylline may increase Ca 2+ uptake into intracellular stores has not been followed up [47].…”

Section: Inhibition Of Calcium Ion Fluxmentioning

confidence: 99%

Theophylline in the management of asthma: time for reappraisal?

Barnes¹,

Pauwels²

1994

Eur Respir J

248

107

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T Th he eo op ph hy yl ll li in ne e i in n t th he e m ma an na ag ge em me en nt t o of f a as st th hm ma a: : t ti im me e f fo or r r re ea ap pp pr ra ai is sa al l? ?P.J. Barnes*, R.A. Pauwels** Theophylline is now considered to be a bronchodilator, but it is increasingly recognized that theophylline has other anti-asthma activities, which may be more important. Theophylline, even at low plasma concentrations, inhibits the late asthmatic reaction following allergen challenge. These clinical pharmacological observations are substantiated by experimental animal and in vitro data showing that theophylline has several anti-inflammatory activities relevant to asthma. These include the inhibition of cytokine synthesis and release, the inhibition of inflammatory cell activation and microvascular leakage, and the prevention of airway hyperresponsiveness induced by airway inflammation. Theophylline appears to have immunomodulatory effects, even at relatively low plasma concentrations.Based on these considerations, theophylline can be regarded as a useful alternative to other anti-inflammatory drugs for the chronic treatment of mild to moderate asthma. Theophylline should be used at lower doses to achieve plasma concentrations of 5-10 mg·l -1 , which will avoid the risk of side-effects.Further studies are required to evaluate the role of low-dose theophylline as an adjunct to low-dose inhaled steroids in the management of chronic asthma. It may now be appropriate to re-evaluate the role of theophylline in asthma management.

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“…Several other mechanisms have, therefore, been proposed to explain how methylxanthines exert their bronchodilator effect. These include antagonism of adenosine receptors (Fredholm, 1980), increased secretion of endogenous catecholamines (Higbee et al, 1982), inhibition of constrictor prostanoid formation (Horrobin et al, 1977) and a reduction in intracellular Ca24 concentrations (Kolbeck et al, 1979). To date, none of these proposed mechanisms of action is, in its own right, wholly satisfactory (Persson, 1985).…”

Section: Introductionmentioning

confidence: 99%

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Bryson¹,

Rodger²

1987

British J Pharmacology

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1 The effects of three phosphodiesterase inhibitors (papaverine, igobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2 The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation of histamine-induced contractions of the trachealis. 3 Papaverine-induced relaxation was associated with concentration-related increases in the levels of both cyclic nucleotides. 4 IBMX at low concentrations (1 gmol 1-') produced significant relaxation (36%) of histaminecontracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX-induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels.Only at the highest concentration tested (100 gmol I-) did IBMX increase cyclic AMP levels significantly.5 SKF 94120(1 pmol 1-') elicited a 23% relaxation of the contracted trachealis without altering the tissue content ofeither cyclic nucleotide. At the two higher concentrations tested (10 and 100 pmol 1 -'), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6 In the skinned trachealis Ca2" (10 and 20 gmol I ')-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 gtmol 1I-') and by cyclic AMP (10 pmol 1 1'), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 pmol I') and cyclic GMP (10 pmol l'). 7 Papaverine (1O00Imoll-') significantly inhibited (31 ± 6%) the Ca2t-induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. 8 It is concluded that cyclic nucleotide-dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase-inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.

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Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline

Cited by 101 publications

References 44 publications

Effects of relaxants on electrical and mechanical activities in the guinea‐pig tracheal muscle

Effects of relaxants on electrical and mechanical activities in the guinea‐pig tracheal muscle

Theophylline in the management of asthma: time for reappraisal?

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

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