Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Ogawa, Kouichi; Takagi, Kenzo; Satake, Tatsuo

doi:10.1111/j.1476-5381.1989.tb11983.x

Cited by 22 publications

(35 citation statements)

References 18 publications

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“…3). These results are consistent with the previously reported structureactivity relationship of xanthine derivatives, between the low K, cyclic AMP PDE inhibitory effect and the trachealis muscle relaxant effect (Ogawa et al 1989).…”

Section: Discussionsupporting

confidence: 94%

Inhibition of Cyclic GMP Phosphodiesterase by Xanthine Derivatives Relaxes Guinea‐pig Trachealis Smooth Muscle

Tanaka

Ogawa

Takagi

et al. 1991

Clin Exp Pharma Physio

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1. For the purpose of clarifying the mechanism of the airways smooth muscle relaxant action of xanthines, cyclic guanosine monophosphate (GMP) phosphodiesterase (PDE) from guinea-pig trachealis muscle was purified with diethylaminoethyl ether (DEAE) cellulose column chromatography. 2. Five 3-alkylxanthines (3-methylxanthine, 3-ethylxanthine, 3-n-propylxanthine (enprofylline), 3-n-butylxanthine, and 3-iso-butylxanthine), and five 1-methyl-3-alkylxanthines (1-methyl-3-methyl-xanthine (theophylline), 1-methyl-3-ethylxanthine, 1-methyl-3-n-propylxanthine, 1-methyl-3-n-butylxanthine, and 1-methyl-3-iso-butylxanthine (IBMX] were compared in terms of purified cyclic GMP PDE inhibition. The relationship between the structure and inhibition of cyclic GMP PDE was studied. 3. The -log EC50 values for relaxation of spontaneous tone of isolated guinea-pig trachealis preparations by the 3-alkylxanthines and 1-methyl-3-alkylxanthines were determined. 4. The five 1-methyl-3-alkylxanthines were each more potent in relaxing isolated trachealis smooth muscle than the corresponding 3-alkylxanthines. The 1-methyl-3-alkylxanthines were also more potent than the corresponding 3-alkylxanthines in their cyclic GMP PDE inhibitory effect. There was a strong positive correlation between the concentration of inhibitor which inhibited hydrolysis by 50% (IC50) values for cyclic GMP PDE inhibition by the xanthine derivatives and their EC50 values for trachealis muscle relaxation. 5. It is suggested that the mechanism by which xanthine derivatives relax trachealis smooth muscle involves inhibition of cyclic GMP PDE in addition to inhibition of cyclic adenosine monophosphate PDE.

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Section: Discussionsupporting

confidence: 94%

Inhibition of Cyclic GMP Phosphodiesterase by Xanthine Derivatives Relaxes Guinea‐pig Trachealis Smooth Muscle

Tanaka

Ogawa

Takagi

et al. 1991

Clin Exp Pharma Physio

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“…Adenosine antagonism may account for this effect, as xanthines are known to act as competitive antagonists at adenosine receptors and there is evidence to suggest that this mechanism underlies their relaxing effects. In accordance, 3-MX was found to be less potent than theophylline in both relaxing the guinea pig tracheal smooth muscle and elevating the concentration of cyclic nucleotides [24,25]. In the same line, 8-p-sulphophenyltheophylline (8-PT), a xanthine analogue, was shown to block the purinergic-receptormediated enhancement of electrical field stimulation in the rabbit bronchial smooth muscle [41].…”

Section: Relaxing Effects Of 1-mx and 3-mx And Speculations For The Umentioning

confidence: 74%

“…However, apart from the recently shown effects on the rabbit small intestine and ascending colon [26], information about the actions of theophylline's metabolites is strictly confined to airway tissues. Thus, 3-MX was documented to relax the human, cat and guinea pig airways [21,24,25], while 1-MX has been shown to relax in vitro dog and guinea pig airway smooth muscles [22,23].…”

Section: Discussionmentioning

confidence: 99%

“…The lower, than the parent drug, potency of 3-MX in producing relaxation has been shown in isolated human and guinea pig airways [21,24,25], as well as in anaesthetized cats [21]. On the other hand, experimental evidence indicates that the xanthines' relaxing effect may also derive from their ability to inhibit non-selectively the PDEs, the enzymes that degrade the cyclic nucleotides, thus resulting in increased cAMP and/or cGMP levels [13,24,25]. Adenosine antagonism may account for this effect, as xanthines are known to act as competitive antagonists at adenosine receptors and there is evidence to suggest that this mechanism underlies their relaxing effects.…”

Section: Relaxing Effects Of 1-mx and 3-mx And Speculations For The Umentioning

confidence: 99%

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Relaxing and contracting effects of theophylline’s metabolites on the rabbit upper gastrointestinal tract

Psarra

Batzias

Peeters

et al. 2008

Fundamemntal Clinical Pharma

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The present study, aimed to clarify whether the gastrointestinal adverse effects following administration of the bronchodilator theophylline are owing to the action of the drug itself or its metabolites, investigates the pharmacodymanic effects of theophylline's metabolites on the spontaneous contractility in the rabbit upper gastrointestinal tract. Comparative examination reveals that while two of the metabolites, namely 1-methylxanthine (1-MX) and 3-methylxanthine (3-MX), cause a similar, but less pronounced than the parent drug, concentration-dependent relaxation on the isolated oesophagus, lower oesophageal sphincter (LOS), fundus, antrum and pylorus, the remaining two metabolites, 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU), produce either a weak stimulating effect, or an even weaker relaxation. The relaxation which is muscle-mediated, non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent is probably mediated via inhibition of the metabolites on phosphodiesterases (PDEs), while a presynaptic cholinergic pathway is involved in the weak stimulating effect. The effects of all substances are additive. As a consequence, the net result of the cumulative action of all metabolites in the oesophagus, LOS, antrum and pylorus is, at 10(-3) m, comparable with that of theophylline, but in the fundus it is lower than that of the parent drug, because in the latter tissue the stimulating effect of 1,3-DMU and 1-MU counteracts the relaxing effect of the other two metabolites. However, combination of the parent drug with its metabolites leads to a considerable relaxation in all the gastrointestinal regions extending from the oesophagus to pylorus. Conclusively, upper gastrointestinal adverse effects following theophylline's administration are also because of theophylline's metabolites.

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“…Knowledge about the bio‐activity of these metabolites is limited to their convulsive activity in mice (Yamamoto et al. , 1996) and in rats (Ramzan & Levy, 1986), as well as to the relaxing activity of 3‐MX on the human, cat and guinea‐pig airways (Persson & Andersson, 1977; Ogawa et al. , 1989; Tanaka et al.…”

Section: Introductionmentioning

confidence: 99%

Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

Psarra¹,

Batzias²,

Peeters³

et al. 2007

Vet Pharm & Therapeutics

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The present study examines comparatively the effects of theophylline and its metabolites, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU) along the rabbit intestine, and explores the underlying mechanism(s). In the small intestine, theophylline produces atropine- and hexamethonium-sensitive increases in both the amplitude of phasic contractions and the basal tone. All metabolites mimic the theophylline's stimulating effect. In particular, concerning the phasic contractions, all metabolites are more potent than theophylline in the duodenum and jejunum, while in the ileum, only 1-MU is more potent. Regarding the basal tone, the metabolites show, in most cases, higher efficacy in all small intestinal regions, the maximum effects of 3-MX and 1-MU on the duodenum and ileum being double or triple the one of theophylline. In the ascending colon, while lower concentrations of theophylline produce an atropine- and hexamethonium-sensitive increase in the basal tone, higher ones produce a postsynaptic, nonadrenergic noncholinergic (NANC) relaxing effect. 1-MU mimics, in a weaker manner, theophylline's effect, while the other metabolites produce only relaxation, the potency rank of order being 3-MX>1-MX=1,3-DMU>theophylline. It is suggested that the theophylline and its metabolites stimulatory effect involves a cholinergic pathway, while the relaxing one is due to 3('),5(')-cyclic adenosine monophosphate (cAMP) elevation mediated by the theophylline and its metabolites inhibitory action on phosphodiesterases (PDEs).

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Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Cited by 22 publications

References 18 publications

Inhibition of Cyclic GMP Phosphodiesterase by Xanthine Derivatives Relaxes Guinea‐pig Trachealis Smooth Muscle

Inhibition of Cyclic GMP Phosphodiesterase by Xanthine Derivatives Relaxes Guinea‐pig Trachealis Smooth Muscle

Relaxing and contracting effects of theophylline’s metabolites on the rabbit upper gastrointestinal tract

Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

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