Effects Of Methylxanthines Research Articles

Effects of methylxanthines on superprecipitation of myosin B extracted from rabbit fast skeletal muscle.

Myosin B was extracted from rabbit fast skeletal muscle. Caffeine (2-70 mM), theophylline (2-30 mM), and theobromine (2 mM) were examined for their effects on the rate and extent of myosin B superprecipitation at a low ionic strength (50 mM KCl) and a low concentration of ATP (40 microM) by the turbidimetric method. The rate of the superprecipitation was significantly (p less than 0.05 and p less than 0.01) reduced by 30-70 mM caffeine and 2-30 mM theophylline, while the extent was significantly (p less than 0.01) increased by 10-30 mM theophylline. The onset of the superprecipitation was also delayed and a clearing phase was even induced by 50-70 mM caffeine. Theobromine had no significant effect on the rate or extent of the superprecipitation at the concentration used. These results indicate that caffeine and theophylline are retardants of the myosin B superprecipitation reaction in the concentration ranges investigated.

Adenosine receptors and behavioral actions of methylxanthines.

Central stimulant actions of 10 methylxanthines in mice correlate with affinities for adenosine receptors labeled with N6-[3H]cyclohexyladenosine. Affinities of methylxanthines for adenosine receptors are consonant with central levels attained at behaviorally effective doses. The much higher concentrations of methylxanthines required to influence benzodiazepine receptor binding do not correlate with behavioral potency. N6-(L-Phenylisopropyl)adenosine (L-PIA), a metabolically stable analog of adenosine with high affinity for adenosine receptors, is an extremely potent behavioral depressant, reducing locomotor activity of mice at doses as little as 0.05 mumol/kg. The D isomer, which has much less affinity for adenosine receptors, is much less active as a central depressant. Theophylline stimulates locomotor activity and reverses depressant effects of L-PIA. Caffeine or 1,7-dimethylxanthine, when administered alone, elicits biphasic effects, with locomotor depression at lower doses and stimulation at higher doses. When administered with L-PIA, even low doses of caffeine produce marked stimulation. 3-Isobutyl-1-methylxanthine given alone elicits only behavioral depression. However, like theophylline and caffeine, isobutylmethylxanthine reverses the L-PIA-evoked depression, converting it into pronounced locomotor stimulation. The data strongly suggest that the behavioral stimulant effects of methylxanthines involve a blockade of central adenosine receptors.

Methylxanthine effects on cyclic adenosine 3′:5′ monophosphate phosphodiesterase activity in preparations of neonatal rat cerebellum: Modification by trifluoperazine

Paradoxically, caffeine was found to stimulate the activity of 3′:5′-cyclic AMP phosphodiesterase at substrate concentrations of 14μM, in cerebellar tissue from 10-day-old rats. Pretreatment with trifluoperazine, an inhibitor of calmodulin-dependent enzyme activation, converted the stimulatory effect of caffeine to the expected inhibitory action. Trifluoperazine pretreatment also increased the inhibitory action of theophylline on the cerebellar phosphodiesterase, but had no effect on the inhibitory action of 3-isobutyl-1-methylxanthine. It is suggested that caffeine and to a lesser extent theophylline in addition to their intrinsic phosphodiesterase inhibitory activity can also cause calmodulin dependent effects on cerebellar phosphodiesterase due to calcium mobilisation.

Effects of methylxanthines on urinary prostaglandin E excretion in rats.

Effect of methylxanthines (theophylline, theobromine and caffeine) on urinary prostaglandin E (PGE) excretion in male rats was studied. Oral administration of xanthines significantly increased the urinary excretion of PGE. Dose-response studies showed that the maximal excretion of urinary PGE and water was obtained by administration of theophylline (50 mg/kg), where the increase in PGE was about 20 times that of the control. The excretion of urinary sodium, potassium and chloride was also markedly increased by xanthines, particularly, theophylline. Increases in urinary PGE excretion, urine volume and electrolytes excretion were inhibited by 10 mg/kg of indomethacin administered prior to theophylline. The increase of urinary PGE excretion after theophylline administration (50 mg/kg) preceded increases in water and sodium excretion. These results suggest that renal PGE mediates, at least in part, the diuretic effect of theophylline.

A tentative explanation of the stimulatory effect of methylxanthines (pentoxifylline and isobutylmethylxanthine) on the secretory process in rat extraorbital lacrimal gland.

In the present paper we report the effect of two methylxanthines (pentoxifylline and isobutylmethylxanthine) on the protein secretion in a model of exocrine gland (rat lacrimal gland). Both compounds are able to increase the protein release. This effect is dependent on the calcium concentration gradient between the extra- and intracellular media. The larger the difference, the greater the pentoxifylline or isobutylmethylxanthine effect. Moreover, pentoxifylline and isobutylmethylxanthine can potentiate the norepinephrine or isoproterenol effect by inhibiting phosphodiesterases (even in the absence of calcium). All these data suggest pentoxifylline and isobutylmethylxanthine can act on the cell functions in two ways: (a) by a calcium-dependent mechanism, either by increasing the influx of calcium into the cell or by mobilizing the pool of intracellular calcium; (b) by a mechanism independent of calcium and dependent on a system involving cyclic nucleotides. The first possibility seems to be very attractive for further investigations of the mechanism of action of pentoxifylline and especially when this drug is used to affect the cell motility or deformability controlled by calcium.

Inhibitory effects of methylxanthines on the activity of xanthine oxidase

The in vitro and in vivo effects of three methylxanthines caffeine, theophylline and theobromine on the activity of the enzyme xanthine oxidase (EC 1.2.3.2.) was investigated with a view to understand their biochemical action. The studies revealed all the three methylxanthines to be inhibitors of the milk xanthine oxidase activity and the inhibition was found to be competitive in nature. The preincubation studies indicated a greater inhibition of the enzyme with the methylxanthines. Excessive amount of the substrate (2.5 × 10 −4M) resulted in progressive inhibition of the enzyme activity. Low concentrations of methylxanthines exerted a definite inhibitory effect on the xanthine oxidase activity at lower substrate concentrations. At higher concentrations of the substrate, the inhibitory effect due to the same concentration of methylxanthines did not produce any added inhibition of the enzyme activity to that produced by the substrate alone. However, added inhibition by high concentrations of methylxanthines was detectable even when the enzyme activity was markedly inhibited by higher concentrations of the substrate. The in vivo administration of methylxanthines caused a significant inhibition of the xanthine oxidase activity in lungs, kidneys, heart and brain of rats. Consequently, the level of uric acid in the tissues of the drug treated animals was also found to be reduced.

Enhancement effect of methylxanthines on the intestinal absorption of poorly absorbable dyes from the rat small intestine

The effect of theophylline or caffeine on the absorption of phenol red (PR) or bromphenol blue (BPB) (poorly absorbable dyes) from the rat small intestine was investigated by using the in situ recirculation technique. The disappearance of PR and BPB from the recirculated solution was increased by pretreatment of the intestinal lumen with 5 mM theophylline and 5 mM caffeine. With BPB, increases in tissue accumulation and net absorption were observed in the presence of 5 mM theophylline or 5 mM caffeine. However, the administration of 15 μmoles theophylline or 25 μmoles caffeine into a femoral vein by a single injection failed to produce an increasing effect on the disappearance of PR or BPB from the recirculated solution. A possible mechanism of the enhancement effect of the methylxanthines on dye absorption was discussed.

Glucose-dependent effect of methylxanthines on the 45Ca distribution in pancreatic β-cells

Glucose-dependent effect of methylxanthines on the 45Ca distribution in pancreatic β-cells

Effect of Methylxanthines in Sexuality ofSchizophyllum Commune

Effect of Methylxanthines in Sexuality of<i>Schizophyllum Commune</i>

Regulation of adenylate cyclase by adenosine

Adenosine may well be as important in the regulation of adenylate cyclase as hormones. Sattin and Rall first demonstrated in 1970 that adenosine was a potent stimulator of adenylate cyclase in the brain. However, adenosine is an equally potent inhibitor of adenylate cyclase in other cells such as adipocytes. The concentration of adenosine required for this regulation of adenylate cyclase is in the nanomolar range (10 to 100 nm). Both the inhibitory and stimulatory effects of low concentrations of adenosine on adenylate cyclase are antagonized by methylxanthines. This antagonism of adenosine action may account for all or part of the effects of methyl xanthines on cyclic AMP levels in many tissues. Adenosine appears to be a particularly important endogenous regulator of adenylate cyclase in brain, smooth muscle and fat cells. Under conditions in which intracellular AMP rises, adenosine formation and release is accelerated. In addition to its direct effects on adenylate cyclase, adenosine (at higher concentrations approaching millimolar) exerts multiple effects on cellular metabolism as a result of its intracellular metabolism and especially conversion to nucleotides.

Are methylxanthine effects due to antagonism of endogenous adenosine?

Caffeine, theophylline and other methylxanthines have a large number of effects, some of which are clinically important. The effects of these compounds are commonly ascribed to an inhibitor of cyclic-AMP breakdown. In cases where this mechanism fails to provide an adequate explanation for the observed actions a direct action on calcium metabolism is commonly invoked. In the following review I will present some of the increasing evidence that adenosine may be physiological modulator of several biological functions and that theophylline in low doses antagonizes the actions of this purine nucleoside. It is concluded that in some instances the question posed in the title could have a positive answer.

In vitro stimulation of prostaglandin synthetase by methyl xanthines

The methyl xanthines theophylline, caffeine and 1-methyl-3-isobutyl xanthine (MIX) stimulated the formation of prostaglandins (PG's) by bovine seminal vesicle microsomes (BSVM) and rabbit renal papilla microsomes (RRPM). The endoperoxide synthetase is probably the primary target of methyl xanthine action, as all the different PG's produced by RRPM were increased. However, a compound tentatively identified as PGD 2 was more increased than other PG's. The experiments further indicate that the effect of methyl xanthines is dependent on a non-microsomal factor, or on removal of a rapidly formed toxic component, for maximal stimulation, and that the stimulation is probably not related to oxygen radical scavenging. MIX was the most potent drug in the BSVM-system (EC 50=0.9 mM), followed by caffeine (EC 50=1.3 mM) and theophylline (EC 50=2.7 mM). Methyl xanthines are well-known inhibitors of cyclic nucleotide phosphodiesterase (PDE) and BSVM was rich in PDE-activity. BSVM-PDE was inhibited by the methyl xanthines, but a non-xanthine, papaverine, which was a potent BSVM-PDE inhibitor, did not stimulate PG-synthesis. Furthermore, cyclic nucleotides had no effect on PG-synthesis. It is therefore concluded that the stimulation of PG's by methyl xanthines is not related to inhibition of PDE. The possibility of a mechanism dependent on impairment of PG-metabolism was also excluded. Thus, methyl xanthines have a direct stimulatory effect on PG-synthesis in vitro.

226 METHYLXANTHINES CAUSE A MARKED REDUCTION IN CHOLESTEROL SYNTHESIS IN CULTURED GLIAL CELLS

Methylxanthines, such as theophylline, aminophylline and caffeine, are used extensively in the treatment of apnea in the neonatal period, a time of active membrane proliferation and myelination in the human brain. C-6 glial cells in culture are good models of the glia found in human brain during this developmental phase. Because cholesterol is a critical constituent of neural membranes, including myelin, we studied the effect of methylxanthines on biosynthesis of this lipid in cultured C-6 glial cells. Exposure of the cells to theophylline, aminophylline, and caffeine for just 24 hours in a concentration of 1×10-3 M resulted in marked reductions of cholesterol synthesis (from [14C] acetate), i.e. 29, 8 and 37% respectively of control values. Cell growth was not significantly affected by the drugs. Lower concentrations produced inhibitory effects after longer exposure times, e.g. theophylline, 5×10-4 M, caused a 50% reduction in cholesterol synthesis after 72 hours. To determine whether the methylxanthines cause an alteration in the critical rate-limiting enzyme, HMG-CoA reductase, we assayed this enzyme in treated and untreated C-6 glial cells. A marked decrease in reductase activity accompanied the decrease in cholesterol synthesis. The mechanism of this effect is currently under investigation. These data raise the possibility that methylxanthines have a deleterious effect on the development of the human brain.

Effect of Methylxanthines on Binding of the Glucocorticoid Receptor to DNA‐Cellulose and Nuclei

The binding of [3H]dexamethasone-receptor complex from rat liver cytosol to isolated nuclei or DNA-cellulose can be greatly enhanced at low temperature by the presence of theophylline. Aminophylline and caffeine can mimic this effect; however, papaverine and 1-methyl-3-isobutylxanthine, at concentrations inhibitory to phosphodiesterase, are without effect on glucocorticoid receptor binding to DNA. Furthermore, theophylline can be added when adenosine 3':5'-monophosphate-(cAMP) hydrolysis is already complete and still enhance DNA binding. These results imply that this effect of theophylline is independent of its known effect on cAMP levels. Activation by methylxanthines does not alter the sedimentation of the glucocorticoid-receptor complex in sucrose gradients but does alter the pI and in this respect brings about changes resembling those which occur upon activation by heat. Recently we have shown that pyridoxal phosphate inhibits the binding of heat-activated receptor to DNA-cellulose. Similarly, we have shown here that pyridoxal phosphate also inhibits the DNA-cellulose binding of theophylline-treated receptor. The presence of theophylline also enhances the rate of binding of [3H]dexamethasone to the receptor and increases its apparent affininty for the steroid. The data suggest that the effect of theophylline is on some cytosolic component, perhaps the receptor itself. Enhanced DNA binding as a result of exposure to theophylline at low temperature can also be demonstrated using the glucocorticoid receptor of kidney, thymus and Reuber H35 cells.

Effect of methylxanthines and elevated external potassium on high energy phosphate content in frog skeletal muscle

Effect of methylxanthines and elevated external potassium on high energy phosphate content in frog skeletal muscle

The effects of methylxanthines on catecholamine‐stimulated and normal chick embryos

Dose of theophylline and caffeine which do not produce aortic arch anomalies in embryonic chicks have been shown to potentiate catecholamine-induced aortic arch malformations in that experimental animal. Theophylline (2.1 X 10(-5) mole per milliliter isotonic saline solution) potentiated the effective dose of norepinephrine more than 100 times. The greatest potentiation observed with epinephrine (2.5 X) was induced by 2.6 X 10(-5) mole caffeine. This study also demonstrated that both methylxanthines specifically induce aneurysms of the ascending aorta and complete absence (or nearly complete constriction) of the right ductus arteriosus. The incidences of these types of cardiovascular malformations proved to be dose dependent with theophylline a more potent teratogen than caffeine. The mobilization of calcium and/or cyclic nucleotide phosphodiesterase inhibition by the methylxanthines are suggested as significant actions in the potentiation of catecholamine-induced aortic arch anomalies.

264) - Effects of methylxanthines on the response of guinea pig taenia coli to transmurai stimulation

264) - Effects of methylxanthines on the response of guinea pig taenia coli to transmurai stimulation

Inhibitory effect of methylxanthines on feedback control of glomerular filtration rate in the rat kidney

Microperfusion experiments were performed in rats to assess the effect of luminal application of theophylline and the more lipophilic 3-isobutyl-1-methylxanthine (IBMX) on feedback regulation of glomerular filtration rate. Elevation of loop of Henle flow from 0 to 40 nl/min caused a 20.3 +/- 4.5% reduction of stop flow pressure (SFP) and a 32.2 +/- 3.7% reduction of early proximal flow rate (EPFR) when the perfusate was a 140 mM NaCl solution. When theophylline was added in a concentration of 5mM SFP fell by only 5.3 +/- 1.8% and EPFR by 7.9 +/- 33%, changes which were significantly smaller than in the control perfusions (P less than 0.01). An identical change of loop of Henle flow in the presence of IBMX in concentration of 1 and 5 mM was associated with a 4.5 +/- 3.9% decrease and a 12.1 +/- 2.7% increase of EPFR. In orthograde perfusion experiments full inhibition of the feedback response was noted at an IBMX concentration of about 1 mM while during retrograde perfusion a concentration of 0.4 mM was sufficient to produce the same effect. This indicates that methylxanthines diffuse out of the loop of Henle to a considerable extent. Methylxanthines reduced absolute and fractional water absorption along the loop of Henle to some extent while Cl absorption rates and early distal Cl concentrations were not significantly altered. Cyclic AMP applied from the luminal side in a concentration of 10 mM did not affect the feedback response of EPFR to flow elevation from 0 to 40 nl/min. Luminal application of dibutyryl cyclic AMP at 10 mM induced a small, but significant reduction of the feedback response when tested by paired t-test (P less than 0.05). Our results show that luminal application of methylxanthines strongly interfere with feedback regulation of glomerular filtration rate. It is unclear at present whether this effect is related to inhibition of cyclic nucleotide phosphodiesterase and a rise in tissue cyclic AMP levels or to interference with a mechanism involving the local action of adenosine or 5'-AMP.

Effects of Methylxanthines on Gonadotropin-Induced Steroidogenesis and Protein Synthesi in Isolated Testis Interstitial Cells

The effects of 1-methyl 3-isobutyl xanthine (MIX) and theophylline on basal and gonadotropin-stimulated production of cyclic AMP and testosterone were evaluated in enzyme-dispersed testicular interstitial cells. The actions of these compounds upon precursor incorporation into RNA and protein were also examined in the same cell preparation. The considerable higher potency of MIX as a phosphodiesterase inhibitor was accompanied by a steeper dose-response curve for cyclic AMP recovery in incubation media of hormone-treated cells. Both inhibitors caused increases in basal and hormone-stimulated cyclic AMP levels. Although low concentrations of theophylline and MIX had no effect on the maximum levels of hCG-stimulated testosterone production, 10 mM theophylline and 1 mM MIX significantly inhibited steroidogenesis. Conversely, basal testosterone levels were increased by MIX and theophylline. The higher concentrations of MIX and theophylline also significantly inhibited precursor incorporation into RNA and protein. These actions of phosphodiesterase inhibitors upon RNA and protein synthesis could contribute to their inhibitory effects at high concentrations upon gonadotropin-induced steroidogenesis.

Effects of methylxanthines and imidazole on hte contractions of guinea-pig ileum induced by transmural stimulation

Methylxanthines (10 −5 to 10 −3 M) were found to increase the amplitude to contractions of guinea-pig ileum induced by transmural stimulation but ot inhibit those induced by acetylcholine or histamine. The order of the abilities of methylxanthines to augment the contractile responses was theobromine > caffeine > theophyline. When the contractions were completely suppressed by reduction of the calcium content in the medium or by addition of cyclic AMP, methylxanthines restored the responses effectively, just ad does addition of calcium. Methylxanthines also accelerated the release of acetycholine from the ileum associated with stimulation. Imidazole (3 × 10 −5 to 10 −3 M) had an essentialy similar effect to methylxanthines in potentiating the contractile response and in augmenting the release of acetylcholine. The present results indicate that the potentiating effects of methylxanthines and imidazole are due to an action on the nerve terminals, not on the postsynaptic membranes or contractile elements. Therefore, it is concluded that their potentiating actions are due to facilitation of the movement of calcium in the nerve terminals on excitation, resulting in increased release of acetylcholine, and due to the effect of cyclic AMP formes as a result of their inhibitory on phosphodiesterase.