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PubMed1974

The effects of caffeine on sodium transport, membrane potential, mechanical tension and ultrastructure in barnacle muscle fibres.

1. The effects of graded concentrations of caffeine on the Na efflux were investigated. External application of 10 mM caffeine usually caused a biphasic response, viz. a fall, followed by a rise in the Na efflux. 1 and 5 mM caffeine usually caused stimulation. Only the stimulatory phase of this response depended on the presence of external Ca(2+).2. Internal application of 100 mM caffeine caused a small rise in the Na efflux, the magnitude of which was independent of external Ca(2+) and comparable to that obtained with external application of 1 mM caffeine. This action, however, could be greatly augmented by pre-treating the fibre with 5 x 10(-5)M ouabain.3. The rise in Na efflux caused by external application of 10 mM caffeine could be greatly augmented by pre-treating the fibre with 5 x 10(-5)M ouabain. The observed stimulatory response was biphasic, more so in the absence of external Ca(2+). Restoration of external Ca(2+) following the onset of the second stimulatory phase resulted in further rise of the Na efflux. Measurements of the Na efflux during treatment with graded concentrations of ouabain and 10 mM caffeine showed that the rate coefficient for Na efflux varied with the ouabain concentration in the range 10(-8)-10(-4)M. Measurements of the ouabain-insensitive Na efflux before and during treatment with 10 mM caffeine in bathing media containing varying concentrations of Ca, disclosed the existence of two Ca(2+)-thresholds, one in the 0-2.5 mM range and the other in the 12.5-15 mM range.4. Comparisons were made between the effects on the Na efflux of 10 mM caffeine followed by external acidification, and external acidification, followed by 10 mM caffeine. The magnitude of the response of the ouabain-insensitive Na efflux to external acidification before treatment with 10 mM caffeine was greater than that found when external acidification followed external application of the alkaloid. It also was considerably greater than that of the response to external application of 10 mM caffeine before external acidification.5. External application of 10 mM procaine prevented 10 mM caffeine from stimulating the Na efflux, and from inducing contractures. Internal application of 100 mM-EGTA reduced the response of the Na efflux to 10 mM caffeine, and also prevented the fibre from contracting. External application of 10(-4)M diphenylhydantoin reduced the response of the Na efflux to 10 mM caffeine but failed to prevent the development of contractures.6. Internal application of 0.05 M-cGMP, cAMP or its dibutyryl derivative caused a large rise in the Na efflux. The magnitude of the effects observed in ouabain-poisoned fibres was often greater than that in unpoisoned fibres. Internal application of 2.5 units/ml. phosphodiesterase beforehand failed to reduce the magnitude of the stimulatory response to injected cyclic nucleotides. Injected phosphodiesterase also failed to reduce the response of the Na efflux to 10 mM caffeine.7. External application of 10 mM caffeine to unpoisoned and ouabain-poisoned fibres caused a fall of approximately 10 mV in the membrane potential. In unpoisoned fibres this effect was transitory. The response of the membrane potential to internal application of graded concentrations of CaCl(2) was biphasic. When low concentrations of CaCl(2) were used the membrane potential underwent a small rise but when high concentrations were used the opposite was found. These results could not be repeated with graded concentrations of MgCl(2).8. The effects of graded concentrations of caffeine on tension development were also studied. Strong contractures were observed with caffeine concentrations as low as 4 mM, while peak tetanus tension was usually exceeded with 7-8 mM concentrations. The tension-external Ca(2+) curve was sigmoidal in shape.9. Electron microscopic studies showed that 10 mM caffeine in ASW caused little or no distension and disorganization of cisternal fine structure. Such structural changes, however, were far more pronounced in fibres suspended in Ca(2+)-free ASW and then treated with 10 mM caffeine in Ca(2+)-free ASW. Fibres soaked in Ca(2+)-free ASW had ruptured mitochondria and mitoplasts, whereas those additionally treated with 10 mM caffeine had relatively intact mitochondria.10. The main conclusions drawn from this work are: (i) that caffeine stimulates the ouabain-insensitive Na efflux (and inhibits the transport enzyme) by raising the internal free Ca(2+) concentration; (ii) that in the presence of inhibition of the transport enzyme, the magnitude of the stimulatory response to 10 mM caffeine depends not only on the external Ca(2+) concentration but mainly on the residual level of activity of the transport enzyme; (iii) that the Ca(2+)-sensitive and CO(2)-sensitive components of the ouabain-insensitive Na efflux, though not the same, may overlap at the level of the plasma membrane or share a common metabolic step away from the membrane; (iv) that cyclic nucleotides participate in the control of the magnitude of the ouabain-insensitive Na efflux, and that the phosphodiesterase system under the present experimental conditions does not seem to be involved in the mechanism underlying the stimulatory action of caffeine; (v) that the membrane potential changes caused by caffeine fail to explain the stimulatory response of the Na efflux, as well as contracture of these fibres; (vi) that the contractile machinery in these fibres is considerably more sensitive to caffeine than that in vertebrate muscle and the muscles of other arthropods, and (vii) that the Ca(2+) released by the sarcoplasmic reticulum which leads to a biphasic response of the Na efflux is the result of cisternal disorganization caused by caffeine.

Acetates↗
PubMed2006

Acute effects of caffeine in volunteers with different patterns of regular consumption.

RATIONALE: The effects of caffeine on mood and performance are well established. One explanation of these effects is that caffeine removes negative effects induced by prior caffeine withdrawal. This was tested here by comparing effects of caffeine in withdrawn consumers and non-consumers (who by definition were not withdrawn). OBJECTIVES: The present study aimed to determine whether caffeine withdrawal influenced mood and performance by comparing regular consumers who had been withdrawn from caffeine overnight with non-consumers. Following this the effects of acute caffeine challenges were compared in withdrawn consumers and non-consumers. In addition, comparisons were made between those with higher and lower caffeine consumption. METHODS: One hundred seventy-six volunteers participated in the study. Regular caffeine consumption was assessed by questionnaire and this showed that 56 of the sample did not regularly consume caffeinated beverages. Volunteers were instructed to abstain from caffeine overnight and then completed a baseline session measuring mood and a range of cognitive functions at 08.00 the next day. Following this approximately half of the volunteers were given 1 mg/kg caffeine in a milkshake or water (in the 'no caffeine' condition they were given just the milkshake or water) and the test battery repeated one hour later. A second test battery was carried out at 12.00 and a second caffeine challenge at 13.00. A final test session was carried out at 15.00. RESULTS: The baseline data revealed little evidence of effects of caffeine withdrawal on performance and mood. In contrast to this, caffeine produced a number of significant improvements in performance. There were some differences in the effects of caffeine on regular and non-consumers, with caffeine tending to reduce reaction time in regular consumers while the opposite was true for non-consumers. CONCLUSIONS: The present results show little evidence of effects of caffeine withdrawal on performance. In contrast, caffeine challenge produced improvements in aspects of performance and these were often not modified by regular caffeine consumption patterns. The differences in effects of caffeine that were observed between non-consumers and regular consumers were in functions that were unaffected by caffeine withdrawal. These findings show that the observed beneficial effects of caffeine cannot be interpreted in terms of a reversal of caffeine withdrawal.

Adolescent↗
PubMed2001

Teratogen update: evaluation of the reproductive and developmental risks of caffeine.

Caffeine is a methylated xanthine that acts as a mild central nervous system stimulant. It is present in many beverages, including coffee, tea, and colas, as well as chocolate. Caffeine constitutes 1-2% of roasted coffee beans, 3.5% of fresh tea leaves, and approximately 2% of mate leaves (Spiller, '84; Graham, '84a,b). Many over-the-counter medications, such as cold and allergy tablets, headache medicines, diuretics, and stimulants also contain caffeine, although they lead to relatively minimal intake (FDA, '86). In epidemiological studies, it is assumed that one cup of coffee contains < or =100 mg of caffeine, and soft drinks, such as colas, contain 10-50 mg of caffeine per 12-ounce serving. The per-capita consumption of caffeine from all sources is estimated to be about 3-7 mg/kg per day, or approximately 200 mg/day (Barone and Roberts, '96). Consumption of caffeinated beverages during pregnancy is quite common (Hill et al., '77) and is estimated to be approximately 144 mg/day, or 2.4 mg/kg for a 60-kg human (Morris and Weinstein, '81). However, pregnant women appear to consume slightly less than do other adults, approximately 1 mg/kg per day (Barone and Roberts, '96). This decrease may be interrelated with taste aversion (Hook, '76; Little, '82). The medical literature contains many varied references that appear to indicate that human adverse reproductive/developmental effects are produced by caffeine. If caffeine indeed causes such effects, the reproductive consequences could be very serious because caffeine-containing foods and beverages are consumed by most of the human populations of the world, and consumption in the United States is estimated to be 4.5-kg/person/year (Narod et al., '91). Therefore, the medical literature dealing with developmental and reproductive risks of caffeine was reviewed, and the biological plausibility of the epidemiological and animal findings, as well as the methods and conclusions of previous investigators, were evaluated. The epidemiological studies describe exposures of women to caffeine during pregnancy, as well as the occurrence of congenital malformations, fetal growth retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral effects, and maternal fertility problems that presumably resulted from the caffeine consumption. A few epidemiological studies were concerned with the genetic effects of preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats and mice, were designed to produce malformations. The objectives of the present review are to summarize the findings from the various clinical and animals studies, objectively discuss the merits and/or faults inherent in the studies and establish a global reproductive risk assessment for caffeine consumption in humans during pregnancy. It should be noted that evaluation of the developmental risks of caffeine based solely on epidemiological studies is difficult because the findings are inconsistent. Even more important, is the fact that caffeine users are subject to multiple confounding factors that make analyses difficult and prevent investigators from reaching definitive conclusions. For example, the caffeine content of foods and beverages can vary considerably, which can interfere with obtaining valid interpretations from many human studies. Isolated epidemiological studies dealing with the risk of abortion, without evaluating other developmental and reproductive effects, are the most difficult to interpret, because they present special problems that are sometimes ignored in epidemiological studies. The results of animal studies are probably most helpful in solving some of the dilemmas created by the epidemiological studies. An animal study reported in 1960 first focused our attention on the potential developmental effects of caffeine. However, the exposure reported by Nishimura and Nakai ('60) was an intraperitoneal dosage of 250 mg/kg in the mouse, an extremely high dosage that would result in a blood plasma level that could never be obtained from consuming caffeine containing products. More recent animal studies have demonstrated, that depending on the method of administration and species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately 80-120 mg/kg per day. Lack of biological plausibility to support the concept that caffeine has been responsible for human malformations is another important part of this analysis. For example, no one has described the Caffeine "teratogenic syndrome," a cluster of malformations associated with caffeine ingestion. Proven human teratogens have an identifiable syndrome. The malformations described in the animal studies at very high doses fit the description of vascular disruptive types of malformations. (ABSTRACT TRUNCATED)

Abortion, Spontaneous↗
PubMed2002

Effects of caffeine and exercise on the development of bone: a densitometric and histomorphometric study in young Wistar rats.

High doses of caffeine will induce calcium loss and influence the normal development of bone, whereas the proper exercise has positive effects on bone metabolism. This study investigated the possible effects of exercise to antagonize the caffeine-induced impairment of bone development in young male Wistar rats. A total of 32 male rats (5 weeks old) were divided randomly into four groups: group 1 rats were fed caffeine; group 2 rats were prescribed an exercise program; group 3 rats were fed caffeine and prescribed an exercise program; and group 4 rats served as the control group. The caffeine was fed via the animals' dietary water and the dosage was 10 mg/100 g body weight per day, 3 days a week. The exercise program was carried out on a treadmill for 10 weeks (5 days/week, 1 h/day, 70% VO(2)max). Body weight was measured weekly. After sacrifice, the tibia length was measured and the tibia was processed for histomorphometric analysis. Bone mineral density was measured by dual-energy X-ray absorptiometer at three different sites of the tibia. In addition, the calcium content of the right femur was measured by atomic absorptiometry. The results showed that both exercise and caffeine significantly lowered the body weight gain. Rats fed with caffeine (groups 1 and 3) had a significantly longer tibia as compared with the non-caffeine-fed rats (groups 2 and 4) (p = 0.0149). The histomorphometry study showed that thickness of the growth plate in the proliferative zone, the hypertrophic zone, and total growth plate was greater in caffeine-fed groups than in non-caffeine-fed groups. The cell number in the proliferative zone was higher in the caffeine-fed groups. Area ratio of trabeculae in the primary spongiosa of rats in groups 1 and 2 were significantly greater than the control group. Caffeine feeding (groups 1 and 3) induced a lower area ratio of bone trabeculae in the secondary spongiosa, whereas exercise training (groups 2 and 3) increased the thickness of the trabeculae. The exercise program counteracted the negative effect of caffeine on the trabecular thickness, but did not correct the trabecular bone ratio. The bone mineral density (BMD) of the tibia was significantly lower in caffeine-fed rats, and the exercise program did not show any counteracting effect on the caffeine-induced BMD reduction. The calcium content assay showed that caffeine feeding decreased the weight and total calcium content of the femur. Again this exercise program did not counterbalance the negative effects of caffeine. In conclusion, high doses of caffeine seemed to stimulate the growth of long bone. However, it caused more serious negative effects on bone, including bone mineral loss, lower BMD, and lower calcium content. Exercise training at 70% VO(2)max had little antagonizing effect on caffeine-induced impairment of bone formation. Therefore, the best way to prevent caffeine-induced negative effects on bone development is to lower caffeine exposure.

Animals↗
PubMed1999

Human brain metabolic response to caffeine and the effects of tolerance.

OBJECTIVE: Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. METHOD: Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. RESULTS: The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. CONCLUSIONS: These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.

Adult↗
PubMed1992

Caffeine tolerance and choice in humans.

Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

Adult↗
PubMed1996

Activation of Ca2+ release by caffeine and voltage in frog skeletal muscle.

1. Using a fast flow, computer-controlled, two-Vaseline-gap chamber, single muscle fibres were subjected to 'pulses' of caffeine at Ca2+ releasing concentrations, combined with voltage-clamp depolarizations, while monitoring intracellular [Ca2+]. 2. Ca2+ release flux elicited by caffeine reached 2.5 mM s-1, or less, after 3 s of exposure, then decayed to zero. The caffeine-releasable pool of sarcoplasmic reticulum (SR) Ca2+ was 2.9 +/- 0.4 mM (mean +/- S.E.M., n = 10). 3. In parallel with release induced by caffeine, release induced by voltage pulses applied during a caffeine exposure increased in the first second of exposure, then decreased, to abolition after 5 s. 4. The amount of Ca2+ releasable by depolarizing pulses was always equal to the amount of Ca2+ in the caffeine-releasable pool. Therefore, there is a single releasable Ca2+ pool. This pool is well stirred-it takes much more time to lose its Ca2+ by release than to diffusionally homogenize its [Ca2+]. Its depletion explains quantitatively the decay of release induced by caffeine or voltage during an exposure to caffeine. 5. A 1.5 s pulse to 10 mV, applied during exposure to caffeine, resulted in large Ca2+ release and, upon repolarization, termination of the caffeine-induced release. This is similar to repolarization-induced stop of caffeine contracture (RISC) in embryonic murine myoballs. The permeability elicited by caffeine (ratio of flux to calcium in the releasable pool) was not affected by depolarizing pulses. Therefore, the mechanism of the RISC-like effect was Ca2+ depletion. 6. Caffeine-induced release did not depend on the holding potential. 7. Whether caffeine was present or not, release activated by voltage remained always under voltage control, ending rapidly upon repolarization. A depolarizing pulse induced a release permeability with an early peak, followed by decay to a steady level. Caffeine (10 mM) shifted the mid-activation voltage of both peak and steady components by -15 mV and increased the steepness of their voltage dependence by 15%. The maximum permeability increased by 30% for the peak and 25% for the steady component (n = 5). These results neither support nor disprove the hypothesis that the peak of Ca2+ release is activated by Ca2+. 8. The similar potentiation by caffeine of both components of release, the continued ability of voltage to control release in the presence of caffeine, and its failure to alter caffeine-induced permeability indicate that caffeine and the voltage sensor enhance independently the channel's tendency to open.

Animals↗