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PubMed2005

Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation.

OBJECTIVE: Investigation of the effect of a green tea-caffeine mixture on weight maintenance after body weight loss in moderately obese subjects in relation to habitual caffeine intake. RESEARCH METHODS AND PROCEDURES: A randomized placebo-controlled double blind parallel trial in 76 overweight and moderately obese subjects, (BMI, 27.5 +/- 2.7 kg/m2) matched for sex, age, BMI, height, body mass, and habitual caffeine intake was conducted. A very low energy diet intervention during 4 weeks was followed by 3 months of weight maintenance (WM); during the WM period, the subjects received a green tea-caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine per day) or placebo. RESULTS: Subjects lost 5.9 +/-1.8 (SD) kg (7.0 +/- 2.1%) of body weight (p < 0.001). At baseline, satiety was positively, and in women, leptin was inversely, related to subjects' habitual caffeine consumption (p < 0.01). High caffeine consumers reduced weight, fat mass, and waist circumference more than low caffeine consumers; resting energy expenditure was reduced less and respiratory quotient was reduced more during weight loss (p < 0.01). In the low caffeine consumers, during WM, green tea still reduced body weight, waist, respiratory quotient and body fat, whereas resting energy expenditure was increased compared with a restoration of these variables with placebo (p < 0.01). In the high caffeine consumers, no effects of the green tea-caffeine mixture were observed during WM. DISCUSSION: High caffeine intake was associated with weight loss through thermogenesis and fat oxidation and with suppressed leptin in women. In habitual low caffeine consumers, the green tea-caffeine mixture improved WM, partly through thermogenesis and fat oxidation.

Adipose Tissue↗
PubMed1994

A caffeine- and ryanodine-sensitive intracellular Ca2+ store can act as a Ca2+ source and a Ca2+ sink in PC12 cells.

We have investigated the modulation of stimulus-induced changes in intracellular Ca2+ concentration ([Ca2+]i) by a caffeine-and ryanodine-sensitive Ca2+ store in PC12 cells. In populations of fura-2-loaded cells, caffeine cause a concentration-dependent increase in [Ca2+]i that was saturable, reversible and inhibited in a use-dependent fashion by ryanodine. Maximal Ca2+ release occurred with 40 mM caffeine, with an EC50 of 13 mM caffeine and a Hill coefficient (h) of 2.7, indicating that the release mechanism was co-operative. Pretreatment of intact cell populations with increasing concentrations of caffeine in nominally Ca(2+)-free medium inhibited the subsequent Ca2+ response to a maximal concentration of ATP, in a dose-dependent manner. In permeabilized cells, a maximal concentration (40 microM) of InsP3 still released Ca2+ in the presence of a supramaximal concentration (50 mM) of caffeine, whereas caffeine was unable to release Ca2+ after the InsP3-sensitive store had been completely emptied. These data suggest that PC12 cells contain a uniquely InsP3-sensitive Ca2+ store, and a store that is sensitive to both InsP3 and caffeine. Depletion of the caffeine-sensitive Ca2+ store by caffeine and ryanodine pretreatment in intact cells attenuated the Ca2+ response to ATP, but not to 55 mM K+, suggesting that the caffeine-sensitive Ca2+ store acts as a Ca2+ source after ATP stimulation, but not after depolarization with 55 mM K+. Pretreatment of intact cells with ATP and ryanodine resulted in a use-dependent block of both caffeine- and ATP-mediated Ca2+ release, confirming that ATP stimulation of PC12 cells brings about activation of ryanodine receptors. The rate of recovery, but not the magnitude or rate of onset, of the depolarization-induced [Ca2+]i transient was modulated by the state of filling of the caffeine-sensitive Ca2+ store such that recovery was prolonged if the store was either full, or empty and unable to refill. We conclude that the caffeine- and ryanodine-sensitive Ca2+ store can act as a Ca2+ source and a Ca2+ sink in PC12 cells, and that its role may in part be governed by the nature of the stimulating agent.

Adenosine Triphosphate↗
PubMed1995

Effects of caffeine on cytoplasmic free Ca2+ concentration in pancreatic beta-cells are mediated by interaction with ATP-sensitive K+ channels and L-type voltage-gated Ca2+ channels but not the ryanodine receptor.

In the pancreatic beta-cell, an increase in the cytoplasmic free Ca2+ concentration ([Ca2+]i) by caffeine is believed to indicate mobilization of Ca2+ from intracellular stores, through activation of a ryanodine receptor-like channel. It is not known whether other mechanisms, as well, underlie caffeine-induced changes in [Ca2+]i. We studied the effects of caffeine on [Ca2+]i by using dual-wavelength excitation microfluorimetry in fura-2-loaded beta-cells. In the presence of a non-stimulatory concentration of glucose, caffeine (10-50 mM) consistently increased [Ca2+]i. The effect was completely blocked by omission of extracellular Ca2+ and by blockers of the L-type voltage-gated Ca2+ channel, such as D-600 or nifedipine. Depletion of agonist-sensitive intracellular Ca2+ pools by thapsigargin did not inhibit the stimulatory effect of caffeine on [Ca2+]i. Moreover, this effect of caffeine was not due to an increase in cyclic AMP, since forskolin and 3-isobutyl-1-methylxanthine (IBMX) failed to raise [Ca2+]i in unstimulated beta-cells. In beta-cells, glucose and sulphonylureas increase [Ca2+]i by causing closure of ATP-sensitive K+ channels (KATP channels). Caffeine also caused inhibition of KATP channel activity, as measured in excised inside-out patches. Accordingly, caffeine (> 10 mM) induced insulin release from beta-cells in the presence of a non-stimulatory concentration of glucose (3 mM). Hence, membrane depolarization and opening of voltage-gated L-type Ca2+ channels were the underlying mechanisms whereby the xanthine drug increased [Ca2+]i and induced insulin release. Paradoxically, in glucose-stimulated beta-cells, caffeine (> 10 mM) lowered [Ca2+]i. This effect was due to the fact that caffeine reduced depolarization-induced whole-cell Ca2+ current through the L-type voltage-gated Ca2+ channel in a dose-dependent manner. Lower concentrations of caffeine (2.5-5.0 mM), when added after glucose-stimulated increase in [Ca2+]i, induced fast oscillations in [Ca2+]i. The latter effect was likely to be attributable to the cyclic AMP-elevating action of caffeine, leading to phosphorylation of voltage-gated Ca2+ channels. Hence, in beta-cells, caffeine-induced changes in [Ca2+]i are not due to any interaction with intracellular Ca2+ pools. In these cells, a direct interference with KATP channel- and L-type voltage-gated Ca(2+)-channel activity is the underlying mechanism by which caffeine increases or decreases [Ca2+]i.

Adenosine Triphosphate↗
PubMed1998

Motor stimulant effects of caffeine in 6-hydroxydopamine-lesioned rats are dependent on previous stimulation of dopamine receptors: a different role of D1 and D2 receptors.

Caffeine has been reported to induce contralateral rotational behaviour in rats bearing a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. In order to define the role of dopamine receptors in the mediation of this behaviour, we have evaluated the influence of previous exposure to a dopamine receptor agonist and the importance of the time elapsed from the 6-hydroxydopamine lesion on the rotational behaviour induced by caffeine. Separate groups of rats lesioned with 6-hydroxydopamine 2 weeks previously were exposed to four administrations of the D1/D2 receptor agonist apomorphine (0.3 mg/kg s.c.) (primed) or vehicle (drug-naive). Three days later, all rats received caffeine (30 mg/kg s.c.). Drug-naive 6-hydroxydopamine-lesioned rats did not rotate in response to caffeine, while rats primed with apomorphine rotate contralaterally in response to caffeine. When apomorphine priming was paired to the same environment (hemispherical bowls) where rats received caffeine, rotational behaviour was significantly higher than that obtained in rats primed in an unpaired environment (cylinders). Repeated priming with the D2/D3 receptor agonist quinpirole (0.2 mg/kg s.c.) induced a totally context-dependent contralateral rotation in response to caffeine, while caffeine contralateral rotation was not dependent from the context after repeated priming with the D1 agonist SKF 38393 [1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride, 3 mg/kg s.c.]. Caffeine-mediated contralateral rotation was also evaluated in rats lesioned with 6-hydroxydopamine 12 weeks previously and exposed to four administrations of apomorphine or vehicle. As for rats repeatedly exposed to vehicle or apomorphine 2 weeks after 6-hydroxydopamine lesioning, caffeine failed to induce contralateral rotation in drug-naive rats, while it did induce a partially context-dependent contralateral rotation in apomorphine-primed rats. Different from rats receiving apomorphine priming 2 weeks after 6-hydroxydopamine lesioning, in 12 week-lesioned rats, caffeine also induced contralateral rotation after one priming with apomorphine (0.3 mg/kg s.c.), a condition which fails to induce context-dependent rotation. Administration of selective antagonists of A1 (8-cyclopentyl-1,3-dipropylxanthine), (DPCPX) or A2A (5-amino-2-(2-furyl)-7-(3-phenylpropyl)-pyrazolo[4,3-e]-1 ,2,4-triazolo[5c]pirimidine), (SCH 58261) adenosine receptors failed to induce contralateral rotation either alone or in combination in 12 week-6-hydroxydopamine-lesioned rats repeatedly primed with apomorphine. All together, the results indicate that: (i) caffeine does not induce any contralateral rotation in drug-naive 6-hydroxydopamine-lesioned rats; (ii) priming with a dopamine agonist enables caffeine to induce contralateral rotation, this rotation is, however, context independent only after priming with a selective D1 agonist; (iii) contralateral rotation in response to caffeine is dependent on the time from the 6-hydroxydopamine lesion; (iv) blockade of A1 and A2A adenosine receptors with selective antagonists does not induce contralateral rotational behaviour in 6-hydroxydopamine-lesioned rats.

Animals↗
PubMed2000

Concentrations of caffeine greater than 20 mM increase the indo-1 fluorescence ratio in a Ca(2+)-independent manner.

The methylxanthine, caffeine, quenches the fluorescence of the ratiometric Ca2+ indicator indo-1, but does not affect the ratio (R) of indo-1 fluorescence at 400 and 500 nm in the presence of caffeine concentrations up to 10 mM [1]. We have found that when caffeine is at concentrations of 20 mM or greater in vitro, or in saponinpermeabilized skeletal muscle fibers, a Ca(2+)-independent increase in R occurs, which leads to an overestimation of the free Ca2+ concentration. Depending on experimental conditions, two factors contribute to the alteration in R in vitro. First, when indo-1 fluorescence is low, fluorescence by caffeine, at 400 nm, can be significant. A second, and more dramatic effect, is that quenching of indo-1 fluorescence by 20-50 mM caffeine is dissimilar at 400 and 500 nm. Quenching at 500 nm is not linear, with respect to the concentration of caffeine, and causes a Ca(2+)-independent increase in R, that occurs even when the fluorescence of caffeine is a small portion of total fluorescence. However, unlike R, the Ca2+ calibration constant of indo-1, KD beta, is unchanged in 50 mM caffeine. Therefore, an accurate quantitation of Ca2+ in the presence of even high concentrations of caffeine can be made in vitro by determining the Ca2+ calibration factors of indo-1 (RMIN and RMAX) for each caffeine concentration. These effects of concentrations of caffeine greater than 20 mM are not observed in intact cells loaded with the cell permeant form of indo-1 when caffeine is applied extracellularly. This suggests either that the concentration of caffeine within the cell does not reach that necessary to produce the effect, or that the effects of caffeine on the dye are modified by the environment within the cell.

Animals↗
PubMed2000

Ibuprofen plus caffeine in the treatment of tension-type headache.

BACKGROUND: The effectiveness of caffeine as an adjuvant to ibuprofen has been documented in investigations of acute pain. Our objectives were to assess this agent in the treatment of tension-type headache and to establish clinical trial methods capable of assessing this agent in comparison with various tension headache treatments. Stopwatch technology was used for measurement techniques. METHODS: A randomized, double-blind, parallel, multicenter, single-dose, placebo- and active-controlled study included 301 subjects diagnosed with tension-type headache. Treatment groups included ibuprofen and caffeine, ibuprofen alone, caffeine alone, or placebo. Subjects measured onset of relief (both time to first perceptible relief and time to meaningful relief) after taking a single oral dose of their assigned medication. Pain intensity and pain relief were rated over a 6-hour study period. Overall evaluation was made on completion of all other ratings. RESULTS: Ibuprofen and caffeine administered together provided significantly greater analgesic activity than ibuprofen alone, caffeine alone, and placebo. Ibuprofen and caffeine administered together demonstrated significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; significantly greater total analgesia than ibuprofen alone, caffeine alone, or placebo; and significantly greater peak relief than ibuprofen alone, caffeine alone, or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone or placebo. More patients reported complete headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone, or placebo. Ibuprofen and caffeine administered together was rated significantly better by patients than either ibuprofen alone, caffeine alone, or placebo. No subjects ended participation in the study early because of adverse events. CONCLUSIONS: Sensitive methods have been introduced to assess differences in analgesia among over-the-counter analgesic agents in relieving tension-type headache pain. A double-blind study with this method suggests that ibuprofen and caffeine administered together provides greater analgesic effectiveness than either component alone.

Administration, Oral↗
PubMed2006

Influence of caffeine on perception of effort, metabolism and exercise performance following a high-fat meal.

This study examined the effects of caffeine, co-ingested with a high fat meal, on perceptual and metabolic responses during incremental (Experiment 1) and endurance (Experiment 2) exercise performance. Trained participants performed three constant-load cycling tests at approximately 73% of maximal oxygen uptake (VO2max) for 30 min at 20 degrees C (Experiment 1, n = 8) and to the limit of tolerance at 10 degrees C (Experiment 2, n = 10). The 30 min constant-load exercise in Experiment 1 was followed by incremental exercise (15 W . min-1) to fatigue. Four hours before the first test, the participants consumed a 90% carbohydrate meal (control trial); in the remaining two tests, the participants consumed a 90% fat meal with (fat + caffeine trial) and without (fat-only trial) caffeine. Caffeine and placebo were randomly assigned and ingested 1 h before exercise. In both experiments, ratings of perceived leg exertion were significantly lower during the fat + caffeine than fat-only trial (Experiment 1: P < 0.001; Experiment 2: P < 0.01). Ratings of perceived breathlessness were significantly lower in Experiment 1 (P < 0.01) and heart rate higher in Experiment 2 (P < 0.001) on the fat + caffeine than fat-only trial. In the two experiments, oxygen uptake, ventilation, blood [glucose], [lactate] and plasma [glycerol] were significantly higher on the fat + caffeine than fat-only trial. In Experiment 2, plasma [free fatty acids], blood [pyruvate] and the [lactate]:[pyruvate] ratio were significantly higher on the fat + caffeine than fat-only trial. Time to exhaustion during incremental exercise (Experiment 1: control: 4.9, s = 1.8 min; fat-only: 5.0, s = 2.2 min; fat + caffeine: 5.0, s = 2.2 min; P > 0.05) and constant-load exercise (Experiment 2: control: 116 (88 - 145) min; fat-only: 122 (96 - 144) min; fat + caffeine: 127 (107 - 176) min; P > 0.05) was not different between the fat-only and fat + caffeine trials. In conclusion, while a number of metabolic responses were increased during exercise after caffeine ingestion, perception of effort was reduced and this may be attributed to the direct stimulatory effect of caffeine on the central nervous system. However, this caffeine-induced reduction in effort perception did not improve exercise performance.

Adult↗
PubMed2003

Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine.

The combined effects of caffeine (1,3,7-trimethylxanthine) with iodine deficiency (ID) were examined in a rat two-stage thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male F344 rats were divided into 6 groups each consisting of 10 animals, and received a single s.c. injection of 2800 mg/kg DHPN. From 1 week after the DHPN initiation, the rats were respectively fed a basal diet in which the protein was exchanged for 20% gluten, containing 1500 ppm caffeine + ID, 300 ppm caffeine + ID, 60 ppm caffeine + ID, 1500 ppm caffeine or ID or a basal diet alone for 12 weeks. Relative thyroid weights were significantly (P < 0.05) increased due to the development of proliferative lesions induced by the ID diet as compared to the DHPN-alone group value, which was enhanced by caffeine, albeit without statistical significance. Relative pituitary weights were significantly (P < 0.05) increased with 300 or 1500 ppm caffeine + ID as compared to the DHPN-alone group value. Serum thyroid stimulating hormone (TSH) levels were slightly increased by ID, an effect which was further enhanced by 300 or 1500 ppm caffeine. Serum thyroxine (T(4)) levels were slightly increased by caffeine or ID alone, but decreased by caffeine with ID. Histopathologically, thyroid follicular carcinomas were found only in the 1500 ppm caffeine + ID group, although thyroid follicular adenomas were detected in all the ID-treated groups. The multiplicity of focal thyroid follicular hyperplasias was significantly (P < 0.05) increased by 1500 ppm caffeine. These results indicate that caffeine may synergistically promote thyroid carcinogenesis with ID partially through a pituitary-dependent pathway in rats, implying the possible implication of routine caffeine intake in the promotion of thyroid carcinogenesis.

Adenocarcinoma, Follicular↗
PubMed1996

The measurement of caffeine concentration in scalp hair as an indicator of liver function.

Caffeine concentration in plasma and scalp hair has been determined for subjects consuming normal daily amounts of caffeine and the results used as an indicator of individual hepatic metabolic capacity. Daily exposure to caffeine was assessed in six healthy Japanese volunteers by direct HPLC measurement of the concentrations of caffeine in aliquots of all caffeine-containing beverages consumed by the subjects. The measurements were repeated on three different occasions for each subject and caffeine consumption (mean +/- s.d.) was calculated as 178.0 +/- 84.3 mg day-1 with an intra-individual variability of 23.8 +/- 6.3% as coefficient of variation. A survey of daily caffeine consumption in 121 adult Japanese by means of a questionnaire revealed a similar value (231.8 +/- 177.8 mg day-1). Caffeine concentration in the plasma sampled during an overnight caffeine-free interval was measured by HPLC and a comparison made between healthy subjects and patients with liver disease (0.71 +/- 0.32, 0.77 +/- 0.45 and 3.92 +/- 1.91 micrograms mL-1 for healthy volunteers (n = 6), patients with hepatitis (n = 11) and those with liver cirrhosis (n = 4), respectively). Strands of scalp hair were collected from six healthy subjects and six patients with liver cirrhosis. Caffeine in hair was identified and measured by gas chromatography-mass spectrometry after digestion of the hair matrix with protease and extraction of the caffeine with chloroform. Caffeine concentration in hair collected from patients with liver cirrhosis (26.5 +/- 5.04 ng mg-1 hair) was significantly higher than that in hair sampled from healthy subjects (7.21 +/- 3.11 ng mg-1). These findings suggest that the determination of caffeine concentration in the plasma and hair of subjects consuming normal daily amounts of caffeine-containing beverages provides a practical assessment of individual liver metabolic capacity.

Adult↗
PubMed1983

Differences and similarities in the noradrenaline- and caffeine-induced mechanical responses in the rabbit mesenteric artery.

1. The properties of noradrenaline (NA)-induced and caffeine-induced contractions in the rabbit mesenteric artery were investigated and compared, using intact and skinned muscles.2. NA (> 10(-7) M) depolarized the membrane and reduced the membrane resistance. Increased concentrations of NA (> 10(-5) M) rarely produced oscillatory potential changes yet consistently produced oscillatory contractions which were abolished by pre-treatment with prazosin or Ca-free solution. Application of low concentrations (0.5 mM) of caffeine hyperpolarized the membrane and high concentrations (5 mM) depolarized the membrane.3. NA- and caffeine-induced contractions, but not a K-induced contraction, could be recorded in Ca-free, EGTA (2 mM) containing solution.4. In Ca-free, EGTA containing solution, repetitive applications of NA or caffeine led to a cessation of contractions. Responses persisted longer with applications of NA than with caffeine. In Na-free, Ca-free solution, the contractions evoked by both agents applied repetitively persisted much longer than those evoked in the presence of [Na](o).5. When 50 mug/ml. saponin was applied for 8 min, NA produced only one contraction and with application of 10(-6) M-Ca, only a small contraction was evoked. When saponin was applied for 20 min, NA produced no contraction while 10(-6) M-Ca produced a large contraction, indicating that NA produced a contraction under conditions of incomplete skinning, while caffeine consistently released Ca from incompletely and completely skinned muscles.6. After 20 min of saponin treatment (50 mug/ml.), the pCa-tension relationship could be measured. The minimum concentration of Ca required to produce the contraction was just over 10(-7) M, and the maximum contraction occurred with 3 x 10(-6) M-Ca and was greater than that produced by 128 mM-K in intact muscles. The sigmoidal relationship with this rabbit tissue was sharper than that observed in the guinea-pig mesenteric artery. Application of 10 mM-procaine and 10 mM-caffeine slightly inhibited the pCa-tension relationship.7. In skinned muscles, the amount of stored Ca was estimated from the amplitude of the caffeine-induced contraction. Addition of NA (10(-5) M) with 10(-6) M-Ca had no effect on the caffeine-induced contraction. A reduction of Na from 10 mM to zero in the relaxing solution slightly suppressed the caffeine - induced contraction, i.e. there was a slight inhibition of Ca accumulation.8. Thus, different mechanisms are involved in the NA- and caffeine-induced activations, but both agents do release Ca stored in the same site. Release of Ca from the store site by NA requires the presence of an intact muscle membrane with adrenoceptors but this is not the case with caffeine. The different mechanical responses to NA or caffeine may also relate to the behaviour of Ca; i.e. Ca may be extruded into the extracellular space in the presence of caffeine, while this ion may be extruded and to some extent, re-accumulate into the store site in the presence of NA. The oscillatory contraction evoked by treatment with NA is discussed in relation to the activation of a Ca-induced Ca-release mechanism in the store site.

Animals↗
PubMed1984

The effects of caffeine on tension development and intracellular calcium transients in rat ventricular muscle.

The effects of caffeine on tension and intracellular [Ca2+] were investigated in rat ventricular muscle using the Ca2+-sensitive photoprotein, aequorin. Contracture was induced by rapid application of 0.5-10 mM-caffeine solution at 20 degrees C. In normal Tyrode solution at 8 degrees C, or in Na+-deficient solution in which Na+ was isotonically replaced by sucrose, peak tension of caffeine contracture was potentiated and relaxation was prolonged. Caffeine contracture could not be induced immediately after a prior contracture. Repriming time was 10 min in Tyrode solution, and was much shorter in Na+-deficient solution or in high-K+ solution containing 105.9 mM-K+. Caffeine prolonged the plateau of action potential dose dependently. At low temperature, prolongation of the plateau phase by caffeine was more marked. Twitch tension showed a triphasic change after application of caffeine; peak tension transiently increased in a potentiating phase (P phase), and then decreased below control level in an inhibitory phase (I phase) followed by gradual recovery in a recovery phase (R phase). The effects of caffeine on the Ca2+ transients during a twitch were also complex, depending on time after application and dose of caffeine. In low caffeine concentration (below 0.5 mM) the peak of the Ca2+ transient was potentiated in the I phase, although the peak tension was suppressed. At high concentration (above 3 mM) the peaks of both the Ca2+ transient and twitch tension were suppressed. In every concentration of caffeine tested (0.1-5 mM), time to the Ca2+ transient and twitch tension peaks was prolonged, and the falling phases of both were delayed. Caffeine might release Ca2+ from intracellular store(s) and enhance the slow inward current. The Ca2+ transient obtained in this study clearly indicate that the prolonged time to peak tension in the presence of caffeine is due to the slow rise of intracellular [Ca2+] and prolonged time to peak of the Ca2+ transient. It is also quite possible that caffeine modulates the Ca2+ sensitivity of a contractile system in dose- and time-dependent manners.

Action Potentials↗
PubMed1984

The effects of caffeine on the noradrenaline-sensitive calcium store in rabbit aorta.

The effects of caffeine on the noradrenaline-sensitive Ca store in rabbit aorta have been studied measuring tension development and stimulated 45Ca efflux in Ca-free solution. In addition, the inhibitory effects of caffeine on transmembrane Ca movements and on intracellular Ca release have been investigated, again comparing contractile force and 45Ca fluxes. The maximally effective caffeine concentration fully depletes the noradrenaline-sensitive Ca store as found from both contraction and 45Ca efflux experiments. Within the concentration ranges used in this study for either caffeine and noradrenaline, a linear relation exists between the amplitude of contraction and the amount of stimulated 45Ca efflux. The Ca content of the store (presumably sarcoplasmic reticulum, s.r.) is 74 mumol/kg aorta, corresponding to an s.r. Ca concentration of 5.3 mM. After exposure of the cells to a high-K solution the s.r. Ca concentration reached a value of 8.5 mM. At 37 degrees C the Ca is lost from the store in Ca-free solution with a half-time of 34 min. Although a comparable amount of 45Ca is released by the maximal doses of caffeine and noradrenaline, the caffeine-induced contraction is much smaller than the noradrenaline-induced one. The increase in adenosine 3',5'-cyclic monophosphate (cyclic AMP) after caffeine was less than after noradrenaline, so could not account for the small size of the caffeine-induced contraction. Asynchrony in response to caffeine by successive layers of smooth muscle, and a separate inhibitory action of caffeine, may contribute to the small size of caffeine-induced contractions in thick muscle preparations. Caffeine inhibits high-K-induced contractions by inhibition of Ca influx. Caffeine also inhibits the noradrenaline-induced contractions in Ca-free solution. These inhibitory actions could be dissociated from caffeine-induced release of intracellular Ca.

Animals↗
PubMed1988

Caffeine contracture in guinea-pig ventricular muscle and the effect of extracellular sodium ions.

1. The mechanisms underlying the virtual absence of caffeine contracture in guinea-pig heart in a Na+-rich external solution were reinvestigated in small (50-120 microns thick) bundles of intact and skinned papillary muscle fibres. 2. In Na+-free solution, the peak tension of 30 mM-caffeine contracture corresponded to the maximum tension of the skinned fibres, and was independent of changes in [Ca2+]o and [K+]o. In the presence of external Na+, the peak tension, which was at most several per cent of the maximum, was affected by [Ca2+]o, [Na+]o and [K+]o, and enhanced by Mn2+ and Ni2+. 3. In the absence of Ca2+, replacement of Na+ with K+ allowed caffeine to evoke a large contracture, showing that there was sufficient calcium stored in the cells under Na+-rich conditions. After treatment with 30 mM-caffeine in the Na+-rich, Ca2+-free solution, and upon replacement of all Na+ with Li+, caffeine was still able to produce a large contracture, which was dependent upon Ca2+ pre-loading of the cells before the first caffeine treatment and upon the subsequent duration in the Na+-free solution. 4. Replacement of Li+ with Na+ during the contracture led to rapid relaxation which was delayed by an increase in [Ca2+]o, depolarization by K+, and addition of La3+ and Mn2+. After Na+-induced complete relaxation in the absence of Ca2+, upon removal of the drugs and Na+, subsequent application of caffeine to the cells evoked a large contracture without Ca2+ reloading. 5. In the skinned fibres, 30 mM-caffeine increased the Ca2+ sensitivity of the contractile system and depressed the maximum tension. An increase in Na+ from 8.4 to 58.4 mM altered neither Ca2+ sensitivity nor the rate of tension development in the absence or presence of caffeine. 6. Increase in Na+ affected neither the rate nor the amount of Ca2+ uptake by the sarcoplasmic reticulum (SR) in the absence or presence of caffeine. Increasing Na+ slightly inhibited the caffeine-induced Ca2+ release from the SR, but more than 10 mM-caffeine produced SR Ca2+ depletion. 7. In the presence of a strong Ca2+ buffer, the steady level of Ca2+ uptake by the SR with 1 mM-caffeine was equal to the amount of Ca2+ remaining in the SR just after the application of caffeine, indicating that Ca2+ release was not inactivated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Reinforcing effects of caffeine in coffee and capsules.

In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.

Adult↗
PubMed2005

[Enhancement effect of caffeine on chemotherapy of osteosarcoma in Fischer 344/N rats].

OBJECTIVE: To determine the enhancement effects of caffeine on chemotherapy of transplanted osteosarcoma in Fischer 344/N rats. METHODS: Osteosarcoma-bearing Fischer 344/N rats were treated with cisplatin 2.5 mg/kg (Group DDP), caffeine 90 mg/kg x 2 d (Group caffeine), and cisplatin 2.5 mg/kg plus caffeine 90 mg/kg x 2 d (Group DDP+caffeine), and the control group was treated with normal saline in the same volume. All drugs were given by intra-peritoneum injection with micro-pump, in the rate of 0.5 ml/h. The tumor volume was measured and evaluated. The tumors were stained in TUNEL, and PCNA was detected with immunohistochemistry. The tumor growth inhibition rate, PCNA index and apoptosis index were calculated, and the survival time were recorded. RESULTS: The tumor inhibition rate was -0.5219 +/-0.1429 in control group, 0.0362 +/-0.0957 in Group DDP, -0.4193 +/-0.1345 in Group caffeine, and 0.3646 +/-0.1313 in Group DDP+caffeine (P <0.01). PCNA index was 0.4587 +/-0.1312 in control group, 0.1847+/-0.0535 in Group DDP, 0.4381 +/-0.0706 in Group caffeine, and 0.0314 +/-0.0231 in Group DDP+caffeine (P <0.01). Apoptosis index was 0.0008 +/-0.0005 in control group, 0.0077 +/-0.0060 in Group DDP, 0.0011 +/-0.0003 in Group caffeine, and 0.0295 +/-0.0069 in Group DDP+caffeine (P <0.01). And the survival time was (33.63 +/-4.63)d in control group, (52.13 +/-11.74)d in Group DDP, (35.63 +/-5.15)d in Group caffeine, and (55.13 +/-16.23)d in Group DDP+caffeine (P <0.01). CONCLUSION: Caffeine could enhance the anti-tumor effect of cisplatin in rat osteosarcoma.

Animals↗
PubMed2005

Caffeine effects on recovery sleep following 27 h total sleep deprivation.

INTRODUCTION: Caffeine is widely used to reverse alertness and performance decrements. However, caffeine's effects on subsequent recovery sleep and post-recovery performance are not well documented and, therefore, were evaluated. METHODS: Six habitually low (LC: < or = 100 mg x d(-1)) and three habitually high (HC: > or = 400 mg x d(-1)) caffeine users completed a randomized crossover design. After 20 h of wakefulness, repeated doses of caffeine gum [0 (placebo) mg, 100 (low dose) mg, or 300 (high dose) mg] were administered at 03:00, 05:00, and 07:00. At 10:00 (27 h sleep deprivation) subjects slept for 8 h, followed by Psychomotor Vigilance Task (PVT) administration at 33 and 65 min post-awakening. RESULTS: Low dose caffeine increased stage 1 minutes only. However, high dose caffeine impaired sleep maintenance (reduced total sleep time/increased wake) and reduced sleep depth (increased stage 1 minutes/percentage and slow-wave sleep (SWS) latency, and reduced SWS minutes during the first third of the sleep period). With high dose caffeine, LC users had less SWS percentage as compared with HC users. The HC users had reduced stage 2 percentage with high dose caffeine as compared with placebo and low dose caffeine. Caffeine dose and habitual caffeine use did not influence post-recovery sleep PVT performance. DISCUSSION: Caffeine exerts mild deleterious dose-response effects on recovery sleep following total sleep deprivation, primarily early in the sleep period, with potential recovery from these effects after sufficient sleep as suggested by lack of post-recovery sleep performance deficits. Habitual caffeine use appears to minimally reduce caffeine effects.

Adolescent↗
PubMed1996

Ca(++)-dependence of caffeine modulation of the rate-force relation in canine cardiac Purkinje fibers.

The effects of caffeine on rate-force relation and their Ca++ dependence were studied in canine cardiac Purkinje fibers. At constant rate, caffeine increased and then decreased force. During drives at different rates (15, 60 and 120/min), 1 mM caffeine caused the largest positive inotropic effect at the slowest rate, but in 8.1 mM [Ca++]o caffeine no longer increased force even at 15/min. Interruptions of drive were followed by a positive and then a negative staircase: caffeine (1-4 mM) blunted these effects. A sudden decrease in rate caused a positive staircase: caffeine decreased and caffeine plus 8.1 mM [Ca++]o abolished it. A sudden increase in rate caused a negative staircase and on recovery a positive staircase: caffeine reduced and caffeine plus 8.1 mM [Ca++]o could reverse them. In low [Ca++]o (0.54 mM), caffeine caused only a positive inotropic effect and did not modify the rate-force relation patterns. High [Ca++]o ( > 8.1 mM) reversed the staircase patterns induced by a rate increase; adding caffeine shifted the reversal to lower [Ca++]o. Low [Na]o altered the rate-force relation similarly to high [Ca++]o, and caffeine exaggerated its effects. Decreasing [Ca++]i by means of tetrodotoxin or high [K+]o antagonized the caffeine effects on the rate-force relation. We conclude that caffeine markedly modulates the rate-force relation through a Ca(++)-dependent mechanism. This mechanism appears to involve a supraoptimal increase in [Ca++]i rather than a decrease in Ca++ released during the action potential.

Animals↗
PubMed1990

Effect of prostaglandin inhibition on caffeine-induced hypercalciuria in healthy women.

Caffeine ingestion increases urinary calcium excretion. The mechanism is not known, but prostaglandin synthesis has been implicated. We hypothesized that administration of a prostaglandin inhibitor such as acetylsalicylic acid (aspirin) along with caffeine would prevent caffeine-induced hypercalciuria. We measured 3-hour excretion in fasting subjects who each randomly ingested four treatments on nonconcurrent mornings: no drug, caffeine (5 mg/kg body weight), acetylsalicylic acid (650 mg), or caffeine plus acetylsalicylic acid. In experiment 1, nine healthy premenopausal female subjects were studied; each treatment was taken with 200 ml of orange juice. Water was provided hourly to encourage urine flow. Urinary calcium excretion rose with caffeine treatment; mean 3-hour calcium (mmol/mmol creatinine) was 0.49 +/- 0.07 compared with 0.23 +/- 0.04 during the no-drug treatment. Acetylsalicylic acid caused a significant reduction in urinary calcium to 0.13 +/- 0.08; when it was combined with caffeine, caffeine-induced calcium excretion fell significantly to 0.35 +/- 0.08. Sodium excretion tended to reflect calcium excretion. Urinary prostaglandin E(2) fell significantly with acetylsalicylic acid, with and without caffeine. There were no significant changes in creatinine, water, or potassium excretion. Experiment 2 was similar, except that water was substituted for orange juice to test the possibility that acetylsalicylic acid affected elevated but not basal calcium excretion. Similar and even more pronounced results were obtained, with caffeine causing a threefold increase in urinary calcium, acetylsalicylic acid causing a decrease by half, and the combined drug treatment being greater than no drug but less than caffeine alone. Urinary phosphorus rose significantly with caffeine alone. Prostaglandin synthesis may not be directly involved in caffeine-induced hypercalciuria, as the magnitude of the caffeine-induced increase was similar when treatments given the acetylsalicylic acid were compared with those without a prostaglandin synthesis inhibitor.

Journal Article↗