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PubMed2001

Different Ca2+ releasing action of caffeine and depolarisation in skeletal muscle fibres of the rat.

1. The relative abilities of caffeine and transverse tubular (T-) system depolarisation to induce Ca2+ release in mammalian skeletal muscle were compared in mechanically skinned fibres of the rat, in order to determine whether normal excitation-contraction (E-C) coupling is achieved by up-regulating the Ca2+-induced Ca2+ release process, as caffeine is known to do. 2. Caffeine triggered Ca2+ release in soleus (slow-twitch) fibres at much lower concentrations than in extensor digitorum longus (EDL) (fast-twitch) fibres when the sarcoplasmic reticulum (SR) of each type was loaded with Ca2+ at close to endogenous levels. The difference in caffeine sensitivity resulted at least in part from the SR being loaded endogenously at near maximal capacity in soleus fibres but at less than half of maximal capacity in EDL fibres. The caffeine sensitivity could be reversed by reversing the relative level of SR loading. 3. The ability of caffeine to induce Ca2+ release was markedly reduced by lowering the level of SR loading or by raising the free [Mg2+] from 1 to 3 mM. Caffeine, even at 30 mM, triggered little or no Ca2+ release in EDL fibres (a) at 1 mM (physiological) Mg2+ when the SR was loaded at two-thirds or less of the endogenous level, and (b) at 3 mM Mg2+ when the SR was loaded at close to the endogenous level. In contrast, depolarisation potently elicited Ca2+ release under these conditions in the same fibres. 4. The inability of 30 mM caffeine to induce Ca2+ release under certain conditions was not attributable to desensitisation or inactivation of the release channels, because there was no response even upon initial exposure to caffeine and depolarisation always remained able to trigger Ca2+ release. It instead appeared that caffeine was a relatively ineffectual stimulus in EDL fibres except under conditions where (a) the SR was heavily loaded, (b) the free [Mg2+] was low, or (c) a high [Cl-] was present. 5. These results show that the normal E-C coupling mechanism in mammalian skeletal muscle does not involve just enhancing Ca2+-induced Ca2+ release, and evidently requires the removal or bypassing of the inhibitory effect of Mg2+ on the Ca2+ release channels.

Animals↗
PubMed1996

Effects of caffeine and 3-isobutyl-1-methylxanthine on voltage-activated potassium currents in vertebrate neurones and secretory cells.

1. The effects of caffeine and 3-isobutyl-l-methylxanthine (IBMX) on voltage-activated K+ currents were examined by use of patch clamp recording techniques in dissociated chick autonomic ganglion neurones, chick pineal cells and rat anterior pituitary cells. 2. In chick ciliary ganglion neurones, caffeine (0.1-10 mM) produced a robust blockade of delayed rectifier K+ currents (IDR). Blockade was rapid in onset and concentration- and voltage-dependent. Caffeine produced greater inhibition with larger depolarizing voltage pulses. Similar inhibition of IDR was observed in excised outside-out 'maxi-patches' indicating a direct effect on the K+ channels. Caffeine also inhibited IDR in chick sympathetic neurones, chick pineal cells and rat anterior pituitary cells. 3. Application of 10 mM caffeine caused inhibition of transient A-currents (IA) in chick ciliary ganglion neurones. Inhibition of IA was voltage-dependent with greater inhibition observed at more positive command potentials. Application of 1 mM caffeine did not cause inhibition of IA. 4. Application of 1 mM IBMX, a structural analogue of caffeine, caused inhibition of IDR and IA in chick ciliary ganglion neurones. The voltage-dependence of the inhibition of both currents was qualitatively different from that observed with caffeine. The inhibitory effects of 1 mM IBMX and 10 mM caffeine on IDR and IA were additive. 5. Direct inhibition of voltage-activated K+ currents can potentially produce significant secondary effects on intracellular free Ca2+. These results indicate that caution must be used in the design and interpretation of experiments in which millimolar concentrations of caffeine or IBMX are used in pharmacological studies of intracellular Ca2+ dynamics or other second messenger mechanisms.

1-Methyl-3-isobutylxanthine↗
PubMed2004

Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: a randomized, double-blind, crossover study.

OBJECTIVE: A phase II, randomized, double-blind, crossover study was designed to evaluate the efficacy of 100-mg diclofenac sodium softgel (formulated using ProSorb technology) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks. BACKGROUND: Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies. A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain, and may have advantages in migraine treatment. In addition, caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics. The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications (ie, aspirin, acetaminophen, ibuprofen, and ergotamine). METHODS: The 3-period crossover study was designed to compare diclofenac softgel 100 mg, diclofenac softgel 100 mg plus caffeine 100 mg, and placebo in the acute treatment of migraine. Subjects treated one moderate or severe attack with each study medication. The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo. Though the sample size estimate required that 72 subjects treat 3 separate attacks, 51 subjects treated 1 migraine attack, 44 treated 2 attacks, and 39 treated 3 attacks. Results.-In the placebo group, 6 (14%) of 43 subjects reported headache relief at 60 minutes versus 12 (27%) of 45 subjects in the diclofenac softgel group, and 19 (41%) of 46 subjects in the diclofenac softgel plus caffeine group. Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.7). Rescue medication was used by 27 (63%) of 43 subjects treated with placebo, 15 (33%) of 45 subjects treated with diclofenac softgel, and 14 (30%) of 46 subjects treated with diclofenac softgel plus caffeine. This result is highly statistically significant (chi22= 11.56, P=.003). Both the diclofenac plus caffeine (P <.03) and diclofenac only (P <.03) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes. CONCLUSIONS: The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes. Diclofenac softgel alone did not differ significantly from placebo, perhaps due to limits in sample size. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels.

Adolescent↗
PubMed1985

Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone.

The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in-vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg-1 i.v.) were elevated significantly (P less than 0.05 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg-1 i.v. was co-administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 +/- 38 ml kg-1 (mean +/- s.d., n = 6) to 97 +/- 33 ml kg-1 (caffeine 5 mg kg-1, P less than 0.05), and 94 +/- 8 ml kg-1 (caffeine 10 mg kg-1, P less than 0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 +/- 106 ml kg-1 (mean +/- s.d., n = 6) to 31 +/- 18 ml kg-1 (caffeine 5 mg kg-1, P less than 0.5) and 36 +/- 31 ml kg-1 (caffeine 10 mg kg-1, P less than 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P less than 0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.

Animals↗
PubMed1985

The mechanism of the increase of tonic tension produced by caffeine in sheep cardiac Purkinje fibres.

The effects of caffeine were examined on contraction and membrane current in voltage-clamped sheep cardiac Purkinje fibres. The photoprotein aequorin was injected into several cells in order to measure the intracellular ionized Ca concentration [( Ca2+]i). When the Na-K pump was inhibited, depolarization produced a twitch followed by a tonic component of tension. Repolarization produced an after-contraction. These components of tension were accompanied by corresponding increases of aequorin light. Caffeine (10 mM) decreased both the twitch and the after-contraction while increasing the tonic component. The application of caffeine also produced a transient increase of aequorin light, both during depolarization and at rest, which was followed by a maintained decrease in all three components of the light signal. In particular, although caffeine decreased the rise of aequorin light during prolonged depolarization it increased the tonic tension. The possibility that the effects of caffeine on tonic tension could be due to suppression of spontaneous Ca oscillations was rejected for the following reasons. (i) Ryanodine (which also abolishes Ca oscillations) decreased the magnitude of the tonic tension. (ii) Caffeine still increased tonic tension when it was added to a fibre exposed to ryanodine (1-10 microM). In the presence of ryanodine it was possible to measure [Ca2+]i and tonic tension without interference from Ca oscillations. The increase of tonic tension produced by caffeine could not be accounted for by a rise of [Ca2+]i. The results showed that, at a given level of Ca, caffeine increased tension. The results show that a large part of the increase of tonic tension produced by caffeine is due to an increase of the Ca sensitivity of the contractile apparatus rather than to changes of [Ca2+]i. The consequence of this observation for the experimental use of caffeine is discussed.

Action Potentials↗
PubMed1991

Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes.

1. Voltage-clamp recording of Ca(2+)-activated chloride currents in Xenopus oocytes was used to study the effects of caffeine on the liberation of intracellular Ca2+ induced by photo-release of inositol 1,4,5-trisphosphate (InsP3) from caged InsP3. Bath application of caffeine, at concentrations between 0.1 and 10 mM, reduced or abolished the current evoked by photo-release of InsP3 and by microinjection of InsP3. 2. Caffeine did not appreciably reduce currents evoked by injection of Ca2+ into oocytes, whereas measurements using the Ca2+ indicator Rhod-2 showed that it instead inhibited the liberation of Ca2+ by InsP3. 3. Caffeine increased the threshold amount of InsP3 required to evoke a current response and proportionally reduced the currents evoked by suprathreshold levels of InsP3. 4. Theophylline and 3-isobutyl-1-methylxanthine (IBMX) were much less potent than caffeine, and few changes were seen in the InsP3 responses following application of forskolin or intracellular injection of cyclic AMP. Thus, inhibition of InsP3 responses by caffeine does not arise through inhibition of phosphodiesterase enzymes. 5. Even at high (10 mM) concentrations, caffeine did not itself elicit any clear Ca(2+)-activated current. It is therefore unlikely that inhibition of the InsP3 responses arise because caffeine itself liberates Ca2+ from intracellular stores. 6. The site of action of caffeine is intracellular, because injections of caffeine into the oocyte strongly inhibited responses to InsP3, whereas local extracellular applications of similar amounts were almost without effect.

Animals↗
PubMed1992

Effects of procaine and caffeine on calcium release from the sarcoplasmic reticulum in frog skeletal muscle.

1. Resting myoplasmic free [Ca2+] and [Ca2+] transients (delta [Ca2+]) were measured in single voltage-clamped frog skeletal muscle fibres in the presence and absence of procaine, caffeine or procaine plus caffeine using Fura-2 fluorescence and antipyrylazo III (Ap III) absorbance signals. The rate of release (Rrel) of calcium from the sarcoplasmic reticulum (SR) was calculated from the calcium transients and corrected for the relatively small decline due to depletion of calcium from the SR. 2. Procaine (1 mM) reversibly suppressed delta [Ca2+] and the corresponding Rrel by about 40% for 60-100 ms depolarizing steps to -40 to +20 mV. Procaine had little effect on either the waveform or voltage dependence of the Rrel records. 3. [Ca2+] transients calculated from Fura-2 fluorescence changes in the presence or absence of procaine had similar time courses and amplitudes as those calculated from the Ap III absorbance changes suggesting that 1 mM-procaine did not interfere with the ability of Ap III or Fura-2 to monitor delta [Ca2+]. 4. Although 1 mM-procaine depressed Rrel it had no effect on intramembrane charge movements (IQ) calculated from membrane currents recorded simultaneously with delta [Ca2+]. 5. Procaine (1 mM) reversibly inhibited the potentiating effect of 0.5 mM-caffeine on delta [Ca2+]. The amplitude and waveform of the Rrel records were similar in control fibres and in the presence of 1 mM-procaine plus 0.5 mM-caffeine. 6. In the presence of 0.5 mM-caffeine delta [Ca2+] after 10-20 ms voltage steps exhibited an increase in the time to peak and a slower decay time course compared with caffeine-free controls, suggestive of significant calcium-induced calcium release in the presence of caffeine. These effects of caffeine were completely and reversibly blocked by 1 mM-procaine. 7. In the absence of caffeine, 1 mM-procaine caused a small decrease in time to peak of delta [Ca2+] after 10-30 ms duration voltage steps compared to the bracketing control and wash runs without procaine. Rrel turned off faster after 10 ms pulses in procaine than in the absence of procaine, but the turn-off of release was about equally fast with or without procaine after pulses of 20 ms or longer. The effect of procaine after 10 ms pulses in the absence of caffeine may indicate suppression of a component of calcium-induced calcium release in control that inactivates during the pulse.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Caffeine regulates neuronal expression of the dopamine 2 receptor gene.

The psychoactive drug caffeine influences neuronal physiology; however, it is unknown whether it can dynamically alter the expression of genes that influence neurotransmission. Here, we report that caffeine stimulates transcription of the dopamine 2 receptor (D2R) gene in PC-12 cells and primary striatal cultures and increases D2R protein expression in the striatum. Physiological doses of caffeine and the specific adenosine 2A receptor antagonist 8-(3-chlorostyryl) caffeine both increased the activity of a D2R/luciferase reporter construct within 24 h, and simultaneous treatment with 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), a specific adenosine 2A receptor agonist, eliminated this effect. Tests of additional constructs revealed that specific regions of the D2R promoter (-117/-75) and 5'-untranslated region (+22/+317) were required for activation of D2R gene expression by caffeine. In primary striatal cultures, caffeine increased spontaneous firing of neurons between 12 and 80 min after treatment, whereas it increased D2R mRNA expression after only 4 h. These results indicate that regulation of D2R gene expression by caffeine occurs after the initial physiological response has subsided. In vivo, female mice treated with a dose of caffeine (50 mg/kg) showed 1.94- and 2.07-fold increases in D2R mRNA and protein expression, respectively. In contrast, male mice exhibited a 31% decrease in D2R mRNA expression and showed no changes in D2R protein expression. Collectively, these results demonstrate for the first time that caffeine alters D2R expression in neurons. They also suggest that caffeine consumption can lead to sexually dimorphic patterns of gene expression in the brain.

Animals↗
PubMed1991

Caffeine clearance by enzyme multiplied immunoassay technique: a simple, inexpensive, and useful indicator of liver function.

The clinical value and sensitivity of serum caffeine clearance measurement has been evaluated as an indicator of hepatic disease. After a 17 hour caffeine exclusion period, 300 mg of caffeine citrate was administered orally to the study subjects. Serum samples were taken four and 16 hours later. Serum caffeine concentrations were measured using an enzyme multiplied immunoassay technique (EMIT) and a clearance value derived. Conventional liver function tests were measured at the same time. A total of 103 subjects attending the medical unit in a district general hospital were studied. Twenty one had alcoholic liver disease, 11 non-alcoholic cirrhosis, nine non-cirrhotic liver disease, 21 suspected liver disease, six hepatic tumours, and 35 were hospital and normal control subjects. Caffeine clearance values were lowest in subjects with alcoholic liver disease (median 0.19 ml/min/kg, range 0.04-0.61 ml/min/kg) and significantly reduced in all subjects with liver disease (median 0.32 ml/min/kg, range 0.04-2.68 ml/min/kg) compared with control subjects (median 1.27 ml/min/kg, p less than 0.001). In subjects with suspected liver disease subsequently shown to have another explanation for abnormal liver function test results, caffeine clearance values were normal (median 1.31 ml/min/kg, range 0.23-2.64 ml/min/kg) and significantly different, p less than 0.001, from those of subjects with liver disease. Serum albumen values were not different for these latter two groups. Using a cut off value of 0.86 ml/min/kg, caffeine clearance measurement was 100% sensitive for alcoholic liver disease and 89% sensitive for all liver disease. The respective sensitivities for conventional liver function test measurement were 76% and 83%. In the suspected liver disease group, caffeine clearance was abnormal in only 24%, conventional liver function tests were abnormal in 95%. The respective specificities for caffeine clearance and liver function test measurement in control subjects were 93% and 100%. Caffeine clearance determined by EMIT is a simple inexpensive hepatic metabolic function test. This study indicates that it is a more sensitive indicator of structural liver disease than conventional liver function tests, especially for alcoholic liver disease. The test could be widely introduced as a useful, repeatable assessment of hepatic function.

Adult↗
PubMed1991

Effects on birthweight of alcohol and caffeine consumption in smoking women.

STUDY OBJECTIVE: Previous work found no effect on birthweight of alcohol and caffeine consumption in non-smokers but such an effect was found in smokers. This report investigates further the effects on birthweight of alcohol and caffeine at three stages of pregnancy in smoking women. DESIGN: This was a prospective population study. SETTING: District general hospital in inner London. PARTICIPANTS: Out of 1309 women who completed all pregnancy interviews, 895 were excluded because they did not smoke, leaving a sample of 414 smokers. MEASUREMENTS AND MAIN RESULTS: Number and brand of cigarettes smoked, and quantity of alcohol and caffeine consumed were obtained by interview at booking, 28, and 36 weeks gestation. Birthweight was corrected for gestation and adjusted for maternal height, sex of infant and parity. The effect on birthweight of alcohol consumption was not explained by the amount smoked in terms of quantity and yield. Similarly the effect of caffeine was independent of smoking. When alcohol, caffeine, and smoking were analysed together, alcohol and caffeine were both associated with reductions in birthweight. Alcohol was associated with a reduction of up to 8% after adjusting for tobacco and caffeine intake, and caffeine was associated with a reduction of up to 6.5% after adjusting for tobacco and alcohol intake. Women who at booking were heavy smokers (greater than or equal to 13 cigarettes/day or greater than or equal to 15 mg carbon monoxide/cigarette), heavy drinkers (greater than or equal to 100 g/week alcohol), and had high caffeine intake (greater than or equal to 2801 mg/week) had a predicted reduction in mean birthweight of 18% (95% CI 11% to 24%). CONCLUSIONS: It is well known that women who smoke in pregnancy have smaller babies than non-smokers. Our study suggests that if these women also drink alcohol and high quantities of caffeine then the risk of poor fetal growth is increased even further.

Alcohol Drinking↗
PubMed2006

Wingate performance and surface EMG frequency variables are not affected by caffeine ingestion.

The ergogenic effect of caffeine and its mechanism of action on short-term, high-intensity exercise are controversial. One proposed mechanism is caffeine's stimulatory effect on the central nervous system and thus, motor-unit excitation. The latter is non-invasively determined from surface electromyographic signal (EMG) frequency measures. The purpose of this study was to determine if power output and surface EMG frequency variables during high-intensity cycling were altered following caffeine ingestion. Eighteen recreationally active college males (mean +/- SD age, 21.5 +/- 1.8 y; height, 181.8 +/- 0.5 cm; body mass, 84.7 +/- 11.4 kg) performed the Wingate test (WG) after ingestion of gelatin capsules containing either placebo (PL; dextrose) or caffeine (CAFF; 5 mg/kg body mass). The trials were separated by 1 week and subjects were asked to withdraw from all caffeine-containing products for 48 h before each trial. From the resulting power-time records, peak power (PP; highest power output in 5 s), minimum power (MP; lowest power output in 5 s), and the percent decline in power (Pd) were calculated. Surface EMG records of the right vastus lateralis (VL) and the gastrocnemius (GA) muscles corresponding to the PP and MP periods were collected and used to determine the integrated electromyogram (IEMG), the mean (MNPF), and the median (MDPF) of the signal's power spectrum. A 2-way repeated measures analysis of variance (ANOVA) (treatment x time) was conducted to determine the effect of caffeine on these variables across levels of time. Caffeine ingestion had no effect on PP (PL, 1049 +/- 192 W; CAFF, 1098 +/- 198 W), MP (PL, 762 +/- 104 W; CAFF, 802 +/- 124 W), or the Pd (PL, 47% +/- 8.9%; CAFF, 48.2% +/- 7.3%) compared with the placebo. For both muscles, MNPF and MDPF diminished significantly (p < 0.001) across time and to a similar degree in both the CAFF and PL trials. Regardless of muscle, CAFF had no effect on the percent change in IEMG from the first 5 s to the last 5 s. For both treatments, the GA displayed a significantly (p < 0.05) greater pre vs. post percent decline in the EMG signal amplitude compared with the VL. These results indicate that caffeine does not impact power output during a 30 s high-intensity cycling bout. Furthermore, these data suggest that caffeine does not impact the neuromuscular drive as indicated by the similar IEMG scores between treatments. Similarly, caffeine does not seem to impact the frequency content of the surface EMG signal and thus the nature of recruited motor units before and after the expression of fatigue. The lack of decline in the IEMG in the VL despite the decline in power output over the course of the WG suggests a peripheral as opposed to a neural mechanism of fatigue in this muscle. The significant difference in the pre vs. post percent decline in the GA IEMG score further supports this notion. The pre vs. post decline in the IEMG noted in the GA may suggest a fatigue-triggered change in pedaling mechanics that may promote dominance of knee extensors with less reliance on plantar flexors.

Adult↗
PubMed1994

Caffeine and exercise: metabolism and performance.

Caffeine ingestion prior to prolonged exercise delays fatigue. However, the mechanisms involved are very unclear. Caffeine is associated with elevated plasma epinephrine but the metabolic impact of this is uncertain. Glycogen sparing occurs in active muscle, at least in the first few minutes, but studies have generally failed to demonstrate enhanced fat metabolism. The demethylation of caffeine by the hepatic cytochrome P-450 oxygenases begins within minutes and dimethylxanthines (especially paraxanthine) are generated. These compounds appear in the plasma within an hour of caffeine ingestion and may have effects on tissues that have been attributed to caffeine and/or epinephrine. While the most widely supported theory is that caffeine and other methylxanthines are adenosine receptor antagonists, this action alone cannot explain all of the observed responses. Nevertheless, habituation to and withdrawal from caffeine are associated with up and down regulation of adenosine receptors. One study demonstrated marked differences in the effects of caffeine on the plasma concentrations of epinephrine and dimethylxanthines between caffeine users and nonusers. Caffeine is clearly a very active drug that has many effects on humans including increasing exercise endurance. This can be associated with muscle glycogen sparing and elevated plasma epinephrine, but the underlying mechanisms are unknown.

Caffeine↗
PubMed2002

Caffeine-stimulated GTH-II release involves Ca(2+) stores with novel properties.

Modulation of Ca(2+) stores with 10 mM caffeine stimulates robust secretion of gonadotropin (GTH-II) from goldfish gonadotropes. Although both endogenous forms of gonadotropin-releasing hormone (GnRH) utilize a common intracellular Ca(2+) store, sGnRH, but not cGnRH-II, uses an additional caffeine-sensitive mechanism. We examined caffeine signaling by using Ca(2+) imaging, electrophysiology, and cell-column perifusion. Although caffeine inhibited K+ channels, this action appeared to be unrelated to caffeine-induced GTH-II release, because the latter was insensitive to tetraethylammonium. The effects of caffeine also were not mediated by the cAMP/protein kinase A pathway. Instead, caffeine-evoked GTH-II responses were Ca(2+) signal dependent because they were abolished by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid loading. Caffeine generated localized Ca(2+) signals that began near secretory granules. Surprisingly, caffeine-stimulated GTH-II release was insensitive to 100 microM ryanodine and, unlike GnRH action, was unaffected by inhibitors of voltage-gated Ca(2+) channels or sarco(endo)plasmic reticulum Ca(2+)-ATPases. Collectively, these data indicate that caffeine-stimulated GTH-II release is not mediated by typical agonist-sensitive Ca(2+) stores found in endoplasmic reticulum.

Animals↗
PubMed1992

Ruthenium red selectively prevents Ins(1,4,5)P3-but not caffeine-gated calcium release in avian atrium.

We previously reported that inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and caffeine evoked contractures in saponin-permeabilized chick atria. The magnitude of contractures evoked by maximally effective concentrations of Ins(1,4,5)P3 were half those evoked by maximally effective concentrations of caffeine. In the present report, we tested the hypothesis that these two agents may act on distinct calcium-release mechanisms by comparing the effects of ryanodine, ruthenium red, and procaine on the responses to Ins(1,4,5)P3 and caffeine. We find that procaine inhibits both responses with similar mean inhibitory concentrations in the millimolar range. Nanomolar concentrations of ryanodine selectively potentiate the contractures induced by Ins(1,4,5)P3 but have no effect on those induced by caffeine. Micromolar concentrations of ryanodine inhibit responses to both Ins(1,4,5)P3 and caffeine in a use-dependent way. Ruthenium red prevents the response to Ins(1,4,5)P3 and potentiates that to caffeine, as if ruthenium red had enhanced calcium accumulation in the caffeine-sensitive pool(s). Because we found that caffeine prevented the subsequent response to Ins(1,4,5)P3, but Ins(1,4,5)P3 had no detectable effect on the caffeine-induced contracture, we conclude that Ins(1,4,5)P3 and caffeine act on pharmacologically distinct calcium-release mechanisms that may reside in the same sarcoplasmic reticulum compartment.

Actin Cytoskeleton↗
PubMed2002

Central nervous system effects of caffeine and adenosine on fatigue.

Caffeine ingestion can delay fatigue during exercise, but the mechanisms remain elusive. This study was designed to test the hypothesis that blockade of central nervous system (CNS) adenosine receptors may explain the beneficial effect of caffeine on fatigue. Initial experiments were done to confirm an effect of CNS caffeine and/or the adenosine A(1)/A(2) receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) on spontaneous locomotor activity. Thirty minutes before measurement of spontaneous activity or treadmill running, male rats received caffeine, NECA, caffeine plus NECA, or vehicle during four sessions separated by approximately 1 wk. CNS caffeine and NECA (intracerebroventricular) were associated with increased and decreased spontaneous activity, respectively, but caffeine plus NECA did not block the reduction induced by NECA. CNS caffeine also increased run time to fatigue by 60% and NECA reduced it by 68% vs. vehicle. However, unlike the effects on spontaneous activity, pretreatment with caffeine was effective in blocking the decrease in run time by NECA. No differences were found after peripheral (intraperitoneal) drug administration. Results suggest that caffeine can delay fatigue through CNS mechanisms, at least in part by blocking adenosine receptors.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed1991

Influence of cold, exercise, and caffeine on catecholamines and metabolism in men.

Recently we found that caffeine ingestion did not enhance either thermal or fat metabolic responses to resting in cold air, despite an increase in plasma epinephrine and free fatty acids. Theophylline, another methylxanthine, has been shown to be effective during exercise but not at rest during cold stress. Therefore we hypothesized that caffeine ingestion before exercise in cold air would have a thermal-metabolic impact by increasing fat metabolism and increasing oxygen consumption. Young adult men (n = 6) who did not normally have caffeine in their diet performed four double-blind trials. Thirty minutes after ingesting placebo (dextrose, 5 mg/kg) or caffeine (5 mg/kg) they either exercised (60 W) or rested for 2 h in 5 degrees C air. Cold increased (P less than 0.05) plasma norepinephrine while both caffeine and exercise increased (P less than 0.05) epinephrine. Serum free fatty acids and glycerol were increased, but there were no differences between rest and exercise or placebo and caffeine. Caffeine had no influence on either respiratory exchange ratio or oxygen consumption either at rest or during exercise. The exercise trials did not significantly warm the body, and they resulted in higher plasma norepinephrine concentrations and lower mean skin temperatures for the first 30 min. The data suggest that skin temperature stimulates plasma norepinephrine while caffeine has little effect. In contrast, caffeine and exercise stimulate plasma epinephrine while cold has minimal effect. Within the limits of this study caffeine gave no thermal or metabolic advantage during a cold stress.

Adult↗
PubMed1993

Caffeine attenuates the exercise-induced increase in plasma [K+] in humans.

This study examined the dose-response effects of caffeine on plasma K+ balance during prolonged exercise. Two series of experiments were performed. In series A, 1 h after ingestion of 9 mg/kg dextrose (placebo) or 9 mg/kg caffeine, eight subjects cycled at 78% of peak O2 consumption until exhaustion; in series B, in four trials, 1 h after ingestion of 0, 3, 6, or 9 mg/kg caffeine, eight subjects ran on a treadmill at 85% of peak O2 consumption until exhaustion. Blood was sampled from an antecubital vein for analysis of hematocrit, plasma concentrations of epinephrine ([Epi]) and norepinephrine, and [K+]. The change in plasma volume was calculated from hematocrit. During exercise, there was a net addition of K+ to and a net loss of fluid from the plasma compartment. Caffeine had no effect on plasma volume and norepinephrine concentration during exercise. In series A and B 9 mg/kg caffeine and in series B 6 mg/kg caffeine resulted in a significant attenuation of the increase in plasma [K+] with exercise. In series A increases in plasma [Epi] were 1.4- to 2-fold greater during exercise with caffeine than with placebo. At exhaustion, plasma [Epi] was twofold higher with caffeine (10.1 +/- 2.3 nM) than with placebo (5.3 +/- 0.8 nM), whereas plasma [K+] was only 4.88 +/- 0.18 meq/l with caffeine compared with 5.37 +/- 0.14 meq/l with placebo. It is concluded that caffeine attenuates the increase in plasma [K+] during exercise by stimulation (via one of its metabolites or by increased [Epi]) of tissue Na-K pump activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Metabolic, catecholamine, and exercise performance responses to various doses of caffeine.

This study examined the exercise responses of well-trained endurance athletes to various doses of caffeine to evaluate the impact of the drug on exercise metabolism and endurance capacity. Subjects (n = 8) withdrew from all dietary sources of caffeine for 48 h before each of four tests. One hour before exercise they ingested capsules of placebo or caffeine (3, 6, or 9 mg/kg), rested quietly, and then ran at 85% of maximal O2 consumption to voluntary exhaustion. Blood samples for methylxanthine, catecholamine, glucose, lactate, free fatty acid, and glycerol analyses were taken every 15 min. Plasma caffeine concentration increased with each dose (P < 0.05). Its major metabolite, paraxanthine, did not increase between the 6 and 9 mg/kg doses, suggesting that hepatic caffeine metabolism was saturated. Endurance was enhanced with both 3 and 6 mg/kg of caffeine (increases of 22 +/- 9 and 22 +/- 7%, respectively; both P < 0.05) over the placebo time of 49.4 +/- 4.2 min, whereas there was no significant effect with 9 mg/kg of caffeine. In contrast, plasma epinephrine was not increased with 3 mg/kg of caffeine but was greater with the higher doses (P < 0.05). Similarly only the highest dose of caffeine resulted in increases in glycerol and free fatty acids (P < 0.05). Thus the highest dose had the greatest effect on epinephrine and blood-borne metabolites yet had the least effect on performance. The lowest dose had little or no effect on epinephrine and metabolites but did have an ergogenic effect. These results are not compatible with the traditional theory that caffeine mediates its ergogenic effect via enhanced catecholamines.

Adult↗