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PubMed2004

Metabolic effects of caffeine in humans: lipid oxidation or futile cycling?

BACKGROUND: Caffeine ingestion stimulates both lipolysis and energy expenditure. OBJECTIVES: Our objectives were to determine whether the lipolytic effect of caffeine is associated with increased lipid oxidation or futile cycling between triacylglycerol and free fatty acids (FFAs) and whether the effects of caffeine are mediated via the sympathetic nervous system. DESIGN: Respiratory exchange and [1-(13)C]palmitate were used to trace lipid oxidation and FFA turnover in 8 healthy, young men for 90 min before and 240 min after ingestion of placebo, caffeine (10 mg/kg), or caffeine during beta-adrenoceptor blockade. RESULTS: During fasting conditions, there were few differences in measured variables between the 3 tests. During steady state conditions (last hour of the test) after ingestion of caffeine, lipid turnover increased 2-fold (P < 0.005), and the mean (+/-SEM) thermic effect was 13.3 +/- 2.2% (P < 0.001), both of which were greater than after ingestion of placebo or caffeine during beta-adrenoceptor blockade. After ingestion of caffeine, oxidative FFA disposal increased 44% (236 +/- 21 to 340 +/- 16 micro mol/min), whereas nonoxidative FFA disposal increased 2.3-fold (455 +/- 66 to 1054 +/- 242 micro mol/min; P < 0.01). In postabsorptive conditions, 34% of lipids were oxidized and 66% were recycled. Caffeine ingestion increased energy expenditure 13% and doubled the turnover of lipids, of which 24% were oxidized and 76% were recycled. beta-Adrenoceptor blockade decreased, but did not inhibit, these variables. CONCLUSIONS: Many, but not all, of the effects of caffeine are mediated via the sympathetic nervous system. The effect of caffeine on lipid mobilization in resting conditions can be interpreted in 2 ways: lipid mobilization alone is insufficient to drive lipid oxidation, or large increments in lipid turnover result in small increments in lipid oxidation.

Adrenergic beta-Antagonists↗
PubMed2003

Use of oral contraceptives blunts the calciuric effect of caffeine in young adult women.

Caffeine consumption increases the urinary excretion of calcium and other minerals. Factors that affect caffeine metabolism such as steroid hormones may modify this effect. The purpose of this study was to evaluate the influence of oral contraceptive (OC) use on the 4-h urinary excretion of calcium, phosphorus, magnesium, zinc, sodium, potassium and caffeine metabolites in response to a high caffeine dose given as coffee beverage. Adult women, 20-29 y, users (+OC, n = 15) and nonusers (-OC, n = 15) of oral contraceptives, with calcium intake approximately 500 mg/d, participated in two tests, caffeine load (5 mg/kg body weight) and no-caffeine control, in a randomized crossover design. The net increase (caffeine load corrected by no caffeine) in urinary excretion of most minerals was significantly higher in -OC than in +OC (P < 0.05), with the larger group difference for calcium (ninefold) followed by magnesium (twofold), zinc (onefold) and potassium (onefold). Net increases in urinary excretion of 1-methylurate and paraxanthine were about three- and fivefold higher, respectively, in -OC than in +OC (P < 0.05) whereas net increases in urinary excretion of 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1,7-dimethylurate were over twofold higher in the +OC than in -OC (P < 0.05). Following the caffeine load, most urinary minerals showed negative correlation with urinary 1-methylurate in -OC (R </= -0.78, P < 0.01), and with urinary AFMU and 1,7-dimethylurate in +OC (R </= -0.84, P < 0.01). Oral contraceptives appear to limit the renal effect of caffeine on mineral excretion possibly by reducing paraxanthine excretion, the most active caffeine metabolite.

Adult↗
PubMed2004

Caffeine ingestion before an oral glucose tolerance test impairs blood glucose management in men with type 2 diabetes.

Caffeine ingestion negatively affects insulin sensitivity during an oral glucose tolerance test (OGTT) in lean and obese men, but this has not been studied in individuals with type 2 diabetes. We examined the effects of caffeine ingestion on insulin and glucose homeostasis in obese men with type 2 diabetes. Men (n = 12) with type 2 diabetes (age = 49 +/- 2 y, BMI = 32 +/- 1 kg/m(2)) underwent 2 trials, 1 wk apart, in a randomized, double-blind design. Each trial was conducted after withdrawal from caffeine, alcohol, exercise, and oral hypoglycemic agents for 48 h and an overnight fast. Subjects randomly ingested caffeine (5 mg/kg body weight) or placebo capsules and 1 h later began a 3 h 75 g OGTT. Caffeine increased (P < 0.05) serum insulin, proinsulin, and C-peptide concentrations during the OGTT relative to placebo. Insulin area under the curve was 25% greater (P < 0.05) after caffeine than after placebo ingestion. Despite this, blood glucose concentration was also increased (P < 0.01) in the caffeine trial. After caffeine ingestion, blood glucose remained elevated (P < 0.01) at 3 h postglucose load (8.9 +/- 0.7 mmol/L) compared with baseline (6.7 +/- 0.4 mmol/L). The insulin sensitivity index was lower (14%, P = 0.02) after caffeine than after placebo ingestion. Overall, despite elevated and prolonged proinsulin, C-peptide, and insulin responses after caffeine ingestion, blood glucose was also increased, suggesting an acute caffeine-induced impairment in blood glucose management in men with type 2 diabetes.

Adult↗
PubMed1996

Central effects of caffeine on renal renin secretion and norepinephrine spillover.

Endogenous adenosine in the brain may inhibit central sympathetic tone and thereby restrain renin release, a mechanism that may be particularly important when sympathetic activity is enhanced. The purpose of our study was to test the hypothesis that the adenosine receptor antagonist caffeine increases renin release in part by disabling the central nervous system (CNS) adenosine brake on renin release. This hypothesis was tested by conducting three protocols in anesthetized rats. In the first protocol, intracerebroventricular (i.c.v.) infusions of caffeine (10 micrograms/kg/min) did not alter either bradycardic responses to intravenous (i.v.) infusion of N6-cyclopentyladenosine (CPA, A1-receptor agonist) or depressor responses to i.v. infusions of CGS21680 (A1-receptor agonist). However, i.c.v. caffeine did block bradycardic responses to i.c.v. boluses of CPA and depressor responses to i.c.v. boluses of CGS21680, thus demonstrating that i.c.v. caffeine at the dose used blocks CNS but not peripheral adenosine receptors. In the second protocol, hydralazine (1 and 10 mg/kg, administered intraperitoneally) significantly enhanced both the renal secretion of renin and the renal spillover of norepinephrine (NE), thus confirming that hydralazine can increase renin release by unloading arterial baroreceptors and increasing sympathetic tone to the kidneys. In the third protocol, the effects of i.c.v. caffeine (10 micrograms/kg/min) on hydralazine-induced (1 and 10 mg/kg, administered intraperitoneally) changes in renal secretion of renin and renal NE spillover were investigated. In this protocol, i.c.v. caffeine did not alter baseline values for either the renal secretion of renin or NE. In contrast, i.c.v. caffeine significantly (p = 0.03) enhanced the increase in renal renin secretion induced by 1 and 10 mg/kg hydralazine (for 1 mg/kg hydralazine delta of 6.4 +/- 46.7 and 142.4 +/- 142.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively; for 10 mg/kg hydralazine, delta 227.8 +/- 73.9 and 600.8 +/- 168.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively). The enhanced renin-secretion response to hydralazine in caffeine-treated rats was accompanied by augmented hydralazine-induced increase in renal NE spillover (p = 0.035). These data strongly support the hypothesis of a CNS adenosine brake on renin release that is disabled by caffeine.

Adenosine↗
PubMed1999

Effects of long-term caffeine consumption on renal function in spontaneously hypertensive heart failure prone rats.

Our previous studies supported the hypothesis that prolonged administration of caffeine to animals with high-renin hypertension causes progressive deterioration of renal function. However, thus far this hypothesis has been tested with only a few animal models of hypertension. The aim of this study was to test this hypothesis further by investigating the effects of long-term caffeine consumption on renal function in adult spontaneously hypertensive heart failure (SHHF/Mcc-fa(cp)) rats, another model of high-renin hypertension. Lean, male, 9-month-old SHHF/Mcc-fa(cp) rats were randomized to receive either normal drinking water (control group) or drinking water containing 0.1% caffeine (caffeine group) for 20 weeks. No changes in body weight, food and fluid intake, urine volume, and sodium and potassium excretion were found in conscious SHHF/Mcc-fa(cp) rats after 10 or 20 weeks of caffeine treatment. However, caffeine treatment accelerated the time-related decline in renal function and augmented urinary protein excretion. Ten weeks into the protocol, creatinine clearance was 3.6+/-0.4 and 5.7+/-0.9 L/kg/day in the caffeine group and control group, respectively (p<0.02), whereas 20 weeks into the study, creatinine clearance was similarly diminished in both groups. Proteinuria was greater in the caffeine group compared with the control group at both 10 (928+/-131 vs. 439+/-21 mg/kg/day, respectively; p<0.02) and 20 weeks (1,202+/-196 vs. 603+/-30 mg/kg/day, respectively; p<0.01) into the protocol. After 20 weeks, all animals were anesthetized and instrumented. Caffeine treatment for 20 weeks had no effects on blood pressure, heart rate, or vascular resistance in four examined vascular beds (abdominal aorta and renal, carotid, and mesenteric arteries). No changes in renal hemodynamics and electrolyte excretion were found, whereas significantly lower glomerular filtration rate (GFR; inulin clearance) and creatinine clearance (p<0.05) were observed in caffeine-treated animals. These data support our hypothesis that prolonged consumption of caffeine has adverse effects on renal function, in high-renin hypertension.

Albuminuria↗
PubMed1996

A fluvoxamine-caffeine interaction study.

The selective serotonin reuptake inhibitor fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalysing the biotransformation of caffeine. Thus, a pharmacokinetic study was undertaken with the purpose of documenting a drug-drug interaction between fluvoxamine and caffeine. The study was carried out as a randomized, in vivo, cross-over study including eight healthy volunteers. In Period A of the study, each subject took 200 mg caffeine orally, and in Period B, the subjects took fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. On day 8 in Period B, the subjects again ingested 200 mg caffeine. After caffeine intake, blood and urine were sampled at regular intervals. Caffeine and its three primary demethylated metabolites, paraxanthine, theobromine and theophylline in plasma and the same four compounds plus 11 more metabolites in urine were assayed by HPLC. During fluvoxamine, the median of the total clearance of caffeine decreased from 107 ml min-1 to 21 ml min-1 and the half-life increased from 5 to 31 h. The N3-demethylation clearance of caffeine to paraxanthine decreased from 46 to 9 ml min-1; the N1- and N7-demethylation clearances decreased from 21 to 9 ml min-1 and from 14 to 6 ml min-1, respectively. The results confirm that CYP1A2 is the main enzyme catalysing the biotransformation of caffeine, in particular the N3-demethylation and partly the N1- and N7-demethylation. The results indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Finally, our study provides additional evidence that fluvoxamine can be used to probe CYP1A2 in drug metabolism.

Adult↗
PubMed1999

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats.

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.

Animals↗
PubMed2005

The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy.

BACKGROUND: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM: To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS: Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS: Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION: The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.

Adult↗
PubMed2005

Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects.

AIM: The combination of ephedrine and caffeine has been used in herbal products for weight loss and athletic performance-enhancement, but the pharmacokinetic profiles of these compounds have not been well characterized. This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects. METHODS: The pharmacokinetic model was developed based on the simultaneous modelling using plasma samples gathered from two clinical trials. The treatments consisted of single-doses of pharmaceutical caffeine and ephedrine, given alone or together, and an herbal formulation containing both caffeine and ephedrine. We used a mixed-effect statistical model and the program NONMEM to take account of intersubject variability. RESULTS: Three hundred and seventy-nine ephedrine, 352 norephedrine, 417 caffeine plasma concentrations and 40 ephedrine urine concentrations were obtained from 24 subjects. A one-compartment model with first-order absorption described the caffeine data. Caffeine clearance was 0.083 l min(-1) (CV 38%) and decreased to 0.038 l min(-1) in presence of oral contraceptive therapy, its volume of distribution was 38.6 l (CV 20%) and its absorption rate constant was 0.064 l min(-1) (CV 50%). A four-compartment model described the pharmocokinetics of ephedrine and norephedrine. Ephedrine was eliminated mostly renally, with a clearance of 0.34 l min(-1) (CV 11%), and a volume of distribution of 181 l (CV 19%). Nonlinearity in the conversion of ephedrine to norephedrine was observed. Different models showed that the simultaneous administration of caffeine, or the amount of caffeine in the absorption compartment, was associated with a slower rate of absorption of ephedrine. A 32% greater relative bioavailability of herbal compared with pharmaceutical ephedrine administration was observed. CONCLUSIONS: We describe a mechanistic model for ephedrine, norephedrine and caffeine pharmacokinetics and their interactions. The relative bioavailability of ephedrine differed between the herbal supplement compared with the pharmaceutical formulation. Concomitant ingestion of caffeine slowed the absorption rate of ephedrine, which is mainly related to the amount of the former in the absorption compartment. A saturable process appears to be involved in the metabolism of ephedrine to norephedrine.

Administration, Oral↗
PubMed1991

Caffeine reverses the cytotoxic and cell kinetic effects of Novantrone (mitoxantrone).

Caffeine is known to potentiate the cytotoxicity of a variety of DNA damaging agents presumably by reducing the ability of the cells to repair potentially lethal lesions. However, in the present study we observe that 5 mM caffeine reverses the cell kinetic and cytotoxic effects of the intercalating drug Novantrone (mitoxantrone) on L1210, HL-60 and CHO cells. Novantrone alone, at a concentration of 20-30 ng/ml, given to cultures for 1 h, inhibits cell growth by about 50% and causes cells to accumulate in S and G2 phase and to enter a higher DNA ploidy level. Treatment of these cell lines with 5 mM caffeine alone for 1 h has a minimal effect on cell proliferation; suppression of cell growth varies from 5 to 10%. Exposure of cells to Novantrone for 1 h in the presence of caffeine results in a significant reduction of the Novantrone effects; the cell growth rate is partially restored (e.g. caffeine reduces suppression of L1210 cell growth from 48 to 83% of control) and in each of the cell lines studied, the Novantrone-induced cell accumulation in S and G2 is abolished. Combined treatment with caffeine and Novantrone also increases the clonogenicity of CHO cells 8.5 times over that seen in cultures treated with Novantrone alone. In contrast to the combined treatment with caffeine + Novantrone, pretreatment of cells with caffeine provides no protection. Likewise, post-treatment with caffeine provides little reversal of growth inhibition and G2 cell accumulation, especially if the post-treatment is delayed in time. The present data, in conjunction with evidence in the literature that caffeine protects cells against the cytotoxic effects of doxorubicin, suggest that caffeine may play a more general role in protecting cells against planar aromatic molecules such as intercalating agents.

Animals↗
PubMed1998

The influence of caffeine on intramembrane charge movements in intact frog striated muscle.

1. The influence of caffeine, applied over a 25-fold range of concentrations, on intramembrane charge movements was examined in intact voltage-clamped amphibian muscle fibres studied in the hypertonic gluconate-containing solutions that were hitherto reported to emphasize the features of qgamma at the expense of those of qbeta charge. 2. The total charge, Qmax, the transition voltage, V*, and the steepness factor, k, of the steady-state charge-voltage relationships, Q(V), were all conserved to values expected with significant contributions from the steeply voltage-dependent qgamma species (Qmax approximately 20 nC microF-1, V* approximately -50 mV, k approximately 8 mV) through all the applications of caffeine concentrations between 0.2 and 5.0 mM. This differs from recent reports from studies in cut as opposed to intact fibres. 3. The delayed transients that have been attributed to transitions within the qgamma charge persisted at low (0.2 mM) and intermediate (1.0 mM) caffeine concentrations. 4. In contrast, the time courses of such qgamma currents became more rapid and their waveforms consequently merged with the earlier qbeta decays at higher (5.0 mM) reagent concentrations. The charging records became single monotonic decays from which individual contributions could not be distinguished. This suggests that caffeine modified the kinetic properties of the qgamma system but preserved its steady-state properties. These findings thus differ from earlier reports that high caffeine concentrations enhanced the prominence of delayed transient components in cut fibres. 5. Caffeine (5.0 mM) and ryanodine (0.1 mM) exerted antagonistic actions upon qgamma charge movements. The addition of caffeine restored the delayed time courses that were lost in ryanodine-containing solutions, reversed the shift these produced in the steady-state charge-voltage relationship but preserved both the maximum charge, Qmax, and the steepness, k, of the steady-state Q(V) relationships. 6. Caffeine also antagonized the actions of tetracaine on the total available qgamma charge, but did so only at the low and not at the high applied concentrations. Thus, 0.2 mM caffeine restored the steady-state qgamma charge, the steepness of the overall Q(V) function and the appearance of delayed qgamma charge movements that had been previously abolished by the addition of 2.0 mM tetracaine. 7. In contrast, the higher applied (1.0 and 5.0 mM) caffeine concentrations paradoxically did not modify these actions of tetracaine. The total charge and voltage dependence of the Q(V) curves, and the amplitude and time course of charge movements remained at the reduced values expected for the tetracaine-resistant qbeta charge. 8. These results permit a scheme in which caffeine acts directly upon ryanodine receptor (RyR)-Ca2+ release channels whose consequent activation then dissociates them from the tubular dihydropyridine receptor (DHPR) voltage sensors that produce qgamma charge movement, with which they normally are coupled in reciprocal allosteric contact.

Algorithms↗
PubMed1990

Caffeine acting on pregnant rat myometrium: analysis of its relaxant action and its failure to release Ca2+ from intracellular stores.

1. The effect of caffeine on mechanical activity was studied in pregnant rat myometrium. 2. In muscle cells with intact plasmalemmae, caffeine (0.1-50 mM) produced no contraction whatever the experimental conditions. 3. Caffeine (0.1-10 mM) inhibited, in a concentration-dependent manner, contractions induced by electrical stimulation, potassium-rich (60 mM K+) solution, sodium-free solution or oxytocin (22.5 nM). 4. In Ca2(+)-free solution, various substances (oxytocin, sodium orthovanadate and prostaglandin E2) evoked sustained contractions that were suppressed by caffeine (5-10 mM). When caffeine (greater than 5 mM) was applied during Ca2(+)-loading of the tissue (2.1 mM Ca2+, 5 min) in the presence of a K(+)-rich solution, the subsequent transient contraction induced by a short application (10s) of oxytocin (22.5 nM) in Ca-free solution was reduced (63 +/- 3.5% reduction for 20 mM caffeine, n = 4). 5. In saponin-skinned strips, application of caffeine (5-10 mM) during loading of the Ca2(+)-store increased the subsequent contraction induced by myo-inositol 1,4,5 trisphosphate (IP3, 10 microM). Caffeine (10-30 mM) decreased calcium-activated contractions in skinned fibres lacking a functional internal Ca-store. This effect was reduced by the cyclic AMP-dependent protein kinase inhibitor Thr-Thr-Tyr-Ala-Asp-Phe-Ile-Ala-Ser-Gly-Arg-Thr-Gly-Arg-Arg-Asn-Ala-Ile- His-Asp (8 microM). 6. In conclusion, it is suggested that the inability of caffeine to cause spasm of rat myometrium is due to the absence of a caffeine-sensitive calcium-release channel in the sarcoplasmic reticulum. Relaxant effects of caffeine can be explained by mechanisms leading to a decrease in both the cytoplasmic free Ca2+ concentration and the Ca2 +-sensitivity of the contractile machinery.

Animals↗
PubMed1991

Mechanisms controlling caffeine-induced relaxation of coronary artery of the pig.

1. We studied the effects of caffeine on coronary artery smooth muscle of the pig by measuring changes in isometric tension, cytosolic free Ca(2+) concentration ( [Ca2+]i) and transmembrane potential. 2. In the absence of tone, caffeine induced a concentration-dependent transient contraction of coronary artery strips, followed by sustained relaxation. Simultaneously with the relaxation, caffeine, 25 mM, hyperpolarized the smooth muscle cells by 7.7 +/- 0.9 mV. 3. Caffeine caused a concentration-dependent relaxation of strips precontracted with 10(-5)M acetylcholine (ACH). A supramaximal relaxing concentration of 25 mM caffeine produced an additional transient increase in [Ca2+]i on the Ca2+ plateau of ACh tonic contraction, which was followed by a decrease in [Ca2+]i to a level slightly below the basal concentration. This relaxation was accompanied by a hyperpolarization of 7.3 +/- 0.9 mV. 4. KCI 120 mM (high K+) contracted the strips with a concomitant depolarization of 38.6 +/- 1.6 mV and sustained increase in [Ca2+]i. Caffeine caused a concentration-dependent relaxation of high K+-induced contraction. Caffeine, 25 mM, decreased the Ca2+ plateau to a level that remained above the basal concentration of Ca2+ but did not change the membrane potential. 5. When strips were placed in a Ca(2+)-free medium with EGTA 2mM, and, in addition, ACh was applied successively three times, both intracellular and extracellular mobilizable Ca2+ pools were depleted. In these conditions, phorbol 12,13 dibutyrate (PDBu) 10(-7) M and prostaglandin F 2 alpha (PGF 2 alpha) 10(-5) M contracted the strips. Caffeine (25 mM) inhibited these contractions with no change in [Ca2+]i. 6. Forskolin, 3 x 10 -7M, inhibited ACh induced-contraction but did not affect those induced by PDBu. 7. In conclusion, these results show that caffeine has multiple cellular effects. During caffeine-induced relaxation, [Ca2" Ii, adenosine 3': 5'-cyclic monophosphate (cyclic AMP) content and membrane potential are modified. The findings suggest, however, that these effects are secondary, and that caffeine acts mainly by another unknown mechanism, possibly involving a direct inhibition of the contractile apparatus.

Acetylcholine↗
PubMed1992

Comparisons of the effects of ryanodine on catecholamine secretion evoked by caffeine and acetylcholine in perfused adrenal glands of the guinea-pig.

1. The effect of ryanodine on catecholamine secretion induced by caffeine and muscarinic receptor activation was investigated in perfused adrenal glands of the guinea-pig. 2. Caffeine (40 mM) caused only a small increase in catecholamine secretion during perfusion with standard Locke solution. Caffeine-induced catecholamine secretion was markedly enhanced after removal of CaCl2 together with replacement of NaCl with sucrose. 3. In the absence of CaCl2 and NaCl, 50 microM ryanodine had no effect on the resting catecholamine secretion. Caffeine (40 mM) administered 15 min after treatment with ryanodine caused an increase in catecholamine secretion similar to that prior to application of ryanodine, but failed to have any effect thereafter. Combined application of ryanodine and caffeine also prevented catecholamine secretion induced by caffeine applied subsequently. 4. Catecholamine secretion induced by 100 microM acetylcholine (ACh) was only partially inhibited after treatment with ryanodine plus caffeine under Ca(2+)-free, Na(+)-deficient conditions. 5. Preferential influence of ryanodine on the response to caffeine was also confirmed in catecholamine secretion evoked by paired stimuli with caffeine and ACh alternately, during perfusion with either Ca(2+)-free Locke or sucrose-substituted solutions. 6. These results indicate that caffeine increases catecholamine secretion by mobilizing Ca2+ from intracellular Ca2+ stores through ryanodine-sensitive mechanisms in guinea-pig adrenal chromaffin cells. Ca2+ stores sensitive to caffeine and muscarinic receptor activation may not overlap entirely.

Acetylcholine↗
PubMed1993

Caffeine and related compounds block inhibitory amino acid-gated Cl- currents in freshly dissociated rat hippocampal neurones.

1. The effects of caffeine and related compounds on responses mediated by inhibitory amino acids were investigated in freshly dissociated rat hippocampal pyramidal neurones by conventional and nystatin perforated patch-clamp techniques. 2. Glycine and gamma-aminobutyric acid (GABA) evoked Cl- currents in hippocampal neurones. The half-maximum effective concentrations (EC50) of glycine and GABA were 8.5 x 10(-5) and 5 x 10(-6) M, respectively. 3. Caffeine reversibly inhibited both 10(-4) M glycine- and 10(-5) M GABA-induced Cl-currents in a concentration-dependent manner. The half-maximum inhibitory concentrations (IC50) of caffeine were 4.5 x 10(-4) M for the glycine response and 3.6 x 10(-3) M for the GABA response. 4. Caffeine shifted the concentration-response curve of IGly to the right without affecting the maximum response. 5. The inhibitory action of caffeine did not show voltage-dependency. 6. The blocking action of caffeine was not affected by intracellular perfusion with 5 mM BAPTA or by pretreatment with the protein kinase A inhibitor, H-8. This excludes the participation of Ca2+ or cyclic AMP in the inhibitory action of caffeine. 7. Caffeine failed to inhibit the augmentations of aspartate- and N-methyl-D-aspartate (NMDA) -gated current by glycine, suggesting that caffeine has no effect on the allosteric glycine binding site on the NMDA receptor. 8. The inhibitory effects of some xanthine derivatives on IGly were compared. The inhibitory potency of those compounds on IGly was in the order of pentoxifylline > theophylline > or = caffeine > paraxanthine > IBMX > or = theobromine > dyphylline. Xanthine had no effect. 9. The results indicate that methylxanthines including caffeine may act directly on the glycine receptor Cl- channel complex in rat hippocampal pyramidal neurones. The blockade of the inhibitory amino acid response by methylxanthines may be involved in the excitatory side effects of methylxanthines in the mammalian central nervous system.

Amino Acids↗
PubMed1995

Sustained contraction produced by caffeine after ryanodine treatment in the circular muscle of the guinea-pig gastric antrum and rabbit portal vein.

1. Caffeine inhibited spontaneous mechanical activity at 0.3-1 mM, but produced a tonic contraction at concentrations higher than 3 mM in the circular muscle of the guinea-pig gastric antrum. In the circular muscle of the rabbit portal vein, caffeine at concentrations higher than 1 mM produced an early phasic contraction followed by a small tonic component. The caffeine-induced contraction was abolished by removal of the external Ca2+ more rapidly in the gastric antrum than the portal vein. 2. When the preparations were pretreated with ryanodine (1 microM) a sustained contraction developed on wash-out of caffeine (10 mM) both in the gastric antrum and portal vein. This contraction was not affected by nicardipine (3 microM) or verapamil (3 microM), but was readily abolished by removal of the external Ca2+ or by addition of cobalt (1 mM). Spontaneous electrical activity, the slow wave, in gastric muscles was blocked in the presence of 10 mM caffeine, but reappeared during the sustained contraction. 3. Both the contractions induced directly by caffeine and those produced following caffeine wash-out after ryanodine treatment were accompanied by a maintained increase in intracellular Ca2+ concentration measured with fura-2. 4. The presence or absence of Ca2+ during the application of ryanodine did not affect the ability of caffeine to initiate sustained contractions, provided Ca2+ was present during the exposure to caffeine. 5. It is concluded that caffeine can induce a sustained contraction after ryanodine treatment both in the guinea-pig gastric antrum and rabbit portal vein, by activating a Ca2+ influx pathway insensitive to organic Ca2+ channel blockers. No clear evidence was obtained for involvement of the Ca2+ influx pathway activated through depletion of intracellular Ca2+ stores. A hypothesis is proposed that the plasma membrane of these preparations is similar to the sarcoplasmic reticulum membrane in that Ca2+permeability can be increased almost irreversibly by a combination of caffeine and ryanodine in the presence of the external Ca2+.

Animals↗
PubMed1995

Occult caffeine as a source of sleep problems in an older population.

OBJECTIVE: To evaluate the impact of caffeine in medication on sleep complaints in a community population of persons aged 67 or older. DESIGN: Cross-sectional analysis. SETTING: Iowa 65+ Rural Health Study. PARTICIPANTS: Those who completed their own interview, including a section on the use of medications, during the third annual in-person follow-up in 1984-1985. MEASUREMENTS MAIN OUTCOMES: trouble falling asleep or other sleep complaints. Covariates: use of caffeine-containing medication, spasmolytic, or sympathomimetic drug; number of drugs used; depressive symptoms; self-perceived health; comorbidity, hip fracture, arthritis, ulcer of stomach or intestines; and consumption of caffeinated beverages. RESULTS: The prevalence of caffeinated medication use by participants was 5.4%. Those reporting the use of any caffeine-containing medication were at an increased risk of having trouble falling asleep (Odds Ratio [OR] = 1.79, 95% confidence interval [CI] = 1.19-2.68). There was no significant risk of other reported nighttime or daytime sleep problems associated with use of caffeine-containing drugs. Even after adjusting for other factors that could interfere with initiation of sleep, such as painful disease, depressive symptoms, polypharmacy, use of specific medications known to interfere with sleep, and coffee consumption, the use of caffeine-containing medication still presented a significantly increased risk of having trouble falling asleep (OR = 1.60, CI = 1.04-2.46). Although those participants using over-the-counter analgesic medication containing caffeine had an increased risk of trouble falling asleep (OR = 1.88, CI = 1.22-2.90), there was no significant risk of trouble falling asleep for those who took similar noncaffeinated OTC analgesic drugs (OR = 1.26, CI = 0.87-1.83). CONCLUSIONS: The use of caffeine-containing medication is associated with sleep problems. Healthcare providers should be aware of potential problems associated with over-the-counter medications containing caffeine and should counsel patients about the potential of sleep problems. Older patients should be encouraged to read the label on medications and to select drugs that are caffeine-free when that is possible.

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PubMed1992

Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects.

To determine whether caffeine antagonizes the decremental effects of triazolam and zopiclone on human performance, oral single doses of 0.250 mg triazolam, 7.5 mg zopiclone, or respective placebos, with and without 300 mg caffeine, were given to parallel groups of student volunteers in two double-blind studies. Objective tests and subjective visual analogue ratings were done at baseline and 30 min. and 90 min. after the intake. In Study I, triazolam produced drowsiness at 30 min. but did not differ from the placebo in other tests. Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured. Caffeine and triazolam were interpreted as being antagonists. In Study II, zopiclone impaired digit substitution and flicker fusion, produced exophoria and lowered systolic blood pressure. Caffeine differed from zopiclone in several test functions, but it also differed from caffeine + zopiclone whereas zopiclone differed from caffeine + zopiclone only in two tests (Maddox wing, systolic blood pressure). Thus, zopiclone counteracted the effects of caffeine more easily than caffeine counteracted the decremental effects of zopiclone. We conclude that triazolam may not differ importantly from diazepam as regards their antagonism towards caffeine, whereas further research on the antagonism between zopiclone and caffeine needs to be done.

Anti-Anxiety Agents↗