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PubMed2005

Effect of caffeine on cerebral blood flow response to somatosensory stimulation.

Despite caffeine's wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine on neurovascular coupling. In the present study, we evaluated the effects of caffeine, an adenosine receptor antagonist, on intracerebral arterioles in vitro and subsequently, on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50 micromol/L) on adenosine-induced vasodilatation. At the lower concentration, caffeine was without effect, but at the higher concentration, caffeine produced significant attenuation. In our in vivo studies, we determined the cerebrospinal fluid (CSF) caffeine concentrations at 15, 30, and 60 mins after intravenous administration of 5, 10 and 40 mg/kg. At the latter two concentrations, CSF levels exceeded 10 micromol/L. We then evaluated the pial arteriolar response during cortical activation caused by contralateral SNS after administering caffeine intravenously (0, 5, 10, 20 30, and 40 mg/kg). The pial circulation was observed through a closed cranial window in chloralose-anesthetized Sprague-Dawley rats. The contralateral sciatic nerve was isolated, positioned on silver electrodes and stimulated for 20 secs (0.20 V, 0.5 ms, and 5 Hz). Arteriolar diameter was quantified using an automated video dimension analyzer. Contralateral SNS resulted in a 23.8% +/-3.9% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose studied (5 mg/kg) had no effect on either resting arteriolar diameter or SNS-induced vasodilatation. However, at higher doses (10, 20, 30, and 40 mg/kg, intravenously), caffeine significantly (P < 0.05; n = 6) attenuated both resting diameter and cerebral blood flow (CBF) responses to somatosensory stimulation. Intravenous administration of theophylline (10, 20, and 40 mg/kg), another adenosine receptor antagonist, also significantly reduced SNS-induced vasodilatation in a dose-dependent manner. Hypercarbic vasodilatation was unaffected by either caffeine or theophylline. The results of the present study show that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Adenosine↗
PubMed2006

Effects of caffeine are more marked on daytime recovery sleep than on nocturnal sleep.

Caffeine is often used to counteract sleepiness generated by sleep deprivation, jet lag, and shift-work, and is consumed at different times of day. Caffeine also has effects on sleep. However, little is known about the interaction between sleep deprivation, circadian timing, and caffeine consumption on sleep. In this study, we compared the effects of caffeine on nocturnal sleep initiated at habitual circadian time and on daytime recovery sleep. Thirty-four moderate caffeine consumers participated in both caffeine (200 mg) and placebo (lactose) conditions in a double-blind crossover design. Seventeen subjects followed their habitual sleep-wake cycle and slept in the laboratory during the night (Night), while 17 subjects were sleep deprived for one night and recovery sleep started in the morning (DayRec). All subjects received a capsule of 100 mg of caffeine (or placebo) 3 h before bedtime, and the remaining dose 1 h before bedtime. Compared to placebo, caffeine lengthened sleep latency, increased stage 1, and reduced stage 2 and slow-wave sleep (SWS) in both groups. However, caffeine reduced sleep efficiency more strongly in the DayRec group, and decreased sleep duration and REM sleep only in that group. The stronger effects of caffeine on daytime recovery sleep compared to nocturnal sleep are probably the consequence of the combined influence of increasing circadian wake propensity drive and the dissipation of homeostatic sleep pressure. We propose that the reduction of SWS by caffeine during daytime sleep increases the impact of the circadian wake signal on sleep. These results have implications for individuals using caffeine during night time.

Adult↗
PubMed1988

Caffeine clearance and biotransformation in patients with chronic liver disease.

1. The clearance and biotransformation of caffeine (1,3,7-trimethylxanthine) were investigated in eight healthy control subjects and 16 patients with cirrhosis, by measuring serial serum caffeine concentrations and recoveries of methylxanthine metabolites in urine for 48 h after a 400 mg oral caffeine load. 2. In the control group, the mean (+/- SD) serum caffeine clearance was 1.3 +/- 0.4 ml min-1 kg-1 and a mean of 56.4 +/- 16.5% of the administered caffeine was recovered from the urine over 48 h as methyluric acids and methylxanthines. The majority of the metabolites were excreted in the first 24 h period and only 2.0 +/- 1.4% of the administered caffeine was excreted unchanged. 3. Patients with compensated cirrhosis (n = 10) metabolized caffeine similarly to the control subjects. Thus the mean serum caffeine clearance was 1.4 +/- 1.2 ml min-1 kg-1 and a mean of 57.2 +/- 11.7% of the administered caffeine was recovered from the urine over 48 h. The majority of the metabolites were excreted in the first 24 h; the pattern of metabolic excretion was unaltered and only 2.2 +/- 0.9% of the administered caffeine was excreted unchanged. 4. In the patients with decompensated cirrhosis (n = 6), significant changes were observed in caffeine metabolism. The mean serum caffeine clearance (0.4 +/- 0.2 ml min-1 kg-1) was significantly impaired compared with controls (P less than 0.01) and a significant delay was observed in metabolite excretion in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Effect of acute and chronic caffeine use on the cerebrovascular, cardiovascular and hormonal responses to orthostasis in healthy volunteers.

1. The effects of acute and chronic caffeine ingestion on supine- and tilt- (60 min at 70 degrees) induced changes in middle cerebral artery velocity (Vmca), heart rate, blood pressure and counter-regulatory hormone levels (catecholamines, growth hormone and cortisol) were studied in nine healthy volunteers. A double-blind, placebo-controlled design was used to study acute effects followed by an open study after 6 days of chronic caffeine use. 2. In the supine position, acute ingestion of caffeine (250 mg) was associated with a fall in Vmca [-11 cm/s, point estimate of difference versus placebo (95% confidence interval: -17, -6) cm/s, P < 0.001] and a rise in mean arterial pressure [+4 (1, 6) mmHg, P < 0.01] and plasma adrenaline levels [+138 (53, 223) pmol/l, P < 0.01]. After chronic caffeine use, the pressor and adrenaline responses, but not the drop in Vmca, were significantly attenuated. 3. On tilting to 70 degrees the fall in Vmca was greater with placebo than after acute caffeine ingestion [-10 (-14, -15) cm/s, P < 0.01], whereas increments (above supine values) in heart rate, mean arterial pressure and hormone levels were unchanged by caffeine. In contrast, the adrenaline [+126 (29, 282) pmol/l, P < 0.01] and noradrenaline [+0.6, 0.9) nmol/l, P < 0.05] responses to tilting were augmented after acute caffeine ingestion. Chronic caffeine supplementation did not alter the fall in Vmca associated with tilting, but significantly attenuated the adrenaline response (P < 0.01 compared with the acute study). 4. Acute caffeine ingestion and orthostasis are both associated with a reduction in Vmca and a rise in mean arterial pressure and adrenaline levels. The acute effects of caffeine on mean arterial pressure and adrenaline but not on Vmca are lost with sustained caffeine intake. These results suggest dissociation between the development of central and peripheral tolerance after chronic caffeine use.

Adult↗
PubMed1999

Prenatal effects of caffeine and restraint stress in mice.

The maternal and developmental toxicity of combined exposure to restraint stress and caffeine was assessed in mice. On Day 9 of gestation, six groups of pregnant mice were treated (p.o.) with a single dose of 30, 60, or 120 mg/kg of caffeine. Immediately after caffeine administration, three of these groups were subjected to restraint for 14 hr. Control groups included unrestrained and restrained pregnant mice not exposed to caffeine. An additional group of animals (unrestrained and not exposed to caffeine) was deprived of food for 14 hr. A two-way (caffeine dose x restraint) analysis of variance revealed an overall effect (reduction) of restraint and caffeine exposure on maternal body weight gain and food consumption on gestation Days 9-11. Significant reductions were also observed in body weight at termination and corrected body weight change of dams concurrently exposed to 120 mg/kg of caffeine and restraint. By contrast, no significant effects of caffeine, restraint, or caffeine plus restraint on embryo/fetal development were noted. The doses of caffeine administered here are much higher than those usually consumed by the general population. Under the current experimental conditions, caffeine alone or combined with restraint stress was not embryotoxic or teratogenic in mice.

Abnormalities, Drug-Induced↗
PubMed1995

Mental effects of caffeine in fatigued and non-fatigued female and male subjects.

In experiment 1 eight male and eight female subjects were randomly assigned to either a caffeine or a placebo condition. Caffeine (150 mg) was given at midnight and at 4 a.m. Oral temperature, subjective ratings of fatigue and mood, and performance in two cognitive tasks (an auditive attention task and a visual coding task) were assessed. Subjective 'drowsiness' and 'tiredness' increased significantly more in subjects given placebo than in subjects given caffeine treatment. The effects of drug treatment in performance and temperature were non-significant. However, the temperature of female subjects increased between midnight and 4 a.m. and the temperature of male subjects decreased during the same period of time. On the other hand, at 5 a.m. female subjects rated themselves as more sleepy, tired and 'disorganized' than the male subjects. In experiment 2 nine female and nine male subjects were assigned randomly to either placebo or caffeine treatment. Caffeine (200 mg) was given at 5 a.m. Oral temperature, subjective ratings of fatigue and mood, and level of performance in three cognitive tasks (the same as above plus Raven's progressive matrices) were assessed. Moreover, the subjects rated the effort of performing each task. The effects of drug treatment in level of performance were non-significant. However, the subjective effort of performing the auditive attention task increased significantly in subjects given placebo treatment, suggesting a compensatory arousal mechanism (Broadbent 1971). The effect of gender on temperature was non-significant. There was a significant interaction between gender and treatment in respect of subjective effort of performing the matrices task. In men caffeine decreased subjective effort and in women subjective effort was increased by caffeine. Experiment 3 was set up to investigate the hypothesis that negative effects of caffeine in women, observed in experiment 2, were due to over-optimal ('vigilance-related') arousal for the visual coding and matrices tasks. Ten female and eight male non-sleep deprived subjects were given 200 mg caffeine or placebos at 3 p.m. and tested at 4 p.m. Experiment 3 was not found to support the over-optimal 'vigilance-related-arousal' hypothesis. Effects of caffeine in performance and effort were non-significant in experiment 3. Combining data from experiments 2 and 3 gave a significant three-way interaction between caffeine, time for experiment and rule complexity in the visual coding task. When there was a complex rule, caffeine was found to have a positive effect in experiment 3 and a negative effect in experiment 2.

Adult↗
PubMed2001

Renal and metabolic effects of caffeine in obese (fa/fa(cp)), diabetic, hypertensive ZSF1 rats.

In Western society, the triad of hypertension, metabolic syndrome and obesity (which caries a high risk for renal disease) is increasing, as is the intake of caffeine. However, no information is available regarding the metabolic or renal consequences of caffeine consumption in this complex disease entity. The purpose of this study was to investigate the effects of chronic caffeine consumption on renal function and metabolic status in obese ZSF1 rats, an animal model of obesity, hypertension and the metabolic syndrome. Fifteen, 18-week-old male, obese ZSF1 rats were randomized to drink tap water (Cont, n = 8) or 0.1% solution of caffeine (Caff, n = 7) for 8 weeks. Metabolic and renal function measurements were performed at baseline and after 4 and 8 weeks of treatment. Caffeine treatment significantly (p < 0.05) reduced body weight, food, and fluid consumption and improved insulin sensitivity (fasting insulin 129.6+/-8.1 vs 97.5+/-3.6 microIU/mL; fed insulin 146.3+/-8.5 vs 110.6+/-3.4 microIU/mL; fasting glucose 138.7+/-13.4 vs 145+/-8.0 mg/dL; fed glucose 373+/-19.4 vs 283.3+/-19.6 mg/dL, Cont vs Caff, respectively). After 8 weeks of caffeine treatment, animals were less glycosuric as compared with control group. Area under glucose curves (AUC-glucose) in oral glucose tolerance test did not differ between the two groups (AUC- glucose: 592.5+/-42.7 vs 589.5+/-20.5 mg/dL x h, Cont vs Caff), whereas caffeine treatment significantly decreased AUC of insulin (AUC-insulin: 257.77+/-12.9 vs 198.0+/-5.9 microIU/mL x h, Cont vs. Caff, p<0.05). No differences were found with regard to plasma triglycerides and glycerol levels; however, caffeine significantly increased cholesterol levels after 4 and 8 weeks (2F-Anova, p<0.001). Moreover, caffeine significantly decreased creatinine clearance after 4 and 8 weeks (CrCl, Cont: 3.5+/-0.4, Caff: 2.2+/-0.2 L/kg/day, p<0.05) and increased protein/CrCl ratio (Cont: 323+/-30, Caff: 527+/-33 mg/L/day). Caffeine treatment for 8 weeks tended to increase plasma norepinephrine levels (p<0.06), but the two groups did not differ with regard to plasma renin activity, blood pressure, renal blood flow or and renal vascular resistance. The study indicates that caffeine improves insulin sensitivity but increases plasma cholesterol levels and impairs renal function in obesity with the metabolic syndrome and hypertension. Our results imply that the health consequences of chronic caffeine consumption may depend heavily on underlying pathophysiology process.

Animals↗
PubMed1994

Caffeine activates a Ca(2+)-permeable, nonselective cation channel in smooth muscle cells.

The effects of caffeine on cytoplasmic [Ca2+] ([Ca2+]i) and plasma membrane currents were studied in single gastric smooth muscle cells dissociated from the toad, Bufo marinus. Experiments were carried out using Fura-2 for measuring [Ca2+]i and tight-seal voltage-clamp techniques for recording membrane currents. When the membrane potential was held at -80 mV, in 15% of the cells studied caffeine increased [Ca2+]i without having any effect on membrane currents. In these cells ryanodine completely abolished any caffeine induced increase in [Ca2+]i. In the other cells caffeine caused both an increase in [Ca2+]i and activation of an 80-pS nonselective cation channel. In this group of cells ryanodine only partially blocked the increase in [Ca2+]i induced by caffeine; moreover, the change in [Ca2+]i that did occur was tightly coupled to the time course and magnitude of the cation current through these channels. In the presence of ryanodine, blockade of the 80-pS channel by GdCl3 or decreasing the driving force for Ca2+ influx through the plasma membrane by holding the membrane potential at +60 mV almost completely blocked the increase in [Ca2+]i induced by caffeine. Thus, the channel activated by caffeine appears to be permeable to Ca2+. Caffeine activated the cation channel even when [Ca2+]i was clamped to below 10 nM when the patch pipette contained 10 mM BAPTA suggesting that caffeine directly activates the channel and that it is not being activated by the increase in Ca2+ that occurs when caffeine is applied to the cell. Corroborating this suggestion were additional results showing that when the membrane was depolarized to activate voltage-gated Ca2+ channels or when Ca2+ was released from carbachol-sensitive internal Ca2+ stores, the 80-pS channel was not activated. Moreover, caffeine was able to activate the channel in the presence of ryanodine at both positive and negative potentials, both conditions preventing release of Ca2+ from stores and the former preventing its influx. In summary, in gastric smooth muscle cells caffeine transiently releases Ca2+ from a ryanodine-sensitive internal store and also increases Ca2+ influx through the plasma membrane by activating an 80-pS cation channel by a mechanism which does not seem to involve an elevation of [Ca2+]i.

Animals↗
PubMed1997

Dietary caffeine intake and bone status of postmenopausal women.

Dietary caffeine intake has been suggested as a risk factor for bone loss in postmenopausal women. We measured the bone density of both hips and the total body in 138 healthy, postmenopausal women aged 55-70 y who had either never used hormone replacement therapy (HRT) or had used HRT for < 1 y. In this cross-sectional study, participants were stratified according to their reported current and long-time caffeinated beverage use into one of three groups: low [0-2 cups (180 mL, or 6 oz per cup) caffeinated coffee per day], moderate (3-4 cups caffeinated coffee per day), or high (> or = 5 cups caffeinated coffee per day). Caffeine intake was measured from diet records and by gas chromatography of each subject's brewed, caffeinated beverages. No association between caffeine intake and any bone measurement was observed. The anthropometric and nutrient intakes of the three groups were similar. Compared with caffeine intake based on chemical analysis of brewed beverages, 3-d prospective food records and computer-assisted analysis overestimated caffeine intake by nearly two-thirds. In conclusion, the habitual dietary caffeine intake of this cohort of 138 postmenopausal women ranged from 0-1400 mg/d and was not associated with total body or hip bone mineral density measurements. This study does not support the notion that caffeine is a risk factor for bone loss in healthy postmenopausal women.

Absorptiometry, Photon↗
PubMed1992

Prediction of malignant hyperthermia susceptibility in low-risk subjects. An epidemiologic investigation of caffeine halothane contracture responses. The North American Malignant Hyperthermia Registry.

The most commonly used laboratory test for predicting malignant hyperthermia susceptibility is the caffeine halothane contracture test. However, the specificity and sensitivity of proposed North American diagnostic guidelines for this test have never been evaluated in a large, human study population. Therefore, the authors conducted a multiinstitutional, prospective study of skeletal muscle contracture responses in a subject population at low risk for malignant hyperthermia susceptibility to help determine the specificity of the proposed guidelines. Subjects were selected arbitrarily from a population of patients undergoing surgery unrelated to performance of a diagnostic muscle biopsy. Subjects were admitted to this study and were presumed nonsusceptible if there was no evidence of any of the following malignant hyperthermia risk factors: prior abnormal response to triggering anesthetic agents, myopathy, or family history of malignant hyperthermia susceptibility. The authors suggested rejection of the proposed diagnostic guidelines if an 85% specificity estimate among subjects could not be obtained. The authors analyzed the responses of 1,022 muscle fascicles, derived from 176 subjects, to the following: 1) separate administration of 3% halothane or incremental caffeine concentrations, or 2) the joint administration of 1% halothane and incremental caffeine concentrations. The following contracture results were obtained. First, for individual fascicles, 9.2% exceeded a greater than 0.7 g threshold for 3% halothane, 15.2% exceeded a greater than or equal to 0.2 g threshold for 2 mM caffeine, 32.4% exceeded a 1-g increase for less than 4 mM caffeine, 2.6% had a greater than 7% maximal increase in tension at 2 mM caffeine, and 63.5% had a "halothane caffeine-specific concentration" at less than or equal to 1 mM caffeine. Second, the percentages of subjects with 1 or more fascicles exceeding the proposed threshold were as follows: 45.8% for the four-component, 28.8% for the three-component, and 32.7% for the two-component contracture test. Third, the percentages of subjects with 1 or more fascicles exceeding the proposed threshold for both halothane and caffeine were as follows: 9.5% for 3% halothane and 2 mM caffeine, 2.0% for 3% halothane and 7% maximal increase in tension at 2 mM caffeine, and 11.0% for 1% halothane and 2 mM caffeine. Fourth, center-to-center differences were the major source of variation in the rate that subjects exceeded proposed thresholds. These data demonstrate that proposed diagnostic guidelines must be modified to improve specificity estimates before adoption by diagnostic centers.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed2002

Heterogeneity in assessing self-reports of caffeine exposure: implications for studies of health effects.

BACKGROUND: Coffee and its metabolite caffeine are widely studied for their health effects but with inconclusive results. Caffeine is particularly difficult to assess, and therefore we explore heterogeneity of caffeine exposure. METHODS: We categorized caffeine exposure among 2,478 pregnant women in southern New England during 1996-2000 by the traditional laboratory-based methods of M. Bunker and M. McWilliams. A subsample was examined to ascertain caffeine levels of brewed or purchased beverages actually consumed. RESULTS: More than half (56.6%) of women drank coffee since becoming pregnant. Serving sizes ranged from 2 to 32 oz and are considerably larger than laboratory standards, which are typically 8-10 oz, as compared with the standard of 5 to 6 oz. Conversely, caffeine content per serving of coffee was one-third the laboratory standard, eg, 100 mg caffeine compared with 300 mg for a 10-oz cup. Tea brewed more than 3 minutes contained 42 mg caffeine as compared with the standard of 94 mg. When the amount of caffeine actually consumed was measured, one-quarter (24.8%) of subjects traditionally classified as consuming 300+ gm caffeine daily were reclassified as consuming 150-299 mg. CONCLUSION: Misclassification of caffeine consumption increases difficulty in identifying health effects from caffeine. Some combination of more precise consumption data and a biomarker such as paraxanthine may more precisely estimate exposure.

Beverages↗
PubMed1985

Comparison of the effects of caffeine and procaine on noradrenergic transmission in the guinea-pig mesenteric artery.

The effects of caffeine and procaine on noradrenergic transmission in the guinea-pig mesenteric artery were investigated by recording electrical responses of smooth muscle cells and by measuring the outflow of noradrenaline (NA) and 3,4-dihydroxyphenylglycol (DOPEG) induced by perivascular nerve stimulation. Caffeine possessed dual actions on the membrane, i.e., at low concentrations (2.5 X 10(-4)-5 X 10(-4)M), it hyperpolarized the membrane and decreased the membrane resistance and at high concentrations (over 2.5 X 10(-3)M) it depolarized the membrane and increased the membrane resistance. Procaine (over 10(-4)M) consistently depolarized the membrane and increased the membrane resistance. The amplitude of the excitatory junction potential (e.j.p.) produced by perivascular nerve stimulation was increased by low concentrations of procaine (2.5 X 10(-5)-10(-4)M) or high concentrations (10(-3)-5 X 10(-3)M) of caffeine and was decreased by low concentrations of caffeine (2.5 X 10(-5)-10(-4)M) or high concentrations of procaine (5 X 10(-4)-10(-3)M). Higher concentrations of caffeine (over 5 X 10(-3)M) induced a spike potential on the e.j.p., while higher concentrations of procaine (over 2.5 X 10(-3)M) inhibited the generation of e.j.ps. Facilitation of e.j.ps produced by repetitive stimulation of perivascular nerves remained unchanged by caffeine, while it was enhanced by procaine at any given concentration (caffeine 2.5 X 10(-4)-10(-3)M; procaine 10(-4)-10(-3)M). The membrane depolarization produced by exogenously applied NA (10(-5)M) was not blocked by pretreatment with procaine. Conduction velocity of perivascular nerve excitation remained unchanged by application of caffeine (up to 5 X 10(-3)M), and was reduced by application of procaine (over 2.5 X 10(-4)M). Outflow of NA during perivascular nerve stimulation remained unchanged by caffeine (10(-4)-3 X 10(-3)M), while it was enhanced by procaine (over 2.5 X 10(-4)M). The outflow of DOPEG was slightly reduced by caffeine (10(-3)-5 X 10(-3)M) and by lower concentrations of procaine (10(-4)-2.5 X 10(-4)M) but was not altered by higher concentrations of procaine (10(-3)-5 X 10(-3)M). It is concluded that in the guinea-pig mesenteric artery, high concentrations of caffeine (over 10(-3)M) increased the e.j.p. amplitude which might be due to an increase in membrane resistance of the smooth muscle cells. No marked effect of caffeine was observed on transmitter release from the nerve terminals. Procaine (over 2.5 X 10(-4)M) increased transmitter release from perivascular nerves and blocked the re-uptake mechanism of released NA. The mechanisms underlying the decrease in ej.p. amplitude by procaine remain to be determined.

Animals↗
PubMed1990

Caffeine-induced behavioural stimulation is dose- and concentration-dependent.

1. The relationship between plasma and brain caffeine and metabolite concentrations and behavioural stimulation was investigated over a 4 h time course. 2. CD-1 mice receiving single intraperitoneal doses of caffeine-sodium benzoate solution (caffeine doses: 0, 20, and 40 mg kg-1) were evaluated in an activity monitor, and their plasma and brain caffeine and metabolite concentrations were determined by high performance liquid chromatography (h.p.l.c.). 3. Kinetic variables for caffeine at low and high caffeine doses were: volume of distribution (Vd), 1.16 and 0.88 l kg-1; plasma elimination half-life (t1/2), 1.25 and 1.62 h; brain t1/2, 0.93 and 1.30 h; clearance, 0.64 and 0.38 l h-1 kg-1, respectively, with Vd and brain t1/2 differing significantly between the two caffeine doses. 4. Low-dose caffeine stimulated vertical behaviours significantly more than high-dose, during the first 150 min post-dosage; both doses stimulated vertical behaviours significantly more than vehicle treatment. 5. Low-dose and high-dose caffeine stimulated horizontal and stereotypic behaviours equivalently, during the first 150 min post-dosage; both doses stimulated these behaviours significantly more than vehicle. 6. Only later, 150 min post-dosage, did high-dose caffeine stimulate all behaviours significantly more than both low-dose and vehicle treatment; this occurred when caffeine concentrations had fallen to approximately 10 micrograms g-1 in the high-dose group. 7. The maximal stimulant effects of caffeine occurred in an intermediate concentration range, between 10-20 micrograms g-1, while lower and higher concentrations produced either no additional stimulation or decrements in activity.

Animals↗
PubMed2005

Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Administration, Inhalation↗
PubMed1985

The effects of caffeine and ryanodine on the electrical activity of the canine coronary sinus.

Cells of the coronary sinus of the canine heart can exhibit triggered activity which each action potential arises from a depolarizing after-potential that follows the previous action potential; an early after-hyperpolarization commonly precedes the delayed after-depolarization and both are increased in amplitude by the addition of noradrenaline. The delayed after-depolarization is thought to be caused by an inward current activated by a rise in intracellular Ca2+ that is, in turn, caused by Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum (s.r.). The effects of caffeine and of ryanodine on the electrical activity of the coronary sinus were investigated because each of those agents is thought to affect the handling of intracellular Ca2+ by the s.r. The steady-state effect of exposure to 5 mM-caffeine is to cause the delayed after-depolarization to move much earlier in the cycle, and become too small to give rise to an action potential so that preparations cannot show triggered activity; moreover, if a burst of activity is in progress it is terminated by exposure to 5 mM-caffeine. Exposure to 0.5 mM-caffeine causes the delayed after-depolarization to move earlier in the cycle but to become larger so that triggered activity is more easily induced and longer lasting than in the absence of caffeine. Shortly after the addition (or wash-out) of 5 mM-caffeine the after-depolarization transiently resembles that seen in the presence of 0.5 mM-caffeine so that bursts of triggered activity may occur just after the addition or removal of 5 mM-caffeine. Exposure to 5 mM-caffeine abolishes early rapid repolarization (phase 1), shifts the plateau to a more positive level and retards the completion of repolarization. The effect on phase 1 is mimicked by exposure to solutions low in Cl-; the effect on the plateau is mimicked by exposure to 20 mM-tetraethylammonium (TEA); fibres exposed to solutions containing 20 mM-TEA and 21 mM-Cl- show action potentials very like those of fibres exposed to 5 mM-caffeine. If a fibre already exposed to a low Cl-, TEA-containing solution is then exposed to 5 mM-caffeine, no further change occurs in the action potential but the characteristic effects of caffeine on the after-depolarization appear. Exposure to ryanodine prevents the appearance of the delayed after-depolarization but leads to the appearance of an exceptionally long depolarizing after-potential that begins very early in diastole and, though waning, persists almost throughout diastole.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1987

Effects of caffeine on intracellular calcium concentrations in frog skeletal muscle fibres.

1. The mechanism of twitch potentiation by caffeine was studied in single muscle fibres dissected from m. tibialis anterior of Rana temporaria. Fibres were injected with a Ca2+-sensitive photo-protein, aequorin, and the resultant light signal and tension were simultaneously recorded. 2. In twitch responses triggered every 60 s, peaks of light and tension were maintained at a constant level. Low concentrations of caffeine (0.2-0.4 mM) potentiated twitch tension accompanied by a slight increase in light signal. 3. Although peak twitch tension was dose-dependently potentiated by caffeine, light peaks were suppressed at relatively higher concentrations of caffeine (0.6-1.5 mM) with prolonged decay of the light and tension signals. 4. Light intensity in the resting muscle (resting glow) was elevated by caffeine (0.2-1.5 mM) dose-dependently without detectable tension development. This effect of caffeine was suppressed by 0.5-1.0 mM-procaine or 10 mM-adenine, inhibitors of Ca2+-induced Ca2+ release. 5. In caffeine-treated preparations, peaks of light and tension were augmented by application of procaine (0.5-1.0 mM). Adenine (10 mM) affected the light signal in essentially the same way as procaine, but the effect varied from fibre to fibre. 6. From these results, the following hypothesis is proposed: low concentrations of caffeine directly induce Ca2+ release from sarcoplasmic reticulum (s.r.) in in the resting state, and facilitates Ca2+ release from s.r. induced by the action potential during twitch. At relatively higher concentrations of caffeine (0.6-1.5 mM), rise of resting [Ca2+]i (intracellular free Ca2+ concentration) before activation might be an important factor in twitch potentiation by caffeine. If the rise of resting [Ca2+]i induced by caffeine is inhibited by procaine and the content of Ca2+ in s.r. is well maintained, caffeine could facilitate Ca2+ release by depolarization and thus potentiate twitch tension.

Action Potentials↗
PubMed1989

Actions of caffeine on fast- and slow-twitch muscles of the rat.

1. The effects of caffeine (0.2-20 mmol l-1) have been examined on calcium transients (measured with aequorin) and isometric force in intact bundles of fibres from soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscles of the rat. 2. At 25 degrees C, threshold caffeine concentration for an observable increase in resting [Ca2+]i was 0.2 and 1.0 mmol l-1 for soleus and EDL muscles respectively. Increases in resting force were first detectable at about 0.5 mmol l-1 caffeine for soleus muscles and 5.0 mmol l-1 caffeine for EDL muscles and occurred in the range 0.2-0.4 mumol l-1 [Ca2+]i for soleus and 0.7-0.9 mumol l-1 for EDL. 3. Caffeine potentiated the twitch responses of soleus and EDL in a dose-related manner. The soleus was more sensitive in this respect, with 50% potentiation occurring at 1 mmol l-1 caffeine compared with 3.5 mmol l-1 for the EDL. Concentrations of caffeine below 2 mmol l-1 potentiated Ca2+ transients associated with twitches in both soleus and EDL muscles with no apparent change in the decay rate constant. 4. High concentrations of caffeine (greater than 2 mmol l-1) further potentiated peak Ca2+ in the EDL but depressed it in the soleus. The rate of decay of the Ca2+ transient in high caffeine was significantly prolonged in the soleus but remained unaffected in the EDL. 5. The phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) had little effect on force or [Ca2+]i at concentrations known to significantly increase intracellular cyclic AMP levels. 6. The Ca2+ transient during fused tetani was characterized by an initial peak, a decline to a plateau level and sometimes a gradual rise towards the end of the stimulus train. Peak [Ca2+]i during normal tetani ranged between 1.1 and 2.4 mumol l-1 in the soleus and 1.9 and 4.0 mumol l-1 in the EDL. 7. Caffeine potentiated both force and [Ca2+]i during tetanus. Since the increase of the Ca2+ transient was significantly greater than potentiation of force, it is likely that saturation of myofilaments occurs. The primary effect of caffeine on the Ca2+ transient was an elevation of the plateau phase. 8. Caffeine concentrations below 5 mmol l-1 potentiate twitch and tetanic force in both fast- and slow-twitch mammalian skeletal muscles primarily by increasing both the basal and stimulus-evoked release of Ca2+ from the sarcoplasmic reticulum.

Action Potentials↗
PubMed1992

Mechanisms of caffeine-induced contraction and relaxation of rat aortic smooth muscle.

1. Using front-surface fluorimetry and Fura-2, we determined the effects of caffeine on cytosolic calcium concentration ([Ca2+]i) and on tension of strips of the rat thoracic aorta. We also determined the effects of caffeine on 45Ca2+ influx into the strips. The objective was to elucidate the mechanism of contraction and relaxation in vascular smooth muscle, as induced by caffeine. 2. In normal physiological salt solution (PSS), caffeine induced a transient tension development, while it induced a biphasic change in [Ca2+]i. The initial transient peak in [Ca2+]i which coincided with tension development was followed by a sustained increase. Thus, changes in tension did not follow changes in [Ca2+]i. In Ca(2+)-free PSS, both the caffeine-induced contraction and the increase in [Ca2+]i were transient. It was suggested that in both the presence and absence of extracellular Ca2+, the transient increase in [Ca2+]i was due to the release of Ca2+ from the intracellular store. Although the sustained increase in [Ca2+]i depended on extracellular Ca2+, it was not affected by diltiazem, a Ca2+ antagonist. 3. Caffeine inhibited the increase in [Ca2+]i and tension development during 118 mM-K+ depolarization, in a concentration-dependent manner. The extent of reduction in tension (relaxation) was greater than that expected from the reduction in [Ca2+]i based on the [Ca2+]i-tension relationship observed with K+ depolarization. Pretreatment of the strips with ryanodine did not alter the inhibitory effects of caffeine. 4. Caffeine inhibited the increased [Ca2+]i and developed tension during stimulation by 10(-5) M-noradrenaline, in a concentration-dependent manner. 5. Dibutyryl cAMP (10(-4) M) inhibited both high K(+)-induced and noradrenaline-induced tension development. Inhibition of an increase in [Ca2+]i in relation to the inhibition of tension during noradrenaline stimulation was much greater than that in 118 mM-K+ depolarization. 6. Although caffeine per se had no effect on 45Ca2+ influx in the strips in normal PSS, caffeine did inhibit the increase in 45Ca2+ influx stimulated by 118 mM-K+ or by 10(-5) M-noradrenaline, to a similar extent and with similar IC50 values. 7. The characteristic features of the effects of caffeine on vascular smooth muscle, i.e. the transient nature of contraction and the relaxation of precontracted strips could be explained as follows: caffeine is able to reduce [Ca2+]i after releasing Ca2+ from intracellular stores; however, this may play a minor role. Independent of the [Ca2+]i reduction, the second messenger, cAMP, might directly influence the [Ca2+]i-tension relationship, and if so, would play a major role.

Animals↗