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PubMed1988

Caffeine consumption and blood pressure: an epidemiological study.

A cross-sectional survey of 5147 Australians attending a health screening clinic was conducted to determine if there was an association between habitual consumption of caffeine, or particular caffeine-containing beverages, and blood pressure. The average caffeine consumption of the study population was 240 mg/day. Caffeine consumption within the last three hours was found to be associated with significantly higher mean systolic and diastolic blood pressure in both sexes after controlling for age, adiposity, first degree relatives with hypertension, serum cholesterol level, alcohol consumption and tobacco smoking. Mean systolic and diastolic blood pressures differed significantly by 4 mmHg and 2 mmHg respectively for both males and females between those who had consumed caffeine within the last three hours and those who had not consumed it within the last nine hours (p less than 0.01). Average caffeine consumption per day was not associated with blood pressure in either sex after controlling for time since caffeine consumption. Logistic regression analysis was used to estimate the relative risk of high blood pressure (treated and untreated) for the groups consuming and not consuming caffeine in the last three hours. This relative risk was significantly greater than unity in females only (p less than 0.05). After controlling for time since caffeine consumption, caffeine consumption per day was not associated with significantly increased risk of high blood pressure.

Adult↗
PubMed1993

Association of delayed conception with caffeine consumption.

This cross-sectional study investigated the relation between intake of caffeine-containing beverages and time to conception in a population of 1,909 married women in New Haven, Connecticut, between May 12, 1980 and March 12, 1982. Women were interviewed shortly after the first prenatal visit regarding the length of time taken to conceive the index pregnancy, consumption of caffeine during pregnancy, and other exposures occurring prior to and during pregnancy. In logistic regression analyses, intake of caffeine from coffee, tea, and caffeinated soft drinks was associated with an increased risk of a delay of conception of 1 year or more. Compared with no caffeine use, consumption of 1-150 mg/day of caffeine resulted in an odds ratio for delayed conception of 1.39 (95% confidence interval (CI) 0.90-2.13), consumption of 151-300 mg/day of caffeine was associated with an odds ratio of 1.88 (95% CI 1.13-3.11), and that of over 300 mg/day (the equivalent of approximately three cups of coffee) resulted in an odds ratio of 2.24 (95% CI 1.06-4.73), after controlling for last method of birth control used, parity, and number of cigarettes per day. When the risk of conception for each cycle was examined using a discrete analogue of the Cox proportional hazards model, women who reported drinking over 300 mg/day of caffeine had a 27% lower chance of conceiving for each cycle, and those who reported drinking less than 300 mg/day had a 10% reduction in per cycle conception rates compared with women who consumed no caffeine. Risks for coffee, tea, and colas were examined simultaneously in logistic models and were found not to improve the fit of a model that contained a variable for total caffeine intake from all sources.

Beverages↗
PubMed1995

Effects of caffeine consumption on delayed conception.

The authors examined the effects of caffeine consumption on waiting time to conception in the Reproductive Health Study, a retrospective study of 1,430 non-contracepting, parous women interviewed between July 1989 and June 1990 at Fishkill, New York, and Burlington, Vermont. Information was obtained on 2,501 pregnancies since 1980. Women's reported consumption of caffeinated beverages during the first month of pregnancy was used to estimate daily caffeine intake, which was categorized as none, 1-150, 151-300, and > or = 301 mg. Information on delayed conception was analyzed as a dichotomous variable (< or = 12 months delay vs. > 12 months delay), and the per cycle probability of conception (fecundability) was estimated using waiting time to conception as a continuous variable. Odds ratios of delayed conception and fecundability ratios adjusted for age, parity, smoking, last contraceptive used, infertility history, and race, were estimated by logistic regression and Cox proportional hazard models, respectively. Women who did not smoke and who consumed no caffeine were used as a reference group. The adjusted odds ratio of delayed conception for more than one year was not increased among women who consumed < or = 300 mg of caffeine daily. However, the odds ratio (OR) was 2.65 (95% confidence interval (CI) 1.38-5.07) among nonsmokers who consumed > or = 301 mg of caffeine daily. Although smoking per se was associated with a significant increased risk of delayed conception (OR = 1.77, 95% CI 1.33-2.37), no effect of high caffeine consumption was observed among women who smoked. Fecundability was reduced among nonsmokers who consumed more than 300 mg caffeine daily (fecundability ratio = 0.74, 95% CI 0.59-0.92). Smoking reduced the fecundability ratio, but the authors observed no effect of caffeine consumption on fecundability among women who smoked. Other studies provide biologic plausibility for these findings. The authors conclude that high levels of caffeine consumption may result in delayed conception among women who do not smoke cigarettes.

Adult↗
PubMed2004

Caffeine intake in outpatients with schizophrenia.

Several studies suggest that caffeine intake is high in patients with schizophrenia and a few of them suggest that caffeine may contribute to schizophrenia symptomatology. None of these studies control for the effect of tobacco smoking, which is associated with induction of caffeine metabolism. Therefore, the high amount of caffeine intake among patients with schizophrenia may be due to their high prevalence of smoking. This is the first large study to explore whether caffeine intake in patients with schizophrenia is related to tobacco (or alcohol) use or to the severity of schizophrenia symptomatology. The sample included 250 consecutive consenting outpatients with a diagnosis of DSM-IV schizophrenia from Granada, Spain. Fifty-nine percent (147/250) of patients consumed caffeine. Current caffeine intake was associated with current smoking and alcohol use. As none of the females used alcohol, the association with alcohol was only present in males with schizophrenia. Among caffeine consumers, smoking was associated with the amount of caffeine intake. Cross-sectional schizophrenia symptomatology was not associated with caffeine intake.

Antipsychotic Agents↗
PubMed1990

Caffeine and halothane contracture testing in swine using the recommendations of the North American Malignant Hyperthermia Group.

Caffeine and halothane contracture testing is widely used to detect malignant hyperthermia (MH) susceptibility. The accuracy and reliability of the 3% halothane test and the incremental caffeine test, as recommended by the North American MH Group, were assessed in 11 swine (five MHS, six control). Nine swine were tested twice, 4-6 weeks apart. Accuracy of the in vitro diagnosis was also assessed by in vivo anesthetic challenge. Of all muscle bundles from MH-susceptible swine, 65% reacted positively to 3% halothane and 70% to 2 mM caffeine. Only 35% had a positive caffeine-specific concentration, and 25% developed an increase in baseline tension greater than or equal to 7% at 2 mM caffeine. However, when only the most positive response to 3% halothane or to 2 mM caffeine was used (a minimum of three fresh muscle strips is recommended), these two tests were highly sensitive and specific. In control swine one of 30 muscle bundles reacted positively to 3% halothane. A positive caffeine-specific concentration developed in one of 25 control muscle bundles exposed to caffeine. The variability in the results of these tests mandated that at least three muscle bundles be used for each test. Nonviable muscle bundles could not be relied upon to provide accurate results. In this porcine model, MH susceptibility could be detected by performing the Caffeine Halothane Contracture Test (CHCT) according to the guidelines of the North American MH Group. However, only the 3% halothane test and the response to 2 mM caffeine produced adequate diagnostic results in this breed of swine.

Animals↗
PubMedDate not supplied

Caffeine effects on learning, performance, and anxiety in normal school-age children.

OBJECTIVE: The purpose of this investigation was to study the acute effects of caffeine on learning, performance, and anxiety in normal prepubertal children. METHOD: Twenty-one children were evaluated in a double-blind, placebo-controlled crossover design. Subjects were studied during four sessions, 1 week apart, under the following conditions: baseline, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine. Subjects were randomized to order of placebo and the two dosages of caffeine. Dependent measures included tests of attention, manual dexterity, short-term memory, and processing speed. Anxiety rating scales were also administered. Saliva samples were analyzed for caffeine levels. RESULTS: Caffeine improved performance on two of four measures of the Test of Variables of Attention and on a test of manual dexterity in the dominant hand. There was a trend toward increased current level of self-reported anxiety after caffeine on a visual analogue measure of anxiety. Children reported feeling significantly less "sluggish" after caffeine ingestion than after placebo ingestion. CONCLUSIONS: In a small sample size, there was indication that caffeine enhanced performance on a test of attention and on a motor task. Children also reported feeling less "sluggish" but somewhat more anxious. Because caffeine is so widely available and frequently consumed by children, these results are important and need replication.

Anxiety↗
PubMed1998

Caffeine withdrawal in normal school-age children.

OBJECTIVE: Caffeine is widely consumed by children around the world. The purpose of this study was to determine whether children manifest withdrawal effects after cessation of caffeine intake. METHOD: Thirty normal children completed the single-blind, within-subjects, repeated-measures study with weekly sessions. Subjects were tested four times: (1) baseline (on regular caffeine diet); (2) on caffeine (approximately 120 to 145 mg/day); (3) during withdrawal (24 hours after discontinuation of caffeine taken for 13 consecutive days); and (4) at return to baseline. Subjects were evaluated with self-report measures of symptoms and objective measures of attention, motor performance, processing speed, and memory. RESULTS: During caffeine withdrawal, there was a significant deterioration on response time of a visual continuous performance test of attention. This finding is consistent with caffeine withdrawal. The deterioration in response time appeared to persist for 1 week. CONCLUSIONS: Twenty-four hours after children discontinued caffeine, there was a decrease in performance on reaction time of a task requiring sustained attention. Further work is indicated to determine whether children manifest caffeine withdrawal effects after cessation of caffeine intake.

Analysis of Variance↗
PubMedDate not supplied

Use of salivary levels to predict clearance of caffeine in patients with cystic fibrosis.

The quantification of liver function is possible using the approach of salivary caffeine clearance. Hepatopathy sometimes complicates cystic fibrosis (CF), thus suggesting the use of this diagnostic tool in CF as well. Since in CF some compounds are poorly absorbed or abnormally metabolized, and the function of salivary glands or renal tubuli partly impaired, caffeine was measured in urine, blood, and saliva after a single oral dose of 3 mg/kg in CF patients. The urinary excretion rate of caffeine was normal in five CF patients. The caffeine levels in plasma or saliva, measured 4 to 5 h and 16 to 17 h after caffeine intake, were normal in 34 nonhepatopatic CF patients. The calculated salivary caffeine clearance was comparable in the 34 nonhepatopatic CF patients (1.88 +/- 0.46 ml/min/kg) and in the control group (1.88 +/- 0.44 ml/min/kg). In CF patients, no correlation was found between caffeine clearance and body weight, height, relative underweight, dosage of pancreatic enzymes, or Chrispin-Norman x-ray score. The salivary caffeine clearance was reduced in seven hepatopathic CF patients (1.32 +/- 0.63 ml/min/kg, p less than 0.01); nevertheless, the salivary caffeine clearance was reduced (boundary line at 1.1 ml/min/kg) in three CF patients with proven liver cirrhosis but not in four with hepatosplenomegaly and altered liver tests. These data indicate an unaltered caffeine metabolism in CF and open the way for the use of this diagnostic procedure in CF as well. This test might be valuable in CF patients with clinical or laboratory findings suggesting liver involvement.

Adolescent↗
PubMed2000

Time for abstention from caffeine before an adenosine myocardial perfusion scan.

Seventy patients undergoing adenosine myocardial perfusion scintigraphy were studied. All patients reported abstention from products containing caffeine in the 12 h prior to the test. Blood samples were drawn prior to initiation of the stress test, and serum caffeine levels were determined using high-performance liquid chromatography. All patients were also asked about their coffee and tea drinking habits. Seventy-four percent of patients had measurable serum caffeine levels (n = 52) ranging from 0.1 to 8.8 mg.l-1. Results were correlated with maximum pulse rate, systolic and diastolic blood pressure changes and clinical symptoms during the test. There was no correlation between coffee or tea drinking habits and serum caffeine levels. A serum caffeine level of 2.9 mg.l-1 was considered a cut-off point for comparing patients. No significant difference was seen in mean maximum change of pulse rate, systolic and diastolic blood pressure between patients with serum caffeine levels > or = 2.9 mg.l-1 and those with lower serum caffeine levels. Of eight patients with serum caffeine levels > or = 2.9 mg.l-1, six had no symptoms (75%). When patients were classified as patients with no symptoms or patients with symptoms (mild, moderate or severe), a significant difference was demonstrated between patients with serum caffeine levels > or = 2.9 mg.l-1 and those with lower levels. This suggests 12 h abstention from caffeine may be insufficient. Whether this translates into false-negative perfusion scans should be the subject of a larger study.

Adenosine↗
PubMed1998

Evaluation of pharmacokinetic methods used to estimate caffeine clearance and comparison with a Bayesian forecasting method.

Simplified pharmacokinetic methods have been used to estimate caffeine clearance in subjects with liver disease. There is a need to have a reliable, easy to implement method for research and possible clinical use. This study evaluates the use of Bayesian pharmacokinetic forecasting techniques to estimate caffeine clearance and compares its performance to other published methods. Commonly used published methods include the two-concentration overnight salivary clearance method (Jost method) and a method that samples caffeine concentrations over a 4-hour time period (Nagel method). Both have been used in studies incorporating serial measurements of caffeine clearance to predict clinical outcomes in subjects with liver disease, but these approaches have not been proven useful. However, neither method has been formally evaluated for accuracy in estimating caffeine clearance in subjects with cirrhosis. The performance of the Jost, Nagel, and Bayesian methods was compared to a Gold Standard method that accurately measured caffeine clearance in healthy subjects and subjects with cirrhosis using an intravenous infusion of stable isotope-labeled caffeine. The Bayesian method, even when only one measured concentration of caffeine was used, was more accurate, better correlated to the Gold Standard method, and had less intraindividual variation than the two previously published methods. Before the idea of using serial measurements of caffeine clearance for clinical usefulness is rejected, a reevaluation using methods of estimating caffeine clearance that are more accurate than previous paradigms is needed.

Bayes Theorem↗
PubMed2002

Influence of the urine flow rate on some caffeine metabolite ratios used to assess CYP1A2 activity.

Five established metabolite ratios (MRs) to measure P450 CYP1A2 activity--MR1 (17X + 17U)/137X, MR2 (AFMU + 1X + 1U)/17U, MR3 (17X/137X), MR4 (AFMU + 1X + 1U + 17X + 17U)/137X, and MR5 (AFMU + 1X + 1U)/17X--were calculated in urine 4-5 hours after caffeine intake. First, to assess the potential of omeprazole to induce CYP1A2 activity, a caffeine test was performed in 27 subjects on two occasions: before and after 14 days on omeprazole (20 mg/day). Samples of urine were analyzed by high-performance liquid chromatography (HPLC) to quantify caffeine and metabolites used to calculate the different caffeine MRs. MR1, MR3, and MR4 were enhanced after treatment; the percentage of change was inversely associated with that of the urine flow, with r values of -0.48, -0.49, and -0.47, respectively. However, MR2 or MR5 were not modified. To determine the reason for these contradictory results, the authors analyzed data of metabolites, ratios, and their components (numerators and denominators) from 152 subjects (who underwent one caffeine test) and their relationship with the urinary flow. Caffeine concentration in urine was the only compound nondependent on the urine flow. Consistently, ratios containing caffeine (MR1, MR3, and MR4) were highly influenced by the rate of urine excretion, since the flow dependence of their numerators is not canceled out by that of caffeine in their denominators. The dependency of the caffeine excretion on renal factors may explain the opposite results found with the different ratios in the aforementioned prospective study of drug interaction, the absence of closer correlations of the five MRs to each other, the discrepancies about the type of frequency distribution of the different MRs (either normal or multimodal), and the higher sensitivity of MR2 to detect gender differences in CYP1A2 activity found in this study. In summary, the data clearly emphasize the need for a strict control of the liquid intake to avoid high urine flows when MRs containing caffeine are used to assess CYP1A2 activity, especially in studies of drug interactions.

Adolescent↗
PubMed2006

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans.

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine. Eight healthy volunteers were included in our study. A total of 300 mg of caffeine was given on 2 occasions, once alone and once during the coadministration of 300 mg propafenone. Serial blood samples were collected and pharmacokinetic parameters were estimated using a population pharmacokinetic approach. A one-compartment PK model with first-order absorption and elimination described plasma concentration profiles. Concomitant administration of propafenone decreased caffeine oral clearance from 8.3 +/- 0.9 L/h to 5.4 +/- 0.7 L/h (P < 0.05). Elimination half-life of caffeine was also increased 54% by propafenone. One of our volunteers was a poor metabolizer of CYP2D6. Concomitant administration of propafenone to this volunteer caused the greatest increase in caffeine plasma concentrations. These results support the concept of competitive inhibition between propafenone and caffeine. Our results suggest that propafenone causes significant inhibition of CYP1A2 activity leading to a decrease in the clearance of caffeine. Caffeine has intrinsic proarrhythmic effects; thus, its coadministration with an antiarrhythmic agent such as propafenone should be used with caution, especially in patients with poor CYP2D6 activity.

Adolescent↗
PubMed1989

Self-report reliability and symptomatology of habitual caffeine consumption.

1. A large body of research on the demography of caffeine use and its potential health consequences has been undermined by the absence of empirical data on the reliability of retrospective self-reports of caffeine consumption. 2. The principal aim of the present study was to use standard bioanalytic method to assess the reliability of subjects' self-reported caffeine use. Saliva samples were obtained from 142 first-and second-year medical students and assayed for caffeine and paraxanthine. 3. Self-reported caffeine use was found to be significantly correlated with salivary caffeine (r = 0.31, P less than 0.001) and paraxanthine (r = 0.42, P less than 0.001), thereby providing qualified support for use of questionnaires to estimate patterns of caffeine consumption. 4. A secondary aim of the study was to extend previous research concerning the symptomatology of caffeine use by examining the association between caffeine exposure and a variety of measures of somatic and psychological health. Caffeine consumption was reliably associated with the self-reported occurrence of somatic symptoms, but not psychological well-being.

Adolescent↗
PubMed1997

Theophylline has no advantages over caffeine as a putative model drug for assessing CYPIA2 activity in humans.

AIMS: The cytochrome P4501A2 (CYP1A2) catalyses the metabolism of a number of clinically used drugs, and thus there is an interest in determining the activity of CYP1A2 in patients before treatment with CYP1A2 substrates. Caffeine is the most commonly used model drug to assess CYP1A2 function, but due to the complex metabolism of caffeine, there is a need for an alternative drug to use as an index of CYP1A2 activity. In this study the CYP1A2 substrate theophylline was tested as a possible alternative to caffeine as a model drug for CYP1A2. METHODS: Twelve healthy volunteers ingested 200 mg of caffeine, and the caffeine metabolic ratios (CMR), CMRurine = (AFMU + 1MX + 1MU)/17DMU and CMRplasma = 17DMX/137TMX were determined 6 h after drug intake. After a period of about 2 months the volunteers ingested 257 mg theophylline and blood samples were drawn and urine was collected during the following 48 h. The oral and partial clearance of theophylline were calculated via N-demethylation and 8-hydroxylation. The theophylline metabolic ratios, 1MU/13DMX and 3MX/13DMX being evaluated as indices of CYP1A2 catalysed N-demethylation and 13DMU/13DMX as an index of partly CYP1A2 catalysed 8-hydroxylation, were estimated in 0-12 h, 0-24 h and 0-48 h urine samples, and in plasma and spot urine samples 6 h after the intake of theophylline. RESULTS: The theophylline plasma ratios for the N-demethylation pathways correlated with the oral clearance of theophylline (rs = 0.881-0.934, P < 0.001) and with the respective formation clearances of the metabolites (rs = 0.712-0.925, P < 0.05). Furthermore, all of the theophylline plasma ratios correlated with the caffeine plasma ratio (rs = 0.645-0.663, P < 0.05). None of the caffeine metabolic ratios and none of the 6 h urinary theophylline ratios correlated with the oral or the partial clearances of theophylline (rs = 0.042-0.556, P < 0.05). The theophylline 0-12 h urine ratios correlated with the oral clearance of theophylline (rs = 0.677-0.757, P < 0.05) and with the respective formation clearances of the metabolites (rs = 0.705-0.750, P < 0.05). However, none of the theophylline urine ratios correlated with any of the caffeine metabolic ratios. CONCLUSIONS: In summary the theophylline 6 h plasma and 0-12 h urine ratios 1MU/13DMX and 3MX/13DMX, both reflecting N-demethylation seem to be predictors of the CYP1A2 mediated metabolism of theophylline, whereas only the plasma ratio correlated with the caffeine plasma 17DMX/13TMX ratio. Thus, it would appear that the plasma theophylline N-demethylation ratios are superior to the urine ratios as indices of CYP1A2 activity. However, because in some individuals the concentrations of theophylline metabolites in plasma were close to the limit of detection, it is concluded that theophylline does not have marked advantages over caffeine as a model drug for assessing CYP1A2 activity.

Adult↗
PubMed2006

Investigating the caffeine effects in the yeast Saccharomyces cerevisiae brings new insights into the connection between TOR, PKC and Ras/cAMP signalling pathways.

Caffeine is a natural purine analogue that elicits pleiotropic effects leading ultimately to cell's death by a largely uncharacterized mechanism. Previous works have shown that this drug induces a rapid phosphorylation of the Mpk1p, the final mitogen-activated protein (MAP) kinase of the Pkc1p-mediated cell integrity pathway. In this work, we showed that this phosphorylation did not necessitate the main cell wall sensors Wsc1p and Mid2p, but was abolished upon deletion of ROM2 encoding a GDP/GTP exchange factor of Rho1p. We also showed that the caffeine-induced phosphorylation of Mpk1p was accompanied by a negligible activation of its main downstream target, the Rlm1p transcription factor. This result was consolidated by the finding that the loss of RLM1 had no consequence on the increased resistance of caffeine-treated cells to zymolyase, indicating that the cell wall modification caused by this drug is largely independent of transcriptional activation of Rlm1p-regulated genes. Additionally, the transcriptional programme elicited by caffeine resembled that of rapamycin, a potent inhibitor of the TOR1/2 kinases. Consistent with this analysis, we found that the caffeine-induced phosphorylation of Mpk1p was lost in a tor1Delta mutant. Moreover, a tor1Delta mutant was, like mutants defective in components of the Pkc1p-Mpk1p cascade, highly sensitive to caffeine. However, the hypersensitivity of a tor1 null mutant to this drug was rescued neither by sorbitol nor by adenine, which was found to outcompete caffeine effects specially on mutants in the PKC pathway. Altogether, these data indicated that Tor1 kinase is a target of caffeine, whose inhibition incidentally activates the Pkc1p-Mpk1p cascade, and that the caffeine-dependent phenotypes are largely dependent on inhibition of Tor1p-regulated cellular functions. Finally, we found that caffeine provoked, in a Rom2p-dependent manner, a transient drop in intracellular levels of cAMP, that was followed by change in expression of genes implicated in Ras/cAMP pathway. This result may pose Rom2p as a mediator in the interplay between Tor1p and the Ras/cAMP pathway.

Benzenesulfonates↗
PubMed1988

Caffeine- and potassium-induced contractures of mouse isolated soleus muscle: effects of verapamil, manganese, EGTA and calcium withdrawal.

1. The effects of verapamil, manganese, EGTA and Ca2+-withdrawal on caffeine and potassium-induced contractures of the mouse isolated soleus muscle have been studied. All four treatments profoundly inhibited, in concentration-dependent manner, both K+- and caffeine-induced contractures, and recovery from these treatments was slight. 2. Caffeine (5.14-51.4 mmol/l), elicited biphasic contractures, characterized by an initial phasic, and subsequent tonic contractures. K+-induced contractures were monophasic except at the higher concentrations (53.4-214 mmol/l), when biphasic responses were also recorded. The biphasic K+ contracture had a time course similar to the caffeine-induced response. 3. Both phases of the caffeine and K+ responses were abolished by the introduction of CA2+-free Krebs'-Henseleit solution (KHS). Increasing [Ca2+]0 from 1 to 5 mmol/l, markedly inhibited the amplitude of caffeine and K+ contractures. 4. In high [K+]0 KHS, peak contractures to caffeine were reduced to about 50% of those in normal KHS. In the presence of 15.4 mmol/l caffeine, the responses to lower concentrations of K+ (13.4-26.8 mmol/l) increased, while responses evoked by the higher K+ concentrations were depressed compared with controls in normal KHS. 5. Pancuronium or D-tubocurarine severely inhibited caffeine-induced contractures, but only slightly inhibited K+-induced responses. 6. It is suggested that both caffeine- and K+-induced contractures of the mouse soleus are dependent upon the presence of [Ca2+]0, and that these contractures possibly occurred as a result of extracellular Ca2+-influx.

Animals↗
PubMedDate not supplied

Effect of caffeine on response of rabbit isolated corpus cavernosum to high K+ solution, noradrenaline and transmural electrical stimulation.

1. Caffeine has wide-ranging activities on smooth muscles, including contractile and relaxant effects. The aim of the present study was to examine the activity of caffeine on rabbit corpus cavernosum (RCC). 2. The effects of caffeine (0.5-4.0 mmol/L) on the response of RCC to high K+ solution, noradrenaline (NA) and transmural electrical stimulation (EFS) were studied in a tissue bath system. 3. Caffeine did not contract the RCC. However, 0.5-4.0 mmol/L caffeine caused concentration-dependent relaxation of tension development in high-K+ (120 mmol/L) solution in contrast with the solvent control. At 4.0 mmol/L caffeine, high-K+ solution-induced tone of the RCC was reduced by 73.4 +/- 7.3%. Caffeine (0.5-4.0 mmol/L) also concentration-dependently relaxed NA (12.5 micro mol/L)-induced tonic contraction of the RCC. At 4.0 mmol/L caffeine, NA-induced tone of the RCC was reduced by 41.1 +/- 7.0%. Incubation of RCC in 2.0 mmol/L caffeine for 30 min prior to EFS (1-40 Hz) caused a marked rightward shift in the frequency-response curve. 4. The results of the present study suggest that caffeine exhibits relaxant activity on rabbit cavernosal smooth muscle and the mechanism of this activity possibly involves inhibition of Ca2+ signalling.

Adrenergic alpha-Agonists↗
PubMed1995

Properties of the ryanodine-sensitive release channels that underlie caffeine-induced Ca2+ mobilization from intracellular stores in mammalian sympathetic neurons.

The most compelling evidence for a functional role of caffeine-sensitive intracellular Ca2+ reservoirs in nerve cells derives from experiments on peripheral neurons. However, the properties of their ryanodine receptor calcium release channels have not been studied. This work combines single-cell fura-2 microfluorometry, [3H]ryanodine binding and recording of Ca2+ release channels to examine calcium release from these intracellular stores in rat sympathetic neurons from the superior cervical ganglion. Intracellular Ca2+ measurements showed that these cells possess caffeine-sensitive intracellular Ca2+ stores capable of releasing the equivalent of 40% of the calcium that enters through voltage-gated calcium channels. The efficiency of caffeine in releasing Ca2+ showed a complex dependence on [Ca2+]i. Transient elevations of [Ca2+]i by 50-500 nM were facilitatory, but they became less facilitatory or depressing when [Ca2+]i reached higher levels. The caffeine-induced Ca2+ release and its dependence on [Ca2+]i was further examined by [3H]ryanodine binding to ganglionic microsomal membranes. These membranes showed a high-affinity binding site for ryanodine with a dissociation constant (KD = 10 nM) similar to that previously reported for brain microsomes. However, the density of [3H]ryanodine binding sites (Bmax = 2.06 pmol/mg protein) was at least three-fold larger than the highest reported for brain tissue. [3H]Ryanodine binding showed a sigmoidal dependence on [Ca2+] in the range 0.1-10 microM that was further increased by caffeine. Caffeine-dependent enhancement of [3H]ryanodine binding increased and then decreased as [Ca2+] rose, with an optimum at [Ca2+] between 100 and 500 nM and a 50% decrease between 1 and 10 microM. At 100 microM [Ca2+], caffeine and ATP enhanced [3H]ryanodine binding by 35 and 170% respectively, while binding was reduced by > 90% with ruthenium red and MgCl2. High-conductance (240 pS) Ca2+ release channels present in ganglionic microsomal membranes were incorporated into planar phospholipid bilayers. These channels were activated by caffeine and by micromolar concentrations of Ca2+ from the cytosolic side, and were blocked by Mg2+ and ruthenium red. Ryanodine (2 microM) slowed channel gating and elicited a long-lasting subconductance state while 10 mM ryanodine closed the channel with infrequent opening to the subconductance level. These results show that the properties of the ryanodine receptor/Ca2+ release channels present in mammalian peripheral neurons can account for the properties of caffeine-induced Ca2+ release. Our data also suggest that the release of Ca2+ by caffeine has a bell-shaped dependence on Ca2+ in the physiological range of cytoplasmic [Ca2+].

Adrenergic Fibers↗