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PubMed1989

Correlation of caffeine elimination and Child's classification in liver cirrhosis.

Apparent pharmacokinetic parameters of caffeine elimination from the circulation were determined in 27 patients with histologically confirmed liver cirrhosis, 8 patients with miscellaneous liver disease, and 8 patients with other than liver disease. The usefullness of this quantitative test to assess the severity of liver cirrhosis was compared to the Child-Turcotte or Child-Pugh classification score as well as to the galactose elimination capacity of these patients. Using reversed-phase high pressure liquid chromatography caffeine, paraxanthine, theophylline, and theobromine were analysed in blood plasma collected before and after an oral dose of caffeine. Compared to apparent caffeine pharmacokinetics in patients with normal livers or miscellaneous liver disease, cirrhosis was characterized by a statistically significant reduction in apparent caffeine clearance and prolongation in half-life. The reduced apparent plasma disappearance rate of caffeine in cirrhotics was related to the retarded formation of paraxanthine which was the main metabolite of caffeine in blood plasma both in the absence or presence of liver disease. The apparent caffeine clearance in cirrhosis decreased with increasing Child-Turcotte classification score: Child's class A patients differed significantly from Child's class B or Child's class C patients, whereas the difference between Child's class B and C patients did not reach statistical significance (Wilcoxon's rank test). In addition there was a strong correlation between the Child-Pugh classification score and apparent caffeine clearance (P less than 0.001). However, no correlation existed between Child's classification and galactose elimination capacity. Our data emphasize the value of the Child-Turcotte or Child-Pugh classification in assessing the severity of liver cirrhosis in a simpler and less time-consuming way than using quantitative liver function tests.

Administration, Oral↗
PubMed1990

Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo.

CD-1 mice received single intraperitoneal (IP) doses of caffeine-sodium benzoate (caffeine doses: 0, 20 and 40 mg/kg) followed by injections of alprazolampropylene glycol (0, 0.05, and 2 mg/kg, IP) to determine brain concentrations, effects on in vivo receptor binding of a specific high-affinity benzodiazepine receptor ligand [3H]Ro15-1788, and effects on motor activity over a 1-h period. A behavioral monitoring device, using infrared sensors, measured horizontal and ambulatory activity. Caffeine produced significant increases in all motor activity measures as compared to vehicle treatment, with low dose caffeine (with brain concentrations of 13 micrograms/g) stimulating activity to a greater degree than the high dose (with brain concentrations of 30 micrograms/g). The overall effect of caffeine on benzodiazepine receptor binding was not significant. Alprazolam significantly diminished motor activity and altered benzodiazepine receptor binding. Low dose alprazolam increased binding, while the high dose diminished it. Caffeine and alprazolam antagonized each other's behavioral effects in this study, but did not alter each other's uptake into brain. Alprazolam's antagonism of caffeine-induced motor stimulation was associated with decreases in receptor binding, whereas caffeine's reversal of alprazolam-induced motor depression was not associated with any changes in binding. The lack of a clear association between drug effects on benzodiazepine binding and on motor activity suggests that behavioral effects of caffeine and alprazolam may be mediated by other sites in addition to the benzodiazepine receptor.

Alprazolam↗
PubMed1996

Alprazolam, caffeine and their interaction: relating DRL performance to pharmacokinetics.

Three-hour sessions of differential reinforcement of low-rate behavior (DRL 45-s) in rats were used to investigate alprazolam, caffeine, and their interactions at the onset, peak and disappearance of serum alprazolam, while caffeine level remained constant. The dose-response curve (DRC) method of Pöch permitted an extensive evaluation of the kind (additivity or independence) of interactions occurring in combined drug effects. The alprazolam and caffeine DRCs were used to derive theoretical additive and independent relations, and the observed combined effects compared to these functions. Behavior-time profiles of the combined effects were similarly compared. Serum alprazolam and caffeine concentrations correlated with their respective behavior-time profiles. No acute tolerance was observed either for the individual drugs or their combinations. Alprazolam was more potent than caffeine in disrupting DRL behavior. Because alprazolam is much shorter-lived (t1/2 = 32 min) than caffeine (t1/2 = 3 h) in rats, potency ratios between alprazolam and caffeine changed across session time (from 123 to 4), which determined the expression of the combined effects. Although the combined effects were not distinguishable in terms of additivity or independence in both the DRCs and in the behavior-time profiles, they showed neither synergism nor antagonism. The pharmacokinetics of alprazolam were not altered by caffeine, but those of caffeine were affected by alprazolam.

Alprazolam↗
PubMed1996

Acute and repeated exposure to caffeine: effects on reinstatement of extinguished cocaine-taking behavior in rats.

Previously, we demonstrated that caffeine dose-dependently reinstated extinguished cocaine-taking behavior in rats. In the present study, we determined whether this effect of caffeine would extinguish with repeated exposures. Rats were first trained to self-administered cocaine intravenously. Once reliable self-administration was obtained, the pumps that delivered cocaine were turned off and the lever-pressing behavior was extinguished. Every 4 days the rats were given an injection of caffeine (20.0 mg/kg) and its ability to reinstate responding was measured. Some rats received each of four exposures to caffeine in the previously cocaine-associated environment. Other rats received the first three exposures to caffeine in the home cage and the last exposure to caffeine in the previously cocaine-associated environment. The results indicated that although caffeine was an effective cue for reinstatement of extinguished cocaine taking, the effect was reduced when repeated exposures occurred in the test environment. In addition, when 4 drug-free days were interspersed between self-administration and reinstatement testing, the caffeine effect was greater than when testing was conducted 1 day following the last self-administration session. Thus, extended withdrawal increases the priming effects of caffeine. The results are discussed in terms of the effectiveness of cue exposure as an adjunct to current therapies for cocaine abuse.

Analysis of Variance↗
PubMed1991

Studies on secretion of catecholamine evoked by caffeine from the isolated perfused rat adrenal gland.

The influence of caffeine on secretion of catecholamines (CA) was examined in the isolated perfused rat adrenal gland. Caffeine (0.3 mM) perfused into an adrenal vein of the gland produced a marked increase in secretion of CA. This secretory effect of CA evoked by perfusion of caffeine for one minute was considerably prolonged, lasting for more than 90 minutes. The tachyphylaxis to releasing effect of CA induced by caffeine was observed by repeated perfusion of this drug. The caffeine-evoked CA secretion was markedly inhibited by pretreatment with ouabain, trifluoperazine, TMB-8 and perfusion with calcium-free Krebs solution containing 5 mM EGTA, but was not affected by perfusion of calcium-free Krebs solution without other addition. CA secretion evoked by caffeine was not reduced significantly by pretreatment with chlorisondamine but after the first collection of perfusate for 3 min was clearly inhibited. Interestingly, the caffeine-evoked CA secretion was considerably potentiated by pretreatment with atropine or pirenzepine, but after the first collection for 3 min it was markedly decreased. These experimental results suggest that caffeine causes a marked increase in secretion of CA from the isolated perfused rat adrenal gland by an extracellular calcium-independent exocytotic mechanism. The secretory effect of caffeine may be mainly due to mobilization of calcium from an intracellular calcium pool in the rat chromaffin cells and partly due to stimulation of both muscarinic and nicotinic receptors.

Adrenal Glands↗
PubMed1995

Perioperative administration of caffeine tablets for prevention of postoperative headaches.

Interruption of daily caffeine consumption can cause caffeine withdrawal headache. As headache ranks among the most frequent minor postoperative sequelae, the impact of perioperative substitution of caffeine on the incidence of postoperative headache was evaluated. Forty patients undergoing minor surgical procedures with general anaesthesia were randomly allocated to receive either placebo or caffeine tablets at a dosage equal to their individual average daily caffeine consumption. Daily dietary intake was calculated based on an average week-day consumption using conversion factor from previously published sources. The patients were instructed at the preoperative visit to abstain from all external sources of caffeine. Compliance with these dietary restrictions was verified by blood samples obtained immediately before the surgical procedure and on postoperative day 1. The patients were assessed for headache using a standardised checklist immediately before induction of anaesthesia, on the evening of the day of surgery and on the morning of postoperative day 1. Ten patients (50%) who received placebo reported headaches, which persisted in seven patients (35%) until the next day. No patient receiving caffeine substitution therapy reported headache following surgery, and only one complained of headache on postoperative day 1. We suggest that the prophylactic administration of caffeine tablets might be considered for surgical patients who are accustomed to a high daily intake of caffeine.

Adult↗
PubMed2002

Effects of caffeine on mood and performance: a study of realistic consumption.

RATIONALE: There is a vast literature on the behavioural effects of caffeine. Many of the studies have involved single administration of a large dose of caffeine that is not representative of the way in which caffeine is usually ingested. Further information is required, therefore, on the behavioural effects of realistic patterns of consumption. OBJECTIVES: The present study aimed to determine whether a realistic drinking regime (multiple small doses - 4 x 65 mg over a 5-h period) produced the same effects as a single large dose (200 mg). The smaller doses were selected so that the amount of caffeine present in the body after 5 h would be equivalent to that found with the single dose. METHODS: A double-blind, placebo-controlled, within-subjects experiment was, therefore, carried out. The participants ( n=24) attended for four sessions. Each session started with a baseline measurement of mood and performance at 0930 hours. On two of the sessions, coffee was then consumed at 1000, 1100, 1200 and 1300 hours. In one of these sessions 65 mg caffeine was added to the de-caffeinated coffee. In the other two sessions, the participants consumed coffee at 1300 hours and 200 mg caffeine was added in one of the sessions. The volunteers completed the battery of tests again at 1500 hours. RESULTS: The results showed that in both consumption regimes caffeine led to increased alertness and anxiety and improved performance on simple and choice reactive tasks, a cognitive vigilance task, a task requiring sustained response and a dual task involving tracking and target detection. CONCLUSIONS: These results suggest that previous findings from studies using a large single dose may be applicable to normal patterns of caffeine consumption.

Adult↗
PubMed2002

Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U.S. Navy SEAL training. Sea-Air-Land.

RATIONALE: When humans are acutely exposed to multiple stressors, cognitive performance is substantially degraded. Few practical strategies are available to sustain performance under such conditions. OBJECTIVE: This study examined whether moderate doses of caffeine would reduce adverse effects of sleep deprivation and exposure to severe environmental and operational stress on cognitive performance. METHODS: Volunteers were 68 U.S. Navy Sea-Air-Land (SEAL) trainees, randomly assigned to receive either 100, 200, or 300 mg caffeine or placebo in capsule form after 72 h of sleep deprivation and continuous exposure to other stressors. Cognitive tests administered included scanning visual vigilance, four-choice visual reaction time, a matching-to-sample working memory task and a repeated acquisition test of motor learning and memory. Mood state, marksmanship, and saliva caffeine were also assessed. Testing was conducted 1 and 8 h after treatment. RESULTS: Sleep deprivation and environmental stress adversely affected performance and mood. Caffeine, in a dose-dependent manner, mitigated many adverse effects of exposure to multiple stressors. Caffeine (200 and 300 mg) significantly improved visual vigilance, choice reaction time, repeated acquisition, self-reported fatigue and sleepiness with the greatest effects on tests of vigilance, reaction time, and alertness. Marksmanship, a task that requires fine motor coordination and steadiness, was not affected by caffeine. The greatest effects of caffeine were present 1 h post-administration, but significant effects persisted for 8 h. CONCLUSIONS: Even in the most adverse circumstances, moderate doses of caffeine can improve cognitive function, including vigilance, learning, memory, and mood state. When cognitive performance is critical and must be maintained during exposure to severe stress, administration of caffeine may provide a significant advantage. A dose of 200 mg appears to be optimal under such conditions.

Adult↗
PubMed2005

A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors.

RATIONALE: There is no consensus on the contribution of adenosine A(1) and A(2A) receptor blockade to motor-activating effects of caffeine. OBJECTIVE: Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A(1) and A(2A) receptor antagonists. METHODS: The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A(1) receptor agonist N (6)-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined. RESULTS: The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3. CONCLUSIONS: The results indicate a predominant role for A(1) receptors in the motor-activating effects of acutely administered caffeine.

Adenosine↗
PubMed1997

Independent interaction of alprazolam and caffeine under chronic dose regimens on differential reinforcement of low-rate (DRL 45-s) performance.

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.

Alprazolam↗
PubMed1999

Caffeine and prepulse inhibition of the acoustic startle reflex.

RATIONALE: A stimulus presented immediately prior to a startle reflex-eliciting stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI) and is postulated to index automatic and controlled attentional processing of the prepulse. OBJECTIVE: Two experiments investigated the effect of 0, 2, and 4 mg/kg oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic prepulses were used and automatic attention was investigated, whereas in experiment 2, acoustic and tactile prepulses were used and automatic and controlled attention was investigated. Controlled attention was investigated by instructing the subjects to attend to one stimulus (attended stimulus) and not to another stimulus (non-attended stimulus). METHODS: Caffeine was administrated to human subjects in within-subjects designs (n = 24 and n = 18). Startle reflexes to 100 dB noise were recorded by electromyography. A mood scale and readings of blood pressure indexed arousal. RESULTS: Caffeine increased the indexes of arousal. There were, however, no significant main effects of caffeine on startle, nor did caffeine significantly interact with any other variable. Attended acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg abolished this difference between attended and non-attended stimuli. Attended tactile prepulses facilitated startle at short SOAs, and caffeine reduced facilitation of startle by tactile prepulses. CONCLUSIONS: Caffeine did not facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of controlled attention on PPI. Facilitation of startle by attended acoustic prepulses is best explained by facilitation of motoneurons in the facial nucleus.

Acoustic Stimulation↗
PubMed2004

Phenotyping of N-acetyltransferase type 2 by caffeine from uncontrolled dietary exposure.

BACKGROUND AND OBJECTIVE: The standard approach for phenotyping of the human arylamine N-acetyltransferase 2 (NAT2) uses urinary caffeine metabolite ratios after a caffeine test dose taken in after methylxanthine abstinence. We tested whether these standardization measures were still needed when a more sensitive quantification technique was used. METHODS: A new liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the quantification of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U) was developed. Urine samples from 77 healthy volunteers collected before and 5-6 h after oral intake of 150-200 mg caffeine were analyzed. The lower limits of quantification were 0.1 microg/ml for caffeine, 1X, 1U, and AFMU, and 0.2 microg/ml for AAMU. RESULTS: The urinary NAT2 ratios (AFMU+AAMU) / (AFMU+AAMU+1X+1U) before and after caffeine intake correlated well in 65 volunteers (r(2)=0.827; P< 0.0001). In 12 participants (16%), metabolite concentrations in urine before caffeine intake were below the quantification limit. NAT2 genotyping, done in 41 volunteers for four SNPs, corroborated the phenotyping results. CONCLUSION: NAT2 activity can be determined from a spontaneous urine probe in most subjects by quantification of caffeine metabolites arising from non-standardized dietary caffeine exposure using LC-MS/MS. This may facilitate the phenotyping procedure.

Acetylation↗
PubMed1999

Load dependence of left ventricular contraction and relaxation. Effects of caffeine.

OBJECTIVE: Load dependence of left ventricular (LV) contraction and relaxation was investigated at baseline and after alteration of intracellular calcium handling by caffeine. METHODS: Afterload was increased by aortic clamp occlusions (n = 281) in anesthetized open-chest dogs (n = 7). Control and first heartbeat after the intervention were considered for analysis. RESULTS: Caffeine (50 mg/kg, iv) had no inotropic effect. The systolic LV pressure (LVP), developed in response to aortic occlusion, decreased as ejection proceeded and this pressure generating capacity was not affected by caffeine. Late-systolic aortic occlusions induced premature onset and accelerated rate of initial LVP fall at baseline and similarly after caffeine. Graded diastolic aortic occlusions induced systolic LVP elevations of various magnitudes. Smaller LVP elevations prolonged ejection and accelerated LVP fall, while larger elevations had opposite effects. The transition from acceleration to deceleration was observed at 83.1 +/- 1.1% of peak isovolumetric LVP at baseline and at lower loads, at 77.6 +/- 1.2%, after caffeine (p < 0.01). Isovolumetric heartbeats prolonged the time constant tau by 238 +/- 70% at baseline and only by 155 +/- 44% after caffeine (p < 0.01). The relaxation-systolic pressure relation, which describes afterload dependence of relaxation, was also modified by caffeine. CONCLUSIONS: Caffeine affected LV relaxation without altering contractility. As a consequence contraction-relaxation coupling was modified by caffeine. These results might help to understand load dependence of relaxation in conditions where intracellular calcium handling is altered.

Animals↗
PubMed1996

Caffeine-evoked contractures in single slow (tonic) muscle fibres of the frog (Rana temporaria and R. esculenta).

Single slow (tonic) muscle fibres were dissected from cruralis muscles of Rana temporaria and R. esculenta. Increasing concentrations of caffeine were applied in Ringer solution, and contractures were measured isometrically. Sigmoid caffeine concentration-response curves were obtained, the threshold value being near 1.2 mmol/l, and maximum contractures being obtained with 10 to 20 mmol/l concentrations of caffeine. Contracture solutions were modified by varying the Ca2+ concentration or by replacing Ca2+ with 1.8 mmol/l Mg2+, Ni2+, Co2+ or with 0.1-5.0 mmol/l La3+. The effects of low pH (5.3), K+ (6,10 and 95 mmol/l), adenosine (10 mmol/l) and gallopamil (D600; 30 micromol/l) were examined too. The caffeine threshold was lowered by Mg2+, K+, 0 .1 mmol/l La3+ and D600, while all other substances including 0.5-5.0 mmol/l La3+ increased it. The amplitude of contractures evoked by high caffeine concentrations was unaffected. Caffeine (1-40 mmol/l) was also pressure injected into slow fibres. The composition of the solution was modified in a number of ways, but a contractile response was not observed or measured. Extracellular application of caffeine from the same pipettes evoked local contractures. Similar injection experiments in twitch fibres revealed the same results. These observations suggest that an extracellular binding site seems to be involved in the initiation of caffeine-evoked contractures in intact frog muscle fibres. Possible reasons for the ineffectiveness of intracellular caffeine are discussed.

Adenosine↗
PubMed1998

Differential effects of caffeine on DNA damage and replication cell cycle checkpoints in the fission yeast Schizosaccharomyces pombe.

Caffeine potentiates the lethal effects of ultraviolet and ionising radiation on wild-type Schizosaccharomyces pombe cells. In previous studies this was attributed to the inhibition by caffeine of a novel DNA repair pathway in S. pombe that was absent in the budding yeast Saccharomyces cerevisiae. Studies with radiation-sensitive S. pombe mutants suggested that this caffeine-sensitive pathway could repair ultraviolet radiation damage in the absence of nucleotide excision repair. The alternative pathway was thought to be recombinational and to operate in the G2 phase of the cell cycle. However, in this study we show that cells held in G1 of the cell cycle can remove ultraviolet-induced lesions in the absence of nucleotide excision repair. We also show that recombination-defective mutants, and those now known to define the alternative repair pathway, still exhibit the caffeine effect. Our observations suggest that the basis of the caffeine effect is not due to direct inhibition of recombinational repair. The mutants originally thought to be involved in a caffeine-sensitive recombinational repair process are now known to be defective in arresting the cell cycle in S and/or G2 following DNA damage or incomplete replication. The gene products may also have an additional role in a DNA repair or damage tolerance pathway. The effect of caffeine could, therefore, be due to interference with DNA damage checkpoints, or inhibition of the DNA damage repair/tolerance pathway. Using a combination of flow cytometric analysis, mitotic index analysis and fluorescence microscopy we show that caffeine interferes with intra-S phase and G2 DNA damage checkpoints, overcoming cell cycle delays associated with damaged DNA. In contrast, caffeine has no effect on the DNA replication S phase checkpoint in response to inhibition of DNA synthesis by hydroxyurea.

Caffeine↗
PubMed1985

Effects of orally-administered caffeine on the growth of tooth germs in protein-energy malnourished newborn rats.

Lactating dams with 8 suckling pups were fed either a 6 or 20 per cent protein diet from the birth of the pups to day 15. Pups were divided into caffeine and non-caffeine groups and, every other day between days 3 and 13, were either intubated with caffeine (1 mg/100 g body wt) dissolved in 0.1 ml physiological saline solution, or 0.1 ml saline solution as a control. At day 15, the weight of incisors and molar germs, hydroxyproline content, collagen synthesis and calcium contents were determined. Nutritional factors exercised consistent effects on all the parameters, but effects attributable to caffeine intubation were minor. There was lower molar weight in the 20 per cent protein group with caffeine, and collagen synthesis of incisor and molar germs in the caffeine and non-caffeine animals in the 6 and 20 per cent group were different. These parameters showed a significant interaction between nutrition and caffeine. Thus the direct administration of a small amount of caffeine to newborns causes only slight effects on tooth-germ development under some nutritional conditions.

Administration, Oral↗
PubMed1992

Effects of chronic treatment with caffeine on kidney responses to angiotensin II.

Previous studies demonstrate that chronic administration of caffeine causes glomerular filtration to deteriorate in rats with high-renin renovascular hypertension. A partial explanation for these findings could be that chronic administration of caffeine alters the effects of angiotensin II on the kidney. As an initial test of this hypothesis, we compared the acute effects of intrarenal infusions of angiotensin II (3 ng/min) on renal function in control rats versus rats treated with 0.1% caffeine in their drinking water for 1 week. The renal responses to angiotensin II in a group of animals receiving acute intrarenal infusions of adenosine (10 micrograms/min) were also measured to determine whether caffeine and adenosine modulated renal responses to angiotensin II in opposite directions. All studies were performed in the in situ blood perfused rat kidney. Neither caffeine nor adenosine significantly altered angiotensin II-induced changes in renal blood flow, urinary excretory function or renin release. However, caffeine augmented and adenosine attenuated the increase in filtration fraction caused by angiotensin II. The fact that caffeine potentiates angiotensin II-induced increases in filtration fraction without affecting angiotensin II-induced reductions in renal blood flow is consistent with, but does not prove, the hypothesis that chronic administration of caffeine modifies the effects of angiotensin II on the renal microvasculature. If this inference is correct, caffeine could facilitate renal damage in high-renin hypertension by exacerbating angiotensin II-induced increases in glomerular capillary hydrostatic pressure.

Adenosine↗
PubMed1994

Caffeine cross-tolerance to selective dopamine D1 and D2 receptor agonists but not to their synergistic interaction.

This study examined the role of dopamine systems in tolerance to caffeine-induced stimulation of motor activity in the rat. Selective dopamine D1 and D2 receptor agonists were tested alone and combined in rats receiving caffeine chronically by a method of scheduled access to a caffeine solution or in control rats receiving no caffeine. Rats treated chronically with oral caffeine were tolerant to the motor stimulant effects of caffeine (3.0-100 mg/kg, i.p.). The partial dopamine D1 receptor agonist SKF-77434 (1.0-30 mg/kg, s.c.) and the dopamine D2 receptor agonists quinpirole (0.03-10 mg/kg, s.c.) and R(-)-pro-pylnorapomorphine (NPA, 0.03-1.0 mg/kg, s.c.) dose-dependently increased activity in control rats. Caffeine-treated rats were cross-tolerant to the locomotor stimulant effect of these selective dopamine D1 and D2 receptor agonist. The concurrent administration of the partial dopamine D1 receptor agonist SKF-38393 (10 mg/kg, s.c.) with the dopamine D2 receptor agonists quinpirole and R(-)-propylnorapomorphine had a synergistic effect on locomotor activity in both control and caffeine-treated rats. This synergistic effect was also seen when the partial dopamine D1 receptor agonist SKF-77434 (1.0 and 10 mg/kg, s.c.) was given in combination with quinpirole. There was little or no cross-tolerance to the concurrent administration of selective dopamine D1 and D2 receptor agonists. It appears that tolerance to the locomotor stimulant effect of caffeine is mediated by both dopamine D1 and D2 receptor sub-types. Cross-tolerance occurs to drugs that activate a single type of dopamine receptor but not to drug combinations that concurrently activate more than one type of receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗