Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for postprandial hypotension

We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129 +/- 25/78 +/- 12 (mean +/- S.D.) to a maximum of 141 +/- 30/84 +/- 16 mm Hg at 45 minutes (P less than 0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133 +/- 32/80 +/- 15 to a minimum of 105 +/- 21/62 +/- 12 mm Hg at 60 minutes (P less than 0.01). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140 +/- 33/79 +/- 7 to 129 +/- 31/69 +/- 13 mm Hg at 60 minutes (P less than 0.05 vs. values after the control per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P less than 0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin-angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state.     

Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications

Plasma renin exists in an active form or as an inactive zymogen that resembles a prorenin present in homogenates of human kidneys. We examined the relation of diabetes and its microvascular complications with the level of plasma inactive renin activated by dialysis to pH 3.3. Plasma inactive renin was measured in 235 diabetic patients and 90 nondiabetic controls. In the controls, the level of plasma inactive renin increased slightly with age but was never above 50 ng per milliliter per hour. In young diabetic patients studied within three years of the onset of diabetes the concentration of inactive renin was normal, and in some older diabetics without complications it remained within the age-adjusted normal range for many years. However, in patients with retinopathy or albuminuria, plasma inactive renin was above the normal range with few exceptions, reaching levels 50 to 200 per cent above the upper limits of normal in patients with nephropathy. The frequency of neuropathy was also significantly higher among patients with levels above the normal range. In 37 per cent of the diabetics followed during one to three years of conventional treatment, plasma inactive renin increased significantly, but in another group of diabetics under intensive treatment, the level rose in only 7 per cent and fell in 43 per cent. We conclude that there is a close association between a high level of plasma inactive renin and the presence of microvascular complications, and that the level of inactive renin can be modified by intensive treatment of diabetes.     

Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme.

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.     

Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure

Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.     

Timing of caffeine's impact on autonomic and central nervous system measures: clarification of arousal effects

The timing of caffeine effects on arousal levels was examined. From previous work in our laboratory, an increase in skin conductance level (SCL) was used as the marker of arousal increase, and we sought to identify the timing of this and related effects following caffeine ingestion. A single oral dose of caffeine (250 mg) was used in a randomised double-blind placebo-controlled repeated-measures cross-over study. Eyes-closed resting electroencephalogram (EEG) and autonomic data (SCL, heart rate, respiration rate, and systolic and diastolic blood pressure) during 2 min epochs that commenced every 4 min after ingestion, were analysed. The SCL placebo data were used to identify potential arousal measures prior to examining caffeine effects. Caffeine was associated with increased SCL, increased respiratory rate and a global reduction in alpha power. There were no significant cardiovascular effects of caffeine-induced arousal. These caffeine results are consistent with our recent electrodermal and EEG studies of arousal, and confirm the potential use of caffeine as a simple means of experimentally modifying arousal levels without task-related confounds.     

Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine.

Caffeine stimulates gastric acid secretion and reduces the competence of the lower esophageal sphincter in man. These effects of caffeine have been used as evidence that regular coffee should not be used by patients with peptic-ulcer disease or gastroesophageal reflux. We compared the dose-response relations of caffeine, regular coffee and decaffeinated coffee for gastric acid secretion and sphincter pressure in normal subjects. Decaffeinated coffee gave a maximal acid response of 16.5 +/- 2.6 mEq per hour (mean +/- S.E.M.), which was similar to that of regular coffee, 20.9 +/- 3.6 mEq per hour, both values being higher than that of caffeine, 8.4 +/- 1.3, on a cup-equivalent basis. Sphincter pressure showed minimal changes in response to caffeine, but was significantly increased by both regular and decaffeinated coffee (P less than 0.05). These data suggest that clinical recommendations based upon the known gastrointestinal effects of caffeine may bear little relation to the actual observed actions of coffee or decaffeinated coffee.     

Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure

Eight patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were given captopril (seven patients) or teprotide (one patient). All had dyspnea, edema, elevated pulmonary wedge pressure (28.0 +/- 2.6 mm Hg), low cardiac index (1.6 +/- 0.1 liters per minute per square meter), and elevated levels of serum creatinine (2.3 +/- 0.2 mg per deciliter [203.3 +/- 17.7 mumol per liter]), blood urea nitrogen (48 +/- 5 mg per deciliter [17.1 +/- 1.8 mmol of urea per liter]), plasma renin activity (21 +/- 7 ng of angiotensin I per milliliter per hour), plasma angiotensin II (271 +/- 51 pg per milliliter), and plasma aldosterone (65 +/- 14 ng per deciliter). After one week of therapy, all indexes improved. Creatinine and p-aminohippurate clearances were also increased (P less than 0.01). Improvement was sustained (more than six months) and was associated with a statistically significant increase in the cardiac ejection fraction (12 +/- 3 to 26 +/- 7 per cent). With a mean follow-up of seven months, the New York Heart Association Functional Class has been reduced from IV to II, and the number of days of hospitalization to less than 10 per cent of that before captopril therapy. We conclude that captopril reduces afterload in advanced congestive heart failure and induces sustained improvements in clinical status and renal function.     

Differential contributions of theobromine and caffeine on mood, psychomotor performance and blood pressure

The combination of theobromine and caffeine, methylxanthines found in chocolate, has previously been shown to improve mood and cognition. However, it is unknown whether these molecules act synergistically. This study tested the hypothesis that a combination of caffeine and theobromine has synergistic effects on cognition, mood and blood pressure in 24 healthy female subjects. The effects of theobromine (700 mg), caffeine (120 mg) or the combination of both, or placebo were tested on mood (the Bond-Lader visual analog scale), psychomotor performance (the Digit Symbol Substitution Test (DSST)) and blood pressure before and at 1, 2 and 3 h after administration. Theobromine alone decreased self-reported calmness 3 h after ingestion and lowered blood pressure relative to placebo 1 h after ingestion. Caffeine increased self-reported alertness 1, 2 and 3 h after ingestion and contentedness 1 and 2 h after ingestion, and increased blood pressure relative to placebo (at 1 h). The combination of caffeine + theobromine had similar effects as caffeine alone on mood, but with no effect on blood pressure. There was no treatment effect on DSST performance. Together these results suggest that theobromine and caffeine could have differential effects on mood and blood pressure. It was tentatively concluded that caffeine may have more CNS-mediated effects on alertness, while theobromine may be acting primarily via peripheral physiological changes.     

Autonomic nervous system effects of acute doses of caffeine in caffeine users and abstainers

The effects of caffeine on autonomic nervous system (ANS) activity were tested in 20 adult males who were either high or low consumers of caffeine. Subjects received placebo, 3 mg/kg, and 10 mg/kg of caffeine in a counterbalanced order (double-blind) before 3 test sessions 48 h apart. Skin conductance (SC), heart rate, and skin temperature (ST) were recorded during a rest period, a series of non-signal tones, and a simple reaction time task. Caffeine increased resting electrodermal activity (EDA) and increased the SC orienting response to the first non-signal tone, but reduced the increase in tonic EDA due to task performance. ST was reduced by caffeine in both rest and task periods. Increases in nervous/jittery ratings occurred after caffeine ingestion, but task performance was not affected. Low consumers of caffeine showed significantly more ANS responsivity than high consumers under all conditions and did not differ in ANS, behavioral, or subjective effects of caffeine. The acute physiological changes are partly similar to those reported for patients with anxiety disorders, suggesting a possible role of ANS activity in mediating the anxiogenic effects of caffeine. Effects of user status may reflect a predisposing trait, but an effect of chronic caffeine use on ANS sensitivity cannot be ruled out.     

Hypokalemia from beta2-receptor stimulation by circulating epinephrine

To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation, and whether hypokalemia can occur at physiologic concentrations of the agonist, epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute. The circulating epinephrine concentration was increased to 1.74 +/- 0.65 ng per milliliter, plasma potassium was reduced by 0.82 +/- 0.19 meq per liter, plasma insulin fell by 12 +/- 4 mU per liter, plasma renin activity was elevated, and tachycardia occurred. Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia (25 beats per minute) and elevation in plasma renin activity (6.0 to 6.5 ng per milliliter per hour), but no hypokalemia. The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine. This hypothesis was tested in six subjects given infusions of epinephrine (0.05 micrograms per kilogram per minute) after administration of either 2.5 or 5 mg of ICI 118551--a selective beta2-receptor antagonist--or placebo. After placebo, epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium; hypokalemia was prevented by the beta2-antagonist. This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals; there was no tachycardia. Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine. This phenomenon may be of physiologic importance after severe myocardial infarction, when similar increases in plasma epinephrine have occurred.     

Caffeine stimulates in vivo overall cell metabolism. Microcalorimetric measurement of heat production in human platelets

The influence of caffeine on overall cell metabolism was studied in human platelets by measurement of cell heat production rate. One hour after administration of 100-200 mg of caffeine, corresponding to 1-2 cups of coffee, significantly increased values (p less than 0.001) were found, 12 +/- 7%. A return to normal values was noted 1 hour later. The cell metabolic stimulation is presumably due to increased catecholamines. A temporary significant rise in systolic (p less than 0.02) and diastolic (p less than 0.05) blood pressure was observed 1 hour after ingestion of caffeine.     

No effect of caffeine on exercise performance in high ambient temperature

Caffeine, an adenosine receptor antagonist, has shown to improve performance in normal ambient temperature, presumably via an effect on dopaminergic neurotransmission through the antagonism of adenosine receptors. However, there is very limited evidence from studies that administered caffeine and examined its effects on exercise in the heat. Therefore, we wanted to study the effects of caffeine on performance and thermoregulation in high ambient temperature. Eight healthy trained male cyclists completed two experimental trials (in 30°C) in a double-blind-randomized crossover design. Subjects ingested either placebo (6 mg/kg) or caffeine (6 mg/kg) 1 h prior to exercise. Subjects cycled for 60 min at 55% W (max), immediately followed by a time trial to measure performance. The significance level was set at p < 0.05. Caffeine did not change performance (p = 0.462). Rectal temperature was significantly elevated after caffeine administration (p < 0.036). Caffeine significantly increased B-endorphin plasma concentrations at the end of the time trial (p = 0.032). The present study showed no ergogenic effect of caffeine when administered 1 h before exercise in 30°C. This confirms results from a previous study that examined the effects of caffeine administration on a short (15 min) time trial in 40°C. However, caffeine increased core temperature during exercise. Presumably, the rate of increase in core temperature may have counteracted the ergogenic effects of caffeine. However, other factors such as interindividual differences in response to caffeine and changes in neurotransmitter concentrations might also be responsible for the lack of performance improvement of caffeine in high ambient temperature.     

Effects of bile duct ligation and captopril on salt appetite and renin-aldosterone axis in rats.

A ligation of the common bile duct (BDL) produces cholestasis and hypotension and increases the daily ingestion of sodium chloride solutions in rats. Low-dose captopril (CAP) treatment also modifies the ingestion of water and sodium in naive rats, and may do so in cholestatic rats. This study examined whether the elevated ingestion of saline by Long-Evans rats after BDL is associated with increased plasma renin activity (PRA), and whether treatment with a low dose of the angiotensin converting-enzyme inhibitor CAP further exacerbates fluid intake and PRA after BDL. In these experiments water and 0.3 M saline intake and PRA and plasma aldosterone (PA) were measured in naive and CAP-treated BDL and sham-ligated rats. We found that BDL elevated rats' daily saline intake 2 weeks after the ligation procedure but had no effect on PRA. CAP (0.1 mg/mL) placed in the drinking water of some BDL rats further increased saline intake. Both PA and hematocrits tended to be reduced in BDL rats, whereas PRA was elevated in both BDL and sham-ligated rats receiving CAP in the drinking water or by gavage (0.1 mg/mL in 10 mL/kg). The data suggest that the ingestion of saline by rats can be modified by BDL and CAP administration, but that exaggerated saline intake in BDL rats is not associated with excessive renin secretion.     

Sex differences in the hemodynamic responses to mental stress: Effect of caffeine consumption

The effect of caffeine on stress responses was compared in 25 men and 22 women in a 2-week placebo-controlled, double-blind, randomized crossover trial. On each week, participants abstained from all dietary sources of caffeine before undergoing a 6-h laboratory protocol under placebo or caffeine exposure followed by a 30-min mental stressor with blood pressure (BP) and cardiovascular hemodynamic assessments. On the placebo session, men and women showed a significant BP increase to stress, although women had significant cardiac responses whereas men had vascular responses. Caffeine ingestion before stress caused both men and women to have enhanced hemodynamic responses to the stressor associated with an increase in cardiac index and a drop in the peripheral resistance index. Caffeine enhances the cardiovascular fight-or-flight response pattern to stress in men and women.     

The effect of muscular work on the amounts of alcohol in urine,expired air,and blood,after its ingestion by man

Summary The rate of disappearance of alcohol from the human body was studied during 3 hours immediately following ingestion of 30 and 50 cc. of alcohol, with the subject (a man) at rest during the entire time or working and resting for different lengths of time. The work lasted 1/2 hour, 1 hour, or 2 hours, and immediately followed the ingestion of alcohol or was preceded by a 1-hour rest period. The rates of work (performed on a bicycle ergometer) were 275, 415, and 550 kg./m. per minute.The muscular work did not appreciably alter the concentration of alcohol in urine, in blood, or in expired air (as shown by measurements of the amounts eliminated per liter of ventilating air current of the respiration apparatus and by estimations of the amounts eliminated per liter of expired air), and the alcohol eliminated per liter of carbon dioxide exhaled was not changed.The amount of alcohol in the ventilating air current was highest in the first 15-minute period after ingestion and gradually decreased to a very low level in the 3 hours, under conditions both of rest and of work. When the subject was working, the amounts eliminated in the 15-minute periods were greater than when he was at rest and were greater the severer the work, due to the increased total ventilation of the lungs, but after the work ceased the period values approached those found in the same time interval after ingestion in the rest experiments. The total amount of alcohol eliminated in the ventilating air current during 3 hours after ingestion was doubled or more than doubled by 2 hours' work at 275 and 415 kg./m. per minute.The percentage of the total amount ingested that was eliminated in the ventilating air current was from 0.4 to 0.7 in the rest experiments and from 0.9 to 1.6 in the work experiments. The total amount eliminated in the urine and the expired air was from 0.8 to 1.6 per cent in the rest experiments and from 1.1 to 2.1 per cent in the work experiments. The disappearance of alcohol through these paths plays only a small rÔle in reducing the amount of alcohol in the body.     

The effect of muscular work on the metabolism of man after the ingestion of sucrose and galactose

Summary The respiratory exchange was studied in three-hour experiments with a man, both at rest and at work, after ingestion of 70 g. of sucrose and 50 g. of galactose, respectively. The work consisted in riding a bicycle ergometer at the rate of 275 kg./m. per minute for one hour followed by two hours' recovery, or at the rate of 550 kg./m. for one-half hour followed by two and one-half hours' recovery.Comparison of the time relationships in the occurrence of the maximum respiratory quotients and the maximum increases in oxygen absorption after sugar ingestion in rest experiments implies that the intermediary metabolism of sucrose is different from that of galactose.More cane sugar was burned during work than during rest, but this was not the case with galactose. It is questionable whether muscular work has any effect on the metabolism of galactose, except apparently to accelerate the reaction after the ingestion of the sugar.The after-effect of the ingestion of sucrose or galactose and the after-effect of the muscular work lasted for only one-quarter hour after the work (one hour's work at 275 kg./m. per minute) ceased.The metabolic effect of sugar ingestion accompanied by work did not represent a summation of the effect of the ingestion of the sugar (either sucrose or galactose) at rest and the effect of muscular work without sugar.When sugar ingestion was combined with muscular work the efficiency of performance of work was better than when work was performed without sugar. Ingestion of galactose enabled slightly more efficient performance of work at 275 kg./m. per minute than did the ingestion of sucrose. Work accompanied by ingestion of sucrose was carried on more efficiently at the rate of 550 kg./m. per minute for one-half hour than when the same amount of work was accomplished at half this rate. In the more intense work more of the ingested sugar was utilized.     

Prostaglandins are involved in the stimulation of renin gene expression in 2 kidney-1 clip rats

This study was done to obtain information about a possible involvement of prostaglandins in the renal baroreceptor mechanism regulating renin secretion and renin gene expression. To this end the effect of the cyclooxygenase inhibition was examined on renin secretion and on renal renin gene expression in 2 kidney-1 clip rats. The influences of the cyclooxygenase inhibitors indomethacin (2mg/kg twice a day) and meclofenamate (8 mg/kg twice a day) on renal renin m-RNA levels, on plasma renin activity (PRA) and on blood pressure were measured 2 days after clipping the left renal arteries of male Sprague-Dawley rats with 0.2 mm clips. In sham-clipped animals, indomethacin and meclofenamate had no significant effect on basal PRA and renin m-RNA levels. In vehicle-treated animals unilateral renal artery clipping increased blood pressure from 120±4.1 to 150±6.1 mmHg, increased PR6A from 7.4±1.6 to 27.6±3.8 as expressed in nanograms of angiotensin I per hour per millilitre, increased renin m-RNA levels of clipped kidneys from 105±5.9% of standard to 482.6±56% of standard and decreased renin m-RNA levels of contralateral kidneys from 116±9.7% of standard to 34±9.0% of standard. While blood pressure, PRA and renin m-RNA levels of the contralateral kidneys were virtually unchanged by the cyclooxygenase inhibitors indomethacin and meclofenamate, renin gene expression in the clipped kidney was markedly influenced by inhibition of prostaglandin synthesis. Both cyclooxygenase inhibitors attenuated the increase of renin m-RNA levels in response to clipped to 280±26% of standard and 261±35% of standard after application of indomethacin or meclofenamate. These findings suggest that intact prostaglandin formation is at least partially required for the stimulatory effect of low renal perfusion pressure on renin gene expression.     

The effects of caffeine on memory for word lists

The present study investigated the effects of caffeine on memory for supraspan word lists. Twelve groups of male and female college students classified as high or low impulsive were administered (PO) 0 mg/kg, 2 mg/kg or 4 mg/kg of caffeine. Subjects listened to four word lists presented at a fast rate and four at a slow rate. Caffeine inhibited females' recall during the slow rate, but not the fast rate. Caffeine had no effect on the recall performance of males. The observed effects of caffeine were not influenced by subjects' typical amount of caffeine consumption, verbal ability, or level of impulsivity. The results suggest that caffeine may impair the efficiency with which females rehearse information in working memory.     

The effects of chewing versus caffeine on alertness, cognitive performance and cardiac autonomic activity during sleep deprivation

Chewing has been shown to alleviate feelings of sleepiness and improve cognitive performance during the day. This study investigated the effect of chewing on alertness and cognitive performance across one night without sleep as well as the possible mediating role of cardiac autonomic activity. Fourteen adults participated in a randomized, counterbalanced protocol employing a chewing, placebo and caffeine condition. Participants completed tasks assessing psychomotor vigilance, tracking, grammatical reasoning, alertness and sleepiness each hour across the night. All participants received either placebo or caffeine (200 mg), while the chewing condition also chewed on a tasteless and odorless substance for 15 min each hour. Heart rate (HR), root mean square of the successive differences in R-R intervals on the ECG (RMSSD), and preejection period (PEP) were simultaneously recorded. Alertness and cognitive performance amongst the chewing condition did not differ or were in fact worse when compared with placebo. Similarly, measures of HR and RMSSD remained the same between these two conditions; however, PEP was reduced in the later part of the night in the chewing condition compared with a relative increase for placebo. Caffeine led to improved speed and accuracy on cognitive tasks and increased alertness when compared with chewing. Relative increases in RMSSD and reductions in HR were demonstrated following caffeine; however, no change in PEP was seen. Strong associations between cardiac parasympathetic activity and complex cognitive tasks, as well as between subjective alertness and simpler cognitive tasks, suggest a differential process mediating complex versus simple cognitive performance during sleep deprivation.     

Caffeine effects on resting-state arousal in children

From previous work in our laboratory, increases in skin conductance level (SCL), together with global (across-scalp) decreases in electroencephalogram (EEG) alpha power and increases in alpha frequency, are useful indices of arousal increase, and here we sought to identify changes in these indices with caffeine ingestion in children. We explored the effects of a single oral dose of caffeine (80 mg) in a randomised double-blind placebo-controlled repeated-measures cross-over study. Thirty healthy children aged between 8 and 13 years (mean age 10.5 years; 11 females) participated in two sessions, 1 week apart. EEG and SCL from a 3 min eyes-closed epoch, commencing approximately 30 min after ingestion of caffeine or placebo, were examined. Caffeine was associated with increased SCL, and a global reduction in EEG power in the theta and alpha bands, as well as topographically-focused reductions in delta and beta power, and a focal increase in alpha frequency. Only global alpha level demonstrated the expected inverse relationship with SCL in both placebo and caffeine conditions. These results are generally consistent with recent electrodermal and EEG studies of arousal. Together with our previous adult data, they indicate that caffeine can be used to increase arousal in both adults and children, without the potential confounds associated with varying task demands. Caffeine appears useful as a simple tool for manipulating arousal in studies exploring its role in physiological and behavioural functioning. This may be helpful in determining the role of hypothetical arousal anomalies in syndromes such as attention-deficit/hyperactivity disorder.