Caffeine and stress: implications for risk, assessment, and management of hypertension.

Caffeine use is widespread, and its consumption increases during periods of stress. Caffeine raises blood pressure by elevating vascular resistance, and this effect is larger and more prolonged in hypertensive patients than in normotensive. The pressor response to caffeine occurs equally in persons at rest and under stress. The elevated baseline pressures of the hypertensive patient are therefore increased by both caffeine and stress, potentially leading to undesirably high pressures. Such combined effects on blood pressure may potentially confound the evaluation of hypertension, and possibly reduce the effectiveness of antihypertensive therapy. These effects are not abolished by pharmacologic tolerance to caffeine, as tolerance may not be complete with daily intake. The contribution of caffeine's effects to the development of hypertension warrants continued study, and caffeine use by patients merits consideration in terms of assessment and management of this disorder.

Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.

OBJECTIVE: To investigate the psychological (affective and symptomatic) and physiological (autonomic and cortisol) responses to postprandial mental stress in women with irritable bowel syndrome (IBS). It was hypothesized that patients with IBS would show exaggerated autonomic and cortisol responses to the psychological stressor and that the stressor would enhance gastrointestinal symptoms. METHOD: Twenty-four women with IBS and 20 healthy women participated in the two-day study protocol. Both days were identical, with the exception that on one day, a stressful mental task was completed after ingestion of a standard meal. Heart rate variability, cortisol, affective, and symptomatic responses were measured before and after application of the stressor. RESULTS: Patients with IBS demonstrated increased negative affect at baseline and in response to the stressor. Gastrointestinal symptoms were not affected by the stressor. Appraisal of the stressor by patients with IBS was not different from that of controls. There were no group differences in the autonomic response to the stressor. There was no overall cortisol response to the stressor in either group. CONCLUSIONS: Patients with IBS respond with greater negative affect to postprandial psychological stress as well as to food intake alone, and they can be distinguished from controls on the basis of self-report data. Patients with IBS cannot be differentiated from controls on the basis of the pattern of changes in sympathetic activation after the mental stressor. The stressor used in this study did not elicit a cortisol response in either group.

New ambulatory impedance cardiograph validated against the Minnesota Impedance Cardiograph.

The validity and reliability of a new ambulatory impedance cardiograph (AZCG) was tested against the Minnesota Impedance Cardiograph (ZCG) during rest, orthostasis, and mental stress. Impedance cardiography allows noninvasive assessment of stroke volume, cardiac output, and systolic time intervals. A reliable ambulatory device would allow studies outside the lab. The devices were compared at two sites in healthy subjects. In both studies, the AZCG tracked changes across conditions closely with the ZCG (all Period x Device interactions were nonsignificant). Pearson rs, were .65 to .93, random intraclass correlation coefficients ranged from .80 to .98, indicating high degrees of shared measurement variance, and Cronbach's alpha indicated very good internal reliabilities (.91 to .99). Relative to the ZCG, the new AZCG appears to provide valid and reliable estimates of cardiac function at rest and during behavioral challenges in the lab.

Exogenous cortisol exerts effects on the startle reflex independent of emotional modulation.

Exogenous cortisol's modulation of the acoustic startle reflex (ASR) was tested alone and during exposure to affectively valenced photographs in healthy men and women. During nonmodulated startle, oral hydrocortisone had a biphasic dose effect, with 5 mg increasing and 20 mg decreasing, eyeblink reflex magnitude compared to placebo. During emotion modulation, 20 mg of hydrocortisone reduced reflex magnitude without affecting the usual pattern of modulation across positive, neutral, and negatively affective slides. Gender differences were not found in either relationship. These findings illustrate dose-dependent effects of cortisol on the startle pathway independent of emotional state and consistent across genders.

Enhanced memory for emotional material following stress-level cortisol treatment in humans.

Memory tends to be better for emotionally arousing information than for neutral information. Evidence from animal studies indicates that corticosteroids may be necessary for this memory enhancement to occur. We extend these findings to human memory performance. Following administration of cortisol (20 mg) or placebo, participants were exposed to pictures varying in emotional arousal. Incidental memory for the pictures was assessed one week later. We show that elevated cortisol levels during memory encoding enhances the long-term recall performance of emotionally arousing pictures relative to neutral pictures. These results extend previous work on corticosteroid enhancement of memory and suggest that high cortisol levels during arousing events result in enhanced memory in humans.

Hypertension risk status and effect of caffeine on blood pressure.

We compared the acute effects of caffeine on arterial blood pressure (BP) in 5 hypertension risk groups composed of a total of 182 men. We identified 73 men with optimal BP, 28 with normal BP, 36 with high-normal BP, and 27 with stage 1 hypertension on the basis of resting BP; in addition, we included 18 men with diagnosed hypertension from a hypertension clinic. During caffeine testing, BP was measured after 20 minutes of rest and again at 45 to 60 minutes after the oral administration of caffeine (3.3 mg/kg or a fixed dose of 250 mg for an average dose of 260 mg). Caffeine raised both systolic and diastolic BP (SBP and DBP, respectively; P<0.0001 for both) in all groups. However, an ANCOVA revealed that the strongest response to caffeine was observed among diagnosed men, followed by the stage 1 and high-normal groups and then by the normal and optimal groups (SBP F(4),(175)=5.06, P<0.0001; DBP F(4,175)=3.02, P<0.02). Indeed, diagnosed hypertensive men had a pre-to-postdrug change in BP that was >1.5 times greater than the optimal group. The potential clinical relevance of caffeine-induced BP changes is seen in the BPs that reached the hypertensive range (SBP >/=140 mm Hg or DBP >/=90 mm Hg) after caffeine. During the predrug baseline, 78% of diagnosed hypertensive men and 4% of stage 1 men were hypertensive, whereas no others were hypertensive. After caffeine ingestion, 19% of the high-normal, 15% of the stage 1, and 89% of the diagnosed hypertensive groups fell into the hypertensive range. All subjects from the optimal and normal groups remained normotensive. We conclude that hypertension risk status should take priority in future research regarding pressor effects of dietary intake of caffeine.

Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men.

BACKGROUND: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. METHODS: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. RESULTS: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. CONCLUSIONS: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.

Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness.

This study evaluated the influence of overt anger expression style and defensiveness on the hypothalamic-pituitary-adrenocortical (HPA) responses to acute psychological stress. These personality traits are thought to modulate the stress cardiovascular response and influence disease risk, however, little is known about their influence on HPA responses. Forty-six young, healthy male volunteers worked on counterbalanced extended public-speaking and mental arithmetic. The sample was dichotomitized into groups low vs. high in anger-out, using Spielberger's Anger-Expression Inventory, and in defensiveness, using the Marlowe-Crown Social Desirability Scale. Serum cortisol and adrenocorticotropic hormone (ACTH) concentrations were measured before and after performing each task. Heart rate (HR) and blood pressures (BP) were obtained continuously in 2-min intervals before, during and after the tasks. Public speaking produced greater adrenocortical and cardiovascular stress responses than mental arithmetic, and the greatest increases in ACTH occurred in subjects high in anger-out and defensiveness. These preliminary findings provide evidence that a mismatch between traits of preferred anger expression style and defensive style produces pronounced adrenocorticotropic responses during socially salient stress.

Additive pressor effects of caffeine and stress in male medical students at risk for hypertension.

The effects of caffeine on blood pressure (BP) and cortisol secretion were examined during elevated work stress in medical students at high versus low risk for hypertension. Among 31 male medical students who were regular consumers of caffeine, 20 were considered at low risk for hypertension (negative parental history and all screening BP < 125/78 mm Hg) and 11 at high risk based on epidemiologic criteria (positive parental history and average screening BPs between 125/78 and 139/89 mm Hg). Cortisol levels and ambulatory BP were measured with and without caffeine during two lectures (low work stress) and two exams (high work stress) in a randomized, double-blind, crossover trial. Caffeine consumption and exam stress increased cortisol secretion in both groups (P < .05). BP increased with caffeine or exam stress in both groups, low versus high risk, respectively (Caffeine: + 5/4 vs + 3/3 mm Hg; Stress: + 4/1 vs + 7/3 mm Hg; P < .05). The combination of stress and caffeine caused additive increases in BP (Low Risk + 9/5 mm Hg, High Risk + 10/6 mm Hg) such that 46% of high-risk participants had average systolic BP > or = 140 mm Hg. This combined effect of stress and caffeine on BP suggests that it may be beneficial for individuals at high risk for hypertension to refrain from the use of caffeinated beverages, particularly at times when work demands and attendant stressors are high. For the same reasons, recent intake of caffeine should be controlled in patients undergoing BP measurement for the diagnosis of hypertension.

Sex differences in pain perception and cardiovascular responses in persons with parental history for hypertension.

We investigated gender differences in cardiovascular and pain responses to the cold pressor (CP) test in persons with positive (PH+) or negative parental history (PH-) for hypertension. Previous work has suggested an attenuated sensitivity to painful stimulation in hypertensive men and more recently in men with parental disposition for hypertension. It is not known whether this hypoalgesic effect is present in PH+ women. In this study, we evaluated differences in pain perception between men and women with PH+ or PH- using an assessment method to measure current as well as delayed pain. Participants rated their pain every 15 s during a 90-s hand CP (0-4 degrees C) and a 90-s post-CP rest period. Systolic and diastolic blood pressures (SBP, DBP) and heart rate (HR) were measured before, during, and after the CP. PH+ and PH- groups did not differ in age, height, weight, education, resting SBP, DBP, or HR. PH+ men showed greater DBP responses to the CP than PH- men, while female groups did not differ in cardiovascular responses to the CP. Although pain ratings during the CP did not differ between groups, post-CP reported pain receded faster in the PH+ men than in the PH- men. PH+ women, on the other hand, tended to report greater pain than PH- women. These findings question the generalizability of the hypoalgesic effects in hypertension-prone women.

Cortisol fluctuates with increases and decreases in negative affect.

Prior studies have reported cortisol secretion to be primarily influenced by negative affect, but less is known about cortisol activity during states of activation involving increased positive affect and decreased negative affect. On separate days, 30 healthy young men experienced: an activating and humorous video; a speech stressor; and a resting control period. Cortisol was measured in saliva before and after each 30-min mood induction. Positive affect (activation) was increased similarly by both the video and the speech compared to rest (p < .0001). Negative affect increased during the speech and decreased during the video (p < .001). Cortisol increased only during the speech (p < .0001). Following the video, however, cortisol was decreased significantly (p < .0001). Rest day cortisol revealed no differences across periods (p > .1). These results suggest that the hypothalamic-pituitary-adrenocortical axis is a dynamic system influenced by changes in negative affect irrespective of the experience of generalized activation.

Hypothalamic-pituitary-adrenocortical responses to psychological stress and caffeine in men at high and low risk for hypertension.

OBJECTIVE: This study examined pituitary-adrenocortical responses to dietary doses of caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of coffee), alone and combined with behavioral stress, in men at high risk versus low risk for hypertension. A randomized, double-blind, caffeine-placebo crossover design was used. METHOD: Adrenocorticotropic hormone (ACTH) and cortisol levels in plasma were assessed at rest and in response to 60-minutes of continuous work on a mental stressor (arithmetic) and a psychomotor task (reaction time) on four test sessions held on separate days. RESULTS: Tasks alone caused greater ACTH and cortisol increases in high risk men than in the low risk group. Caffeine alone elevated ACTH and cortisol in both groups, with more immediate responses in the high risk group. Both groups showed significant ACTH and cortisol responses to caffeine plus tasks, with the high risk group showing more persistent elevations. The high risk group also showed the highest levels of ACTH and cortisol after caffeine plus tasks. CONCLUSIONS: These findings demonstrate for the first time the combined effects of caffeine plus stress on ACTH and demonstrate greater corticosteroid effects in hypertension-prone men. As such, they may have implications for the dietary use of caffeine during periods of stress and in those at risk for hypertension.

Interactive effects of trait hostility and anger expression on cardiovascular reactivity in young men.

Hostility and anger-expression style are personality traits often associated with elevated cardiovascular reactivity and potential heightened risk for cardiovascular disease. In the present study a sample of 50 young, healthy men were divided into groups low or high on the Cook-Medley Hostility scale and on anger-out from Spielberger's Anger Expression scale. Subjects worked on mental arithmetic and public speaking tasks in counterbalanced order. Heart rate, systolic and diastolic blood pressure and hemodynamic indices were measured at baseline and during the tasks. Hostility and anger-out interacted in their effects on cardiovascular responses. The High Anger-Out/Low-Hostile group displayed the greatest increases in heart rate and blood pressures, while the High Anger-Out/High-Hostile group was least reactive. Furthermore, the High Anger-Out/Low-Hostile group showed a distinct fight/flight response pattern during public speaking, indicated by increases in stroke volume and cardiac output and a decrease in systemic vascular resistance. These results suggest that a mismatch between hostile cognitions and habitual anger expression leads to greater cardiovascular reactivity to challenging tasks, potentially enhancing risk for development of cardiovascular diseases.

Five-year follow-up for adverse outcomes in males with at least minimally positive angiograms: importance of "denial" in assessing psychosocial risk factors.

The purpose of this study was to test the role of "denial" (spouse/friend minus self-ratings on parallel versions of the same questionnaire) in diluting the predictive value of emotional distress for cardiac events (deaths, new MIs, and/or revascularizations). One hundred forty-four men with no history of prior revascularization who had at least minimally positive diagnostic coronary angiograms, and someone they selected as "someone who knows you well," completed parallel versions of the Ketterer Stress Symptom Frequency Checklist (KSSFC). They were followed up by phone an average of 59.7 months after recruitment. Length of follow-up, baseline cardiac risk factors, and a number of baseline-obtained psychosocial risk factors were tested as prospective predictors of combined events (death by any cause, new MIs, and/or revascularizations) and current anginal frequency. Only spouse/friend observed anxiety on the KSSFC predicted current anginal frequency (p = 0.001). On the self-report version of the KSSFC, patients with one or more events reported less anger (p = 0.031), depression (p = 0.008), and anxiety (p = 0.003). These results may be attributable to "denial" because there were no differences in spouse/friend ratings, and difference scores (spouse/friend minus patient) on the KSSFC scales, particularly anger, were also related to events: AIAI (p = 0.002); depression (p = 0.063); and anxiety (p = 0.010). Denial may be a major limiting factor in accurately assessing emotional distress in cardiac populations, and may help account for a number of the previous findings.

Hemodynamics during rest and behavioral stress in normotensive men at high risk for hypertension.

Persons at risk for hypertension may show elevated blood pressure (BP) at rest and during mental stress; however, the hemodynamics underlying the BP of those persons at high risk are not well characterized. We chose 21 high risk and 21 low risk men using their parental hypertension history and resting systolic blood pressures on two screenings. Then, on a day of extended rest versus a day with prolonged mental arithmetic and reaction time tasks, we examined whether high risk BP elevations reflected greater vascular resistance or cardiac output. High risk men had raised systolic/diastolic pressures (Fs = 74/15, ps < .0001/.0001) and higher vascular resistance (F = 6.6, p < .02) with minimal differences in heart rate and cardiac output. This finding implicates vascular resistance as the altered element in BP control in these high risk men tested in a familiar environment with minimal task-related threat.

Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors.

In this study, we evaluated cardiovascular, neuroendocrine, and psychological adjustment to repeated presentations of a public speaking and a mental arithmetic task. Brief versions of mental arithmetic tasks have been used widely in previous reactivity studies, and growing attention to more socially salient tasks has led to the increased use of public speaking tasks. However, psychophysiological adjustment during extended and repeated exposure to these tasks has not been delineated. In the present study, 52 healthy men worked on three 8-min presentations of public speaking and of mental arithmetic in a repeated measure design. Both tasks produced substantial cardiovascular, adrenocorticotropic hormone, and cortisol responses; public speaking produced greater changes. Repeated presentations of public speaking produced a stable pattern of cardiac activation, whereas repetitions of the mental arithmetic initially produced large cardiac responses that changed to a more vascular tonus across task periods. Both tasks increased negative moods. However, correlations between the endocrine, cardiovascular, and negative moods were significant only during the public speaking stressor. The public speaking task is a socially relevant experimental protocol for studying reactivity in the laboratory setting and elicits relatively high, stable, and homogeneous responses.

Men at risk for hypertension show elevated vascular resistance at rest and during mental stress.

Men at risk for development of hypertension may show elevated blood pressure at rest and during work on mental stressors. We examined which component of blood pressure, vascular resistance or cardiac output, accounted for raised blood pressures seen in a high-risk, normotensive sample. Parental history of hypertension and resting systolic blood pressures were used to categorize subjects into high (n = 19) and low (n = 14) risk groups. Blood pressure, heart rate, cardiac output, stroke volume, and vascular resistance were measured during rest, mental arithmetic, and reaction time. Compared to low risk subjects, the high risk men had significantly higher blood pressures accompanied by higher vascular resistances at rest and during mental stress. The groups had negligible differences in heart rate, stroke volume, and cardiac output. This pattern of results implicates vascular resistance as the dominant element in altered blood pressure control in these young men at high risk for hypertension.

Stress-like adrenocorticotropin responses to caffeine in young healthy men.

The effects of oral caffeine (3.3 mg/kg, equivalent to 2-3 cups of coffee) on plasma adrenocorticotropin (ACTH) and cortisol (CORT) were tested in 47 healthy young men at rest in a double-blind, placebo-controlled, crossover study. Following caffeine, ACTH was significantly elevated at all times from 30 min to 180 min, and CORT was elevated from 60 min to 120 min (Fs > or = 8.4, ps < 0.01). Peak increases relative to placebo were: ACTH, 33% (+5.2 pg/ml) and CORT, 30% (+2.7 micrograms/dl) at 60 min postcaffeine. The results suggest that caffeine can activate important components of the pituitary-adrenocortical response in humans during the resting state. Caffeine's known ability to increase CORT production appears at least partly due to an increase in ACTH release at the pituitary.

Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics.

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC0-infinity) values +/- SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 +/- 10.8, 48.7 +/- 15.2, and 49.6 +/- 7.0 micrograms/ml.hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.

Pain perception and cardiovascular responses in men with positive parental history for hypertension.

Evidence suggests a reduced pain sensitivity in hypertensive individuals. This study sought to extend this work to normotensive individuals with hypertensive parents. Men with a positive (PH+) or negative (PH-) parental history for hypertension rated their pain every 15 s during a 90-s hand cold pressor test and for 90 s after the cold pressor test. Systolic (SBP) and diastolic (DBP) blood pressures and heart rate were measured throughout. After the cold pressor test, the men recalled their pain using the McGill Pain Questionnaire. PH+ men showed greater SBP and DBP responses to the cold pressor test. Although pain ratings during the cold pressor test did not differ between groups, posttest reported pain receded faster in the PH+ than in the PH- men. The PH+ men also reported less total pain on the McGill. These findings support the hypothesis that risk for hypertension may be associated with attenuated pain responses to nociceptive stimuli.