Cold pressor stress effects on cardiac repolarization.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

Hydrocortisone reduces altruistic punishment in healthy men.

Psychosocial stress modulates social cognition and behavior in humans. One potentially mediating factor is cortisol as part of the human endocrine stress response. With a double-blind, placebo-controlled between-subject study design, we tested possible dose-dependent effects of hydrocortisone (0 mg, 5 mg and 20 mg) in 85 healthy males. During a socio-economic decision-making task we measured trust, trustworthiness, sharing, punishment, and non-social risk behavior. Social value orientation (SVO) was also assessed. We observed significantly lower levels of punishment after hydrocortisone, especially in the 20 mg group. Drug-induced salivary cortisol correlated negatively with punishment behavior. None of the other facets of social behavior or the SVO were affected by hydrocortisone. Our results suggest that hydrocortisone reduces the propensity to punish unfair behavior. Future studies are needed to further disentangle the role played by various psychobiological mechanisms within the stress response as well as their complex interplay on social behavior and cognition.

The relationship between self-reported chronic stress, physiological stress axis dysregulation and medically-unexplained symptoms.

The positive feedback model of medically-unexplained symptoms posits that chronic stress affects the activity of the physiological stress axes, which in turn generates medically-unexplained symptoms. As a first step to empirically test its model assumptions, we investigated potential associations between chronic stress, physiological stress axis activity and medically-unexplained in a cross-sectional study. One hundred-ninety-nine healthy individuals provided self-reports on chronic stress and medically-unexplained symptoms, resting heart rate/variability (HR/HRV; e.g., root mean square of successive differences/RMSSD, low frequency/LF power), cortisol awakening response (CAR) and diurnal cortisol. Significant positive contributors to medically-unexplained symptoms were the chronic stress scales 'lack of social appreciation' and 'chronic worries', as well as CAR and LF HRV; diurnal cortisol was a negative contributor. Mediation analyses showed that the impact of neural indicators associated with physiological stress axis activity (HR/HRV) related to medically-unexplained symptoms, which was mediated by chronic stress, whereas the mediation effect as suggested by the positive feedback model was not significant. These cross-sectional findings do not support the positive feedback model. Longitudinal studies are required to conclude about potential mechanistic and causal relationships in the model. Nevertheless, our mediation analyses give first indication that the constitution of physiological stress axes may play a major role in how stressors are perceived and which kind of health-consequences (e.g., medically-unexplained symptoms) this may have.

Close(d) to you? Avoidant attachment is associated with attenuated pupil responsivity to social stimuli.

Insecure attachment is thought to impair romantic relationships, presumably also contributing to mental health problems. Previous research has suggested a link to biased automatic processing of social information, potentially reflected in pupil dilation responses. To address this hypothesis, 37 adults were presented with attachment-related, emotional pictures of erotic couples, everyday couples, or interpersonal violence after assessment with the Experiences in Close Relationships Scale. Considerable variation in self-reported attachment behaviors regarding both attachment anxiety and avoidance was observed in our sample. Overall, pupil dilation was most pronounced during viewing of erotica and violence-related pictures. Relative to nature pictures as control, attachment avoidance was associated with attenuated pupillary responses to social content. However, this was not significant with erotica. For pictures of violence, this avoidant bias was also evident in reduced subjective arousal. In contrast, attachment anxiety was unrelated to differential pupil dilation. Our findings, although preliminary, suggest that previous attachment-related experiences may bias the processing of social stimuli, which in turn may be reflected in altered patterns of pupillary responses.

Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release.

BACKGROUND: Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and behavioral effects of cortisol from those of the adrenergic system. Administration (oral or IV) of hydrocortisone is a direct and efficient method to elevate cortisol, and thus, frequently used in psychobiological stress research. However, lowering of cortisol (i.e. blockade of stress cortisol) requires a more sophisticated approach, such as the administration of the corticostatic compound metyrapone (MET). However, there is insufficient knowledge about the temporal dynamics of MET for the blocking of stress-induced cortisol reactivity. Thus, the present study aimed to build up an experimental protocol suitable to suppress acute behavioral stress-induced cortisol secretion by MET. METHODS: 50 healthy young men were randomly assigned to one of five treatment groups. They received 750 mg oral MET either 30 (n = 9), 45 (n = 11), or 60 (n = 10) minutes before exposure to a combined cold pressor and mental arithmetic test (stress induction), or were subjected to two different control treatments (placebo 60 min before stress (n = 10) or MET 30 min before non-stressful warm-water condition (n = 10)). Salivary cortisol concentration, hemodynamics, and subjective ratings were assessed. RESULTS: Suppression of cold stress-induced cortisol release was strongest when MET intake was scheduled 30 min prior to stress onset. Cardiovascular stress-responses and subjective ratings remained unaffected by MET. CONCLUSION: In healthy young males, 750 mg of MET efficiently block cold stress-induced cortisol release when oral administration is scheduled 30 min prior to stress onset. This finding may guide future research in improving timing of suppression of stress-induced cortisol secretion.

Increased pupil and heart-rate responses to sexual stimuli in men after physical exertion.

Physical stress has been found to enhance arousability by visual sexual stimuli on a short-term basis, as reflected in higher phasic pupil dilation responses, probably mediated by sympathetic nervous system (SNS)-related processes. However, previous research has not addressed the specificity of this effect in terms of emotional valence, that is, whether it reflects an instance of general excitation transfer or a more specific mechanism. Thus, to further investigate changes in sexual processing after acute stress exposure, 40 male participants underwent either a predominantly sympathetic stressor (3 min sustained handgrip) or similar control procedure. After stress induction, pictures varying in valence as well as sexual versus non-sexual arousal were presented (for 5000 ms each). Using principal component analysis, pupillary responses during picture viewing were dissociated into fast and slow components (early vs. late response phases). In addition, startle eyeblink responses were elicited by bursts of white noise (50 ms, 105 dB) in half of the trials and recorded at the orbicularis oculi via electromyography. Skin conductance and heart rate were co-registered, as well. While affective startle modulation and skin conductance responses to emotional stimuli were unaffected by previous stress exposure, both evoked heart-rate deceleration (but not acceleration) and pupil responses were specifically enhanced with sexually arousing stimuli in stressed participants, and this effect was mediated by blood pressure reactivity as an index of preceding SNS activation. Taken together, our findings provide strong evidence for enhancement of sexual processing by acute stress exposure in men and suggest differential involvement of parasympathetic versus sympathetic mechanisms.

Stress effects on the top-down control of visuospatial attention: Evidence from cue-dependent alpha oscillations.

Stress is assumed to inhibit the top-down control of attention and to facilitate bottom-up processing. Evidence from human experiments, however, remains scarce. Previous studies have addressed how stress affects the interplay of bottom-up and top-down mechanisms of attention. A key open question is in how far such effects can actually be attributed to a stress-induced modulation of top-down attention control. We sought to isolate top-down from bottom-up effects by assessing stress effects on anticipatory changes in alpha oscillations that precede stimulus processing. Participants performed in a cued target detection task in which a cue prompted them to covertly shift their attention to left or right screen positions, 20 min after being exposed to the bilateral feet cold pressor test or a warm water control procedure. The stressor led to a substantial increase in cortisol, peaking 20 min post stressor, along with rises in heart rate, blood pressure, and subjective ratings of stress and arousal. As expected, cued attention deployment led to higher alpha power over posterior electrodes contralateral versus ipsilateral to the attended hemifield during the cue-target interval. Importantly, this purely endogenous effect was potentiated by stress, however, significant differences were restricted to the middle of the cue-target interval and thus temporally separated from the appearance of the target. These results indicate that stress does not impair top-down attentional control per se but may introduce a qualitative change modulating the way attention is deployed to meet action goals.

Stressed in afterthought: Neuroendocrine effects of social self-threat during physical effort are counteracted by performance feedback after stress exposure.

Social self-threat during physical stress, such as exposure to the cold pressor test and isometric handgrip test, has been shown to induce activation of the HPA axis, in addition to autonomic responses. However, previous research has suggested that dysfunctional post-event processing may play a major role in neuroendocrine reactivity at initial as well as subsequent social stress exposure. In the present study, we investigated how the interplay of context (i.e. performance feedback) with state (i.e., self-esteem) as well as trait-like factors (i.e., ruminative tendencies) affects stress responses to repeated, short bouts of physical activity. On two sessions, 1 week apart, 53 participants (27 women) performed an isometric handgrip task for 3 min, during which they were exposed to social-evaluative threat. In addition, participants received fake feedback on their performance immediately after the task, labeling it as either 'above' (positive) or 'below average' (negative). In addition to neuroendocrine (cortisol), cardiovascular (heart rate, blood pressure) and subjective stress reactivity, performance-related and social dimensions of state self-esteem were assessed before and after stress induction. Substantial increases in cardiovascular parameters were found on both days, regardless of feedback condition. However, positive feedback led to significantly diminished neuroendocrine responses on day 1, whereas baseline cortisol on session 2 was significantly higher in the negative feedback group. Conversely, social self-esteem decreased after stress induction on both days only for participants who had received negative feedback. Changes in self-esteem reported on day 1 were associated with increased baseline cortisol at the second session, while interindividual differences in self-reported (trait) rumination were associated with cortisol reactivity at session 1. Taken together, the results suggest that effects of social evaluation during short periods of physical stress rely on post-event processing and might be counteracted by positive appraisal directly after stress exposure. Post-hoc framing (in terms of success vs. failure) may predict subsequent stress-related hormonal effects better than task demands per se, which should be considered as a potential moderator in future acute stress research, but might also be relevant to many practical applications in fields ranging from sports/performance to health psychology.

Combining mental and physical stress: Synergy or interference?

Both cognitive stressors (such as mental arithmetic tasks) and physical stressors (such as the cold pressor test, CP) are among the most widely employed tools in acute stress research, and there is growing evidence for a high degree of stimulus-response specificity, rather than uniformity, in the human stress response. However, little is known about potential synergistic or interfering effects during concurrent administration. While cognitive tasks have been hypothesized to attenuate pain perception during CP, they are also thought to enhance physiological reactivity. Conversely, physical stress might interfere with effective stress induction by cognitive challenges. To address these questions, 56 participants underwent either the CP (3-min ice-water immersion of feet) or a warm-water control condition. In half of the sample, the Paced Auditory Serial Addition Task (PASAT) was performed simultaneously (fully crossed interventions). Salivary cortisol, cardiovascular parameters, and subjective ratings as well as voice pitch (F0) were assessed. Results show that cortisol responses, self-reported pain and subjective arousal were mainly driven by cold exposure, which also led to increased F0. The PASAT incrementally enhanced cardiovascular reactions, but did not affect pain ratings nor cortisol responses to the CP. However, intra-individual concordance between elevated blood pressure and other reactivity measures was enhanced by PASAT administration during the CP. Importantly, performance decrements in the mental-arithmetic task were not associated with diminished stress responses. In conclusion, our results speak against any strong interference when administering cognitive and painful physical stressors simultaneously, pointing rather to specific additive effects, particularly regarding cardiovascular reactivity.

Cardiac cycle phases affect auditory-evoked potentials, startle eye blink and pre-motor reaction times in response to acoustic startle stimuli.

Startle stimuli evoke lower responses when presented during the early as compared to the late cardiac cycle phase, an effect that has been called 'cardiac modulation of startle' (CMS). The CMS effect may be associated with visceral-afferent neural traffic, as it is reduced in individuals with degeneration of afferent autonomic nerves. The aim of this study was to investigate whether the CMS effect is due a modulation of only early, automatic stages of stimulus processing by baro-afferent neural traffic, or if late stages are also affected. We, therefore, investigated early and late components of auditory-evoked potentials (AEPs) to acoustic startle stimuli (105, 100, 95 dB), which were presented during the early (R-wave +230 ms) or the late cardiac cycle phase (R +530 ms) in two studies. In Study 1, participants were requested to ignore (n = 25) or to respond to the stimuli with button-presses (n = 24). In Study 2 (n = 23), participants were asked to rate the intensity of the stimuli. We found lower EMG startle response magnitudes (both studies) and slower pre-motor reaction times in the early as compared to the late cardiac cycle phase (Study 1). We also observed lower N1 negativity (both studies), but higher P2 (Study 1) and P3 positivity (both studies) in response to stimuli presented in the early cardiac cycle phase. This AEP modulation pattern appears to be specific to the CMS effect, suggesting that early stages of startle stimulus processing are attenuated, whereas late stages are enhanced by baro-afferent neural traffic.

Central Sympathetic Nervous System Effects on Cognitive-Motor Performance.

The intriguing interplay between acute stress physiology and cognitive processes has long been noted. However, while stress-induced release of glucocorticoids has repeatedly been shown to impact brain mechanisms underlying cognition and memory, less experimental research addressed the effects of stress-induced central sympathetic nervous system (SNS) activation on cognitive performance. Moreover, despite the long-standing notion that the way performance is modulated by arousal may crucially depend on task complexity, mechanistic research demonstrating a direct, causal influence of altered SNS activity is scarce. Twelve healthy men participated in a placebo-controlled, pharmacologic dose-response study involving three within-subject assessments (1-week intervals). Subjective and objective indices of SNS activity as well as reaction time (RT) in three different tasks varying in cognitive demand (simple RT, choice RT, and verbal RT in complex mental arithmetic) were assessed during modulation of central SNS tone by intravenous infusions of dexmedetomidine (alpha2-agonist), yohimbine (alpha2-antagonist), and placebo. Cognitive performance was negatively affected by alpha2-agonism in all task conditions. By contrast, administration of yohimbine improved simple RT, while diminishing complex RT, supporting the assumption of a nonlinear way of action depending on task characteristics. Our results highlight the consequences of central (noradrenergic) SNS activation for cognitive-motor performance in RT tasks of varying complexity.

Modulation of startle and heart rate responses by fear of physical activity in patients with heart failure and in healthy adults.

Fear of physical activity (FoPA) has been suggested as a barrier to physical activity in patients with heart failure and might be associated with low adherence to exercise regimen despite medical guideline recommendations. The present study examined physiological indicators of FoPA by assessing startle modulation (via EMG at the orbicularis oculi muscle) and heart rate responses (derived from ECG) after affective priming with lexical stimuli of positive, neutral, and negative valence, as well as words related to physical activity as potentially phobic cues. After screening for FoPA in patients with heart failure and healthy adults, twenty participants each were assigned to one of three subsamples: a healthy control group and two cardiac patient groups scoring either low or high on FoPA. The high-FoPA group showed startle potentiation and more pronounced heart rate acceleration (than did controls) in the phobic prime condition, indicating defensive response mobilization. Among the patients, higher FoPA accounted for 30% of the startle potentiation by phobic priming, whereas general anxiety, depression, and disease severity were no significant predictors of startle modulation. These findings suggest that FoPA in patients with heart failure is associated with defensive responses on a physiological level that might be indicative of avoidance behavior, thereby contributing to low adherence to exercise regimen. Thus, FoPA presents a significant target for psychological interventions to foster physical activity in cardiac patients.

Disentangling sensorimotor and cognitive cardioafferent effects: A cardiac-cycle-time study on spatial stimulus-response compatibility.

Cardiac-cycle-time effects are attributed to variations in baroreceptor (BR) activity and have been shown to impinge on subcortical as well as cortical processes. However, cognitive and sensorimotor processes mediating voluntary responses seem to be differentially affected. We sought to disentangle cardiac-cycle-time effects on subcortical and cortical levels as well as sensorimotor and cognitive processes within a spatial stimulus-response-compatibility paradigm employing startling stimuli of different modalities. Air-puffs and white noise-bursts were presented unilaterally during either cardiac systole or diastole while bilateral startle EMG responses were recorded. Modality, laterality and cardiac-cycle-time were randomly varied within-subjects. Cognitive and sensorimotor stimulus-response-compatibility was orthogonally varied between-subjects: Participants (N = 80) responded to the stimuli via left/right button-push made with either the contra- or ipsilateral hand (sensorimotor compatibility) on either the ipsi- or contralateral button (cognitive compatibility). We found that sensorimotor compatible reactions were speeded during systole whereas sensorimotor incompatible ones were prolonged. This effect was independent of cognitive compatibility and restricted to auditory stimuli. Startle was inhibited during systole irrespective of modality or compatibility. Our results demonstrate how differential cardiac-cycle-time effects influence performance in conflict tasks and further suggest that stimulus-response-compatibility paradigms offer a viable method to uncover the complex interactions underlying behavioral BR effects.

Effects of rejection intensity and rejection sensitivity on social approach behavior in women.

OBJECTIVE: Perceived rejection plays an important role for mental health and social integration. This study investigated the impact of rejection intensity and rejection sensitivity on social approach behavior. METHOD: 121 female participants were randomly assigned to one of three conditions differing in the degree of induced rejection (inclusion, medium rejection, severe rejection). Thereafter they were asked to interact with an unknown person during a touch-based cooperative task. RESULTS: Participants high in rejection sensitivity sought significantly less physical contact than participants low in rejection sensitivity. Individuals in the medium rejection condition touched their partners more often than those in the included condition, while no difference between included and severely rejected participants could be observed. CONCLUSIONS: The results suggest that the intensity of rejection matters with regard to coping. While participants in the medium intensity rejection condition aimed to 'repair' their social self by seeking increased contact with others, severely rejected participants did not adapt their behavior compared to included participants. Implications for therapy are discussed.

Glucocorticoid receptor signaling in leukocytes after early life adversity.

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

Cortisol rapidly increases baroreflex sensitivity of heart rate control, but does not affect cardiac modulation of startle.

Cortisol, the final product of human HPA axis activation, rapidly modulates the cortical processing of afferent signals originating from the cardiovascular system. While peripheral effects have been excluded, it remains unclear whether this effect is mediated by cortical or subcortical (e.g. brainstem) CNS mechanisms. Cardiac modulation of startle (CMS) has been proposed as a method to reflect cardio-afferent signals at subcortical (potentially brainstem-) level. Using a single blind, randomized controlled design, the cortisol group (n = 16 volunteers) received 1 mg cortisol intravenously, while the control group (n = 16) received a placebo substance. The CMS procedure involved the assessment of eye blink responses to acoustic startle stimuli elicited at six different latencies to ECG-recorded R-waves (R + 0, 100, 200, 300, 400 and 500 ms). CMS was assessed at four measurement points: baseline, -16 min, +0 min, and +16 min relative to substance application. Baroreflex sensitivity (BRS) of heart rate (HR) control was measured non-invasively based on spontaneous beat-to-beat HR and systolic blood pressure changes. In the cortisol group, salivary cortisol concentration increased after IV cortisol administration, indicating effective distribution of the substance throughout the body. Furthermore, BRS increased in the cortisol group after cortisol infusion. There was no effect of cortisol on the CMS effect, however. These results suggest that low doses of cortisol do not affect baro-afferent signals, but central or efferent components of the arterial baroreflex circuit presumably via rapid, non-genomic mechanisms.

Childhood Trauma Affects Stress-Related Interoceptive Accuracy.

Early life adversity (ELA) may cause permanent disturbances in brain-body signaling. These disturbances are thought to contribute to physical symptoms and emotional dysregulation in adulthood. The current study investigated the effects of childhood trauma on young adults' interoceptive accuracy as an indicator of brain-body communication that may be dysregulated by ELA. Sixty-six participants completed an online questionnaire followed by a laboratory session including the socially evaluated cold pressor stress test during which ECG, salivary cortisol, and interoceptive accuracy were assessed. Childhood trauma was negatively related to interoceptive accuracy (IAc) after the stressor. This stress effect could not be observed for heart rate and cortisol, which were unrelated to IAc. Participants reporting higher baseline unpleasantness exhibited lower IAc after the stressor, while increases in unpleasantness due to the stressor were associated with higher IAc. Unpleasantness at baseline mediated the effect of childhood trauma on IAc after the stressor.

Test-retest reproducibility of a combined physical and cognitive stressor.

When studying the factors which influence stress reactivity in within-subject designs, test-retest reproducibility data is needed to estimate power and sample size. We report such data regarding a new experimental stress protocol, based on simultaneous application of the socially evaluated, bilateral feet Cold Pressor Test (CPT) and the Paced Auditory Serial Addition Task (PASAT). Cardiovascular, neuroendocrine, and subjective (affective) stress responses of 32 healthy males were measured twice, at an interval of one week. The novel protocol induced substantial stress reactivity in all parameters at both test and retest. Cardiovascular reactivity remained unchanged, but cortisol and subjective responses were lower at second stress exposure, with high test-retest stability of neuroendocrine (r>.7) and cardiovascular measures (r = .5 to r = .9). PASAT performance improved. Response attenuation suggests habituation-like and/or learning effects. Data provided by our study demonstrate feasibility and power of this stress protocol for investigating changes in stress reactivity in repeated, within-subject designs.

Parental divorce is associated with an increased risk to develop mental disorders in women.

BACKGROUND: Parental divorce has been associated with reduced well-being in young adults. It is, however, unclear whether this finding is clinically relevant as studies using structured clinical interviews are missing. This study, therefore, investigated if young adults with divorced parents are at risk to develop mental disorders. Furthermore, differences in parental care, social connectedness, chronic stress and traumatic experiences between children of divorced and non-divorced parents were investigated. METHODS: 121 women (mean age: 23 years) were interviewed using the Structured Clinical Interview for DSM-IV Axis I (i.e., major mental disorders) and II (i.e., personality disorders) Disorders and asked to complete questionnaires assessing parental care, social connectedness (loneliness, attachment anxiety and avoidance), chronic stress, childhood trauma and depression. RESULTS: Young adults of divorced parents had a higher risk for Axis I but not Axis II disorders as compared to young adults of non-divorced parents. Participants from divorced families as compared to non-divorced families reported more depression, loneliness, childhood trauma, attachment avoidance, attachment anxiety, chronic stress and less paterntal care. LIMITATIONS: Due to the cross-sectional design of this study, conclusions about causality remain speculative. CONCLUSION: The increased vulnerability of children of divorced parents to develop mental disorders, and to experience more chronic stress, loneliness, attachment avoidance, attachment anxiety, and traumatic experiences during childhood is alarming and highlights the importance of prevention programs and psycho-education during the process of parental divorce. Parental support with regard to adequate caregiving is needed to help parents to better support their children during and after their divorce.

Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response in vitro and in vivo.

The corticotropin-releasing hormone (CRH) is a neuropeptide mediating stress responses. CRH exerts effects via the hypothalamus pituitary adrenal axis as well as immediate effects on the sympathetic-adrenal-medullary system. Genetic variants of the CRH promoter were previously found to be associated with altered CRH promoter activity and physiological reactions. Functional characterization of three CRH promoter haplotypes have been performed in vitro using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of CRH haplotypes on basal parameters such as post-awakening cortisol and blood pressure as well as on stress reactivity measured after socially evaluated cold pressor test (SeCPT) was investigated. In vitro, CRH haplotype 2 showed the highest promoter activity under baseline conditions and after forskolin stimulation compared with other haplotypes. Forskolin treatment resulted in a two fold increase of haplotype 2 promoter activity compared with the baseline condition. Cell line-dependent promoter activation was found after hydrocortisone treatment. In vivo, CRH haplotype 2 carriers showed significant higher baseline blood pressure (p = .002) and blood pressure after SeCPT (p < .001), but did not differ in cortisol levels. This study provides converging evidence for the importance of CRH promoter variants on physiological stress response parameters.