Robert W. Bonsall

Ischemic, Hemodynamic, and Neurohormonal Responses to Mental and Exercise Stress Experience From the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI)

BACKGROUND The pathophysiology of mental stress-induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood. METHODS AND RESULTS The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress. CONCLUSIONS Mental stress-induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanism involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse

BACKGROUND Previous studies indicate that adverse childhood events are associated with persistent changes in corticotropin-releasing factor neuronal systems. Our aim was to determine whether altered glucocorticoid feedback mediates the neuroendocrine sequelae of childhood trauma. METHODS Standard and low-dose dexamethasone suppression tests (DST) were performed in women with a history of child abuse (n=19), child abuse and major depression (n=16), major depression and no childhood trauma (n=10), and no history of mental illness or childhood trauma (n=19). Secondary analysis with posttraumatic stress disorder (PTSD) as the organizing diagnosis was also conducted. RESULTS In the low-dose DST, depressed women with a history of abuse exhibited greater cortisol suppression than any comparator group and greater corticotropin suppression than healthy volunteers or nondepressed abuse survivors. There were no differences between nondepressed abuse survivors and healthy volunteers in the low-dose DST or between any subject groups in the standard DST. The PTSD analysis produced similar results. CONCLUSIONS Cortisol supersuppression is evident in psychiatrically ill trauma survivors, but not in nondepressed abuse survivors, indicating that enhanced glucocorticoid feedback is not an invariable consequence of childhood trauma but is more related to the resultant psychiatric illness in traumatized individuals.

Human Vaginal Secretions: Volatile Fatty Acid Content

Vaginal samples (682) were collected by a tampon method from 50 healthy young women. Samples were analyzed by gas chromatography. The volatile aliphatic acids increased during the late follicular phase of the menstrual cycle and declined progressively during the luteal phase. Women on oral contraceptives had lower amounts of volatile acids and did not show any rhythmic changes in acid content during the menstrual cycle. These same substances possess sex-attractant properties in other primate species.

Galanin: A Significant Role in Depression?

Abstract: This paper describes a hypothesis that attempts to account for how changes in noradrenergic systems in the brain can affect depression‐related behaviors and symptoms. It is hypothesized that increased activity of the locus coeruleus (LC) neurons, the principal norepinephrine (NE)‐containing cells in the brain, causes release of galanin (GAL) in the ventral tegmentum (VTA) from LC axon terminals in which GAL is colocalized with NE. It is proposed that GAL release in VTA inhibits the activity of dopaminergic cell bodies in this region whose axons project to forebrain, thereby resulting in two of the principal symptoms seen in depression, decreased motor activation and decreased appreciation of pleasurable stimuli (anhedonia). The genesis of this hypothesis, which derives from studies using an animal model of depression, is described as well as recent data consistent with the hypothesis. The formulation proposed suggests that GAL antagonists may be of therapeutic benefit in the treatment of depression.

Left Ventricular, Peripheral Vascular, and Neurohumoral Responses to Mental Stress in Normal Middle-Aged Men and Women Reference Group for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) Study

BACKGROUND The normal cardiovascular response to mental stress in middle-aged and older people has not been well characterized. METHODS AND RESULTS We studied 29 individuals 45 to 73 years old (15 women, 14 men) who had no coronary risk factors, no history of coronary artery disease, and a negative exercise test. Left ventricular (LV) volumes and global and regional function were assessed by radionuclide ventriculography at rest and during two 5-minute standardized mental stress tasks (simulated public speaking and the Stroop Color-Word Test), administered in random order. A substantial sympathetic response occurred with both mental stress tests, characterized by increases in blood pressure, heart rate, rate-pressure product, cardiac index, and stroke work index and rises in plasma levels of epinephrine and norepinephrine but not beta-endorphin or cortisol. Despite this sympathetic response, LV volume increased and ejection fraction (EF) decreased secondary to an increase in afterload. The change in EF during mental stress-varied among individuals but was associated positively with changes in LV contractility and negatively with baseline EF and changes in afterload. EF decreased > 5% during mental stress in 12 individuals and > 8% in 5; 3 developed regional wall motion abnormalities. CONCLUSIONS Mental stress in the laboratory results in a substantial sympathetic response in normal middle-aged and older men and women, but EF commonly falls because of a concomitant rise in afterload. These results provide essential age- and sex-matched reference data for studies of mental stress-induced ischemia in patients with coronary artery disease.

Immunohistochemical labeling of androgen receptors in the brain of rat and monkey

Androgen receptor antibodies have recently been developed using fusion proteins containing fragments of human prostatic androgen receptor. We have used a polyclonal antibody raised in rabbits to label androgen receptors in brain sections from male and female rats and monkeys. Free-floating frozen sections were incubated in primary antibody, and processed by the peroxidase-avidin-biotin complex method using biotinylated anti-rabbit IgG. Nickel intensified diaminobenzidine was used as the chromagen, and neurons were labeled in the amygdala, hippocampus, bed nucleus of stria terminalis, septum, preoptic area, in several hypothalamic nuclei including the supraoptic and paraventricular nuclei, in several brain stem motor nuclei and in cerebral cortex. Staining was most intense in cell nuclei but also occurred in cytoplasm and in some neuronal processes. Labeling was more restricted in monkey than in rat brain. Omitting the primary antibody or pre-incubating the primary antibody with rat prostatic cytosol for control purposes demonstrated the specificity of staining.

Effects of Acute Mental Stress and Exercise on Inflammatory Markers in Patients With Coronary Artery Disease and Healthy Controls

Physical and mental stressors result in increased inflammation markers in populations free of coronary artery disease (CAD). However, inflammatory responses to mental and exercise challenges have not been established in patients with CAD. This study investigated the responses of inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1, in patients with CAD after successful elective percutaneous coronary intervention (n = 36, 59 +/- 8 years of age, 33% women) and healthy controls without a history of CAD (n = 28, 54 +/- 10 years of age, 36% women). Increases in inflammatory markers were examined in response to mental challenge tasks (anger recall and mental arithmetic) and treadmill exercise. Stress echocardiography was used to rule out stress-induced ischemia as a possible confounding factor. Results showed that CRP increased significantly to mental challenge and exercise (p values <0.01), and CRP responses were higher in patients with CAD than in controls (change in mental arithmetic 0.19 +/- 0.11 vs 0.01 +/- 0.03 mg/L, p = 0.003; change in exercise 0.57 +/- 0.11 vs 0.08 +/- 0.0.03 mg/L, p = 0.001). Increased norepinephrine responses were related to larger CRP and IL-6 increases to mental challenge tasks (p values <0.05). Exercise elicited increased CRP, IL-6, and soluble intercellular adhesion molecule-1 levels (p values <0.01), and these responses were larger than with mental challenge tasks (p values <0.05). In conclusion, mental stress and exercise induce increased levels of inflammatory markers in patients with CAD. These stress-induced increases are larger than in healthy subjects, occur in the absence of myocardial ischemia, and are related to the neurohormonal stress response.

Effects of dopamine β-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice

RationaleDopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), thus playing a critical role in catecholamine metabolism.Objectives/MethodsWe examined the effects of Dbh gene dosage and the DBH inhibitor disulfiram in mice with zero, one, or two null Dbh alleles (+/+, +/−, and −/− mice).ResultsDBH protein levels in adrenal and prefrontal cortex (PFC) and adrenal DBH activity were proportional to number of wild-type alleles. Adrenal DA was slightly increased in +/− mice and markedly increased (80-fold) in −/− mice compared to wild-type animals. While adrenal NE and epinephrine (EPI) were undetectable in −/− mice, adrenal concentrations of NE and EPI were similar in +/+ and +/− mice, suggesting that the increase in DA maintains the normal rate of β-hydroxylation in Dbh +/− mice. Disulfiram had little effect on adrenal catecholamine levels, regardless of genotype or dose. NE was absent in the PFC of −/− mice, but only slightly reduced in +/− animals compared to wild-type animals. PFC DA was increased twofold in +/− mice and fivefold in −/− mice, and the NE to DA ratio was reduced (∼35%) in +/− mice, compared to wild-type mice. Disulfiram significantly decreased PFC NE and increased DA in +/+ and +/− animals, with the disulfiram and genotype effects on the PFC NE to DA ratio apparently additive.ConclusionsThe data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

Effects of the nonsteroidal aromatase inhibitor, Fadrozole, on sexual behavior in male rats

The new nonsteroidal aromatase inhibitor, Fadrozole (CGS 16949A, CIBA-Geigy Corp.), was tested for its ability (i) to inhibit the conversion of testosterone (T) to estradiol (E2) in brain and (ii) to suppress male sexual activity. Sprague-Dawley rats were castrated and immediately given sc Silastic T-implants and osmotic minipumps delivering 2.5 mg/kg/day Fadrozole (N = 4), 0.25 mg/kg/day Fadrozole (N = 4), or water (N = 4 controls). T-implants were removed after 6 days and, 3 days later, 3H-T (1 microCi/g) was given as an iv bolus. No 3H-E2 was detected in hypothalamic or amygdaloid nuclear pellets from Fadrozole-treated males but this metabolite predominated in controls. However, nuclear concentrations of 3H-T and [3H]dihydrotestosterone were similar in all groups. In another group of males (N = 18), brain aromatase activity was reduced by more than 96% at the 0.25 mg/kg dose level. Additional castrated, T-implanted males received minipumps delivering 0.25 mg/kg/day Fadrozole (six males) or water (six behaviorally matched controls) and were tested weekly with receptive females. After 2 weeks, ejaculations were reduced by 77% compared with controls (P less than 0.01) and, after 4 weeks, intromissions were also significantly reduced (P less than 0.05) but less so (48%). Radioenzymatic estimates of plasma aromatase inhibitor levels remained elevated throughout Fadrozole treatment. These males were then given Silastic E2 implants: intromissions increased significantly in 1 week (P less than 0.01), but ejaculations remained below control values. Results supported the view that aromatization is important for sexual behavior in male rats and suggested that Fadrozole has utility for studying the mechanisms by which testosterone affects behavior.

Neurohormonal and Inflammatory Hyper-Responsiveness to Acute Mental Stress in Depression

Depression is associated with dysregulated hypothalamic-pituitary-adrenal (HPA) axis function, overactivity of the sympathoadrenal system, and increased levels of inflammation markers. It is not known whether these biological processes are disproportionately elevated in response to acute negative emotional arousal by mental stress (MS). The present study investigates responses of neurohormones and inflammatory markers to MS in 14 clinically depressed (age: 42+/-10 years; 50% female) and 14 non-depressed control (age: 39+/-6 years; 50% female) participants. Heightened acute MS reactivity was documented in depressed participants (adrenocorticotropic hormone, rho=0.001; norepinephrine, rho=0.042; epinephrine, rho=0.039), and a delayed increase in cortisol was observed (rho=0.002). Inflammation markers increased more strongly in depressed versus non-depressed participants (IL-6, rho=0.027; tumor necrosis factor-alpha, rho=0.050; and recovery C-reactive protein, rho=0.003). It is concluded that depressed individuals display hyper-reactivity of neuroimmunological markers in response to acute negative emotions. This hyper-reactivity may serve a pathologic role in the elevated morbidity and mortality risk associated with depression.