Yohimbine increases cerebrospinal fluid and plasma norepinephrine but not arginine vasopressin in humans.

Previous studies have demonstrated alpha 2-inhibitory regulation of central nervous system (CNS) noradrenergic and arginine vasopressinergic systems. We tested the hypothesis that alpha 2-inhibition of CNS noradrenergic and vasopressinergic systems is tonic in nature by measuring the response of cerebrospinal fluid (CSF) norepinephrine (NE) and arginine vasopressin (AVP) to the alpha 2-antagonist yohimbine in 7 young normal male human subjects. We also evaluated the tonic nature of alpha 2-inhibition of the sympathetic nervous system (SNS) and of AVP release into plasma by measuring the response of plasma NE and plasma AVP to yohimbine. CSF NE was significantly higher following yohimbine as compared to placebo. In contrast CSF AVP did not differ between yohimbine and placebo conditions. Similarly, plasma NE was significantly higher following yohimbine as compared to placebo, while plasma AVP was unchanged. These results support a tonic alpha 2-inhibitory regulatory mechanism for both CNS noradrenergic systems and sympathetic outflow. Such tonic alpha 2-inhibition could not be demonstrated for regulation of AVP levels in CSF or plasma in humans.

Neuroendocrine responses to physostigmine in Alzheimer's disease.

To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.

Increased plasma and cerebrospinal fluid norepinephrine in older men: differential suppression by clonidine.

To evaluate the effect of advanced age on central nervous system noradrenergic activity, cerebrospinal fluid (CSF) and plasma norepinephrine (NE) concentrations were measured concurrently in 14 older [mean, 65 +/- 9 (+/- SD) yr] and 33 younger (25 +/- 2 yr) normal men. CSF NE was significantly higher in older men than in young men [214 +/- 75 (+/- SD) vs. 164 +/- 56 pg/mL (1.26 +/- 0.44 vs. 0.97 +/- 0.33 nmol/L); P less than 0.02] as was plasma NE [282 +/- 103 vs. 211 +/- 63 pg/mL (1.67 +/- 0.61 vs. 1.25 +/- 0.37 nmol/L); P less than 0.02]. Subgroups of young and older men underwent two lumbar punctures, one of which was performed 100 min after the administration of 5 micrograms/kg oral clonidine. The young (n = 7) and older (n = 7) men had similar plasma clonidine levels [1.0 +/- 0.1 vs. 0.8 +/- 0.1 ng/mL (4.35 +/- 0.43 vs. 3.48 +/- 0.78 nmol/L)] and CSF clonidine levels [0.18 +/- 0.02 vs. 0.22 +/- 0.03 ng/mL (0.78 +/- 0.09 vs. 0.96 +/- 0.13 nmol/L)]. The suppression of CSF NE by clonidine was significantly greater (P less than 0.015) in young men [189 +/- 44 to 104 +/- 26 pg/mL (1.12 +/- 0.26 to 0.62 +/- 0.15 nmol/L)] than in older men [190 +/- 49 to 164 +/- 58 pg/mL (1.12 +/- 0.29 to 0.97 +/- 0.34 nmol/L)]. In contrast, the suppression of plasma NE by clonidine did not significantly differ between young [242 +/- 72 to 93 +/- 24 pg/mL (1.43 +/- 0.43 to 0.55 +/- 0.14)] and older men [285 +/- 102 to 167 +/- 84 pg/mL (1.68 +/- 0.60 to 0.99 +/- 0.50 nmol/L)]. These data suggest that decreased sensitivity of alpha 2-adrenergic mechanisms regulating CNS noradrenergic activity may contribute to increased CNS noradrenergic activity with aging.

Tricyclic antidepressants and supine, standing, and exercise plasma norepinephrine levels.

Fourteen depressed patients were treated for 1 to 8 wk (4.1 +/- 0.6, mean +/- SEM) with imipramine, doxepin, or amitriptyline to study the effects of tricyclic antidepressants (TCAs) on sympathetic nervous system (SNS) function. Eight had chronic but medically stable cardiac disease and six were medically healthy. Supine plasma norepinephrine (NE) and epinephrine (EPI) levels, mean arterial blood pressure (MAP), and heart rate were measured at rest, after standing, and during graded, supine maximal bicycle exercise. Eight nondepressed patients with cardiac disease were studied without drug intervention as controls. There were no baseline differences in any of these measures among the medically healthy depressed subjects, the depressed cardiac patients, and the eight nondepressed patients matched for cardiac disease. After TCAs, NE was increased by 51 +/- 6% of basal values and heart rate rose, but EPI and MAP were unchanged. The supine to 10-min standing increment in NE increased from 309 +/- 51 pg/ml at baseline to 406 +/- 55 pg/ml during TCA treatment. These findings are compatible with an increase in SNS outflow after TCAs.

Efficacy of antipsychotic medications in behaviorally disturbed dementia patients.

This study compared the therapeutic efficacy of thioridazine, loxapine, and a placebo in the treatment of behavioral disturbances in nursing home patients with dementia. Antipsychotic medications were effective for the specific behavioral problems of anxiety, excitement, emotional lability, and uncooperativeness. Subjects with the most severe symptoms at baseline assessment derived the greatest benefit from treatment. Sedation, extrapyramidal symptoms, and decreased blood pressure were common side effects among patients treated with the antipsychotic drugs. The authors conclude that antipsychotic medication has a definite but limited therapeutic role in the treatment of behavioral disturbances in nursing home patients with dementia.

Cardiovascular and antidepressant effects of imipramine in the treatment of secondary depression in patients with ischemic heart disease.

The authors report on 12 men with ischemic heart disease who developed secondary depression following myocardial infarction or coronary artery bypass-graft surgery and were treated with imipramine hydrochloride for 4 weeks. Imipramine had an antiarrhythmic effect, manifested by reduction in premature ventricular contractions during treatment. This drug did not produce clinically significant disturbances in cardiac conduction, but orthostatic hypotension led to early termination of the drug treatment in 1 subject. Imipramine treatment was associated with significant improvement in both observer-rated and patient-rated depression scales.

Cardiovascular effects of tricyclic antidepressants in depressed patients with chronic heart disease.

Twenty-four depressed patients with heart disease were treated for four weeks in a double-blind trial of imipramine, doxepin, or placebo to assess the effects of tricyclic antidepressants on ventricular function and rhythm. The tricyclic antidepressants had no effect on left ventricular ejection fraction at rest or during maximal exercise, as measured by radionuclide ventriculograms obtained before and after treatment. Premature ventricular contractions were reduced by imipramine but were not consistently changed by doxepin or placebo. Treatment with imipramine and doxepin, but not placebo, was associated with significant improvement (P less than 0.001) in standard ratings of depression. Our findings underscore the need for a reappraisal of the cardiovascular risks of tricyclic antidepressants and suggest that in the absence of severe impairment of myocardial performance, depressed patients with preexisting heart disease can be effectively treated with these agents without an adverse effect on ventricular rhythm or hemodynamic function.

The effects of age on the plasma catecholamine response to mental stress in man.

To determine if sympathetic nervous system activity is heightened during psychological stress in older adults, plasma norepinephrine (NE), epinephrine (EPI), heart rate, and blood pressure were measured in 10 healthy old (mean age, 68.5 yr) men and 10 healthy young (mean age, 26.6 yr) men during a 12-min mental stress test. Basal NE was higher in old than in young men (400 +/- 33 vs. 286 +/- 32 pg/ml: p less than 0.01). Consistent significant increases in plasma NE occurred only in the elderly and mean increases (delta) in NE during testing were significantly greater (P less than 0.01) in the old than in the young men. Compared to basal levels, plasma EPI increased by 2 min in both young (delta EPI, 50 +/- 20 pg/ml; P less than 0.02) and old subjects (delta EPI, 41 +/- 11; P less than 0.01) and remained significantly increased throughout the test. There was no difference in either basal or delta EPI between young and old men. Heart rate and blood pressure were significantly increased throughout testing for both age groups. Although the delta blood pressure during testing tended to be greater in the old men, this difference was not statistically significant. Conversely, the delta heart rate was greater in the young subjects (P less than 0.005). Since EPI increases were similar in old and young men, mental stress-related adrenomedullary activation does not appear to change with age. However, the increased plasma NE response in the elderly suggests that they have heightened activity of postganglionic sympathetic neurons during psychological stress.