Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects.

Increased sympathetic nervous system (SNS) activity has been associated with stress, major depression, aging, and several medical conditions. This study assessed the effect of the selective serotonin reuptake inhibitor (SSRI), sertraline, on sympathetic nervous system (SNS) activity in healthy subjects. Twelve healthy volunteers participated in a double-blind, placebo-controlled, norepinephrine (NE) kinetic study, in which the effects of sertraline on SNS activity were ascertained by determining NE plasma concentrations and NE plasma appearance rates and clearance rates in sertraline or placebo conditions. Subjects received 50 mg of sertraline or placebo for two days and then one week later underwent the same protocol with the other drug. By single compartmental analysis, plasma NE appearance rates were significantly lower in the sertraline compared to the placebo condition (0.26+/-0.10 vs 0.40+/-0.23 microg/m(2)/min; P=0.04). Our study found that the net effect of short-term SSRI treatment is an apparent suppression of SNS activity as indicated by a decreased plasma NE appearance rate in the sertraline condition. If this preliminary finding can be extended to long-term treatment of patients, this could have significant therapeutic relevance for treating depression in elderly patients or those with cardiac disease, in which elevated SNS activity may exacerbate underlying medical conditions.

Halothane anesthesia does not suppress sympathetic activation produced by neuroglucopenia.

To determine the suitability of halothane anesthesia for studies of sympathetic control of the endocrine pancreas in dogs, we assessed the effect of halothane anesthesia (0.8% inspired concentration) on the sympathetic response to central neuroglucopenia. In dogs anesthetized with halothane, intravenous administration of the neuroglucopenic agent, 2-deoxy-D-glucose (2-DG; 100 mg/kg), produced increases of both systemic plasma epinephrine (EPI; delta = 269 +/- 86 pg/ml, P less than 0.025) and norepinephrine (NE; delta = 157 +/- 55 pg/ml, P less than 0.025) equivalent to those previously observed in conscious dogs. Measurement of plasma NE kinetics revealed that the plasma NE response to 2-DG during halothane was due to an increase in the rate of NE appearance that was identical to that of conscious dogs, rather than to an impairment of NE clearance. In contrast, 2-DG at this dose did not increase plasma EPI or NE levels in dogs anesthetized with pentobarbital sodium (30 mg/kg). Plasma glucose increased modestly after 2-DG (100 mg/kg) in both conscious and halothane-anesthetized dogs but not in the pentobarbital-anesthetized dogs. Although 2-DG at a threefold higher dose (300 mg/kg) caused plasma EPI, NE, and glucose (delta = 12 +/- 3 mg/dl, P less than 0.001) to increase in pentobarbital-anesthetized dogs, the responses to this higher dose of 2-DG were all significantly larger in halothane-anesthetized dogs (delta of plasma glucose = 30 +/- 8 mg/dl, P less than 0.005; P less than 0.0025 vs. pentobarbital).(ABSTRACT TRUNCATED AT 250 WORDS)

Age and alpha-2 adrenergic regulation of plasma norepinephrine kinetics in humans.

To investigate whether the age-related elevation of plasma norepinephrine (NE) is due to impaired alpha-2 adrenergic inhibition of sympathetic nervous system (SNS) outflow, arterialized plasma NE kinetics were measured before and 120 to 140 min after 1.5 and 5.0 micrograms m/kg oral clonidine in 6 old (57 to 78 years) and 8 young (25 to 39 years) normotensive male volunteers. Baseline plasma NE levels were higher in old compared with young men (M +/- SEM, 355 +/- 58 vs. 197 +/- 22 pg/ml, p less than .02). Clonidine produced significant (p less than .05) dose-related reductions in plasma NE, NE appearance rate, NE clearance, and mean arterial blood pressure (MAP) in both groups. There was no difference between old and young men in response to low dose clonidine. Following the higher dose, both groups had similar suppression of plasma NE (-51 +/- 7% vs. -58 +/- 2%, p greater than .05) and NE appearance (-60 +/- 6% vs. -62 +/- 2%, p greater than .05), but older men had a greater fall in NE clearance (-20 +/- 2% vs. -10 +/- 1%, p less than .003) and MAP (-28 +/- 3% vs. -10 +/- 4%, p less than .006). These findings suggest that sensitivity to alpha-2 receptor-mediated suppression of plasma NE and NE appearance is not diminished in elderly men.

Peripheral sympathectomy and adrenal medullectomy do not alter cerebrospinal fluid norepinephrine.

Despite a blood-brain barrier for norepinephrine, the concentration of norepinephrine in plasma and cerebrospinal fluid has been observed to be similar. This relationship between plasma and cerebrospinal fluid norepinephrine levels suggest that peripheral sympathetic neurons innervating blood vessels to brain and spinal cord may contribute significantly to cerebrospinal fluid norepinephrine levels, and questions the validity of cerebrospinal fluid norepinephrine as an index of central nervous system noradrenergic activity. We demonstrate that extensive destruction of the peripheral sympathetic nervous system and the adrenal medulla has no effect on rat cerebrospinal fluid norepinephrine. It is therefore unlikely that peripheral sources of norepinephrine contribute significantly to cerebrospinal fluid norepinephrine levels.

Effect of pentobarbital anesthesia on plasma norepinephrine kinetics in dogs.

To assess the effect of barbiturate anesthesia on sympathetic nervous system activity, plasma norepinephrine (NE) kinetics were measured in trained dogs with an indwelling right atrial catheter before and during iv administration of pentobarbital sodium (30 mg/kg, iv, plus continuous infusion at 0.1-0.2 mg/kg X min). Plasma NE levels fell by 64 +/- 6% from 103 +/- 22 to 42 +/- 18 pg/ml (mean +/- SEM; n = 6; P less than 0.001) during pentobarbital anesthesia. As measured with the isotope dilution method using steady state kinetics, basal NE spillover rate into plasma was 203 +/- 92 ng/min; this level fell by 91 +/- 2% (P less than 0.001) to 24 +/- 13 ng/min during anesthesia. Clearance of NE from plasma was also impaired by the anesthesia. Before pentobarbital administration, the NE clearance rate from plasma was 1.7 +/- 0.4 liters/min; this rate fell during anesthesia by 71 +/- 6% (P less than 0.001) to 0.5 +/- 0.2 liters/min. During control studies in which no barbiturate was administered, there was no change in plasma NE levels (111 +/- 11 vs. 116 +/- 19 pg/ml; n = 3), NE spillover rate into plasma (209 +/- 56 vs. 204 +/- 61 ng/min), or clearance of NE from plasma (1.8 +/- 0.4 vs. 1.7 +/- 0.2 liters/min). The marked suppression of the NE spillover rate into plasma during pentobarbital administration suggests that this type of anesthesia causes a profound suppression of baseline sympathetic nervous system activity in trained dogs. The observed fall of plasma NE levels underestimated the degree of suppression of sympathetic nervous activity by the anesthesia, since there was a concurrent fall in NE clearance from plasma.