Basal Norepinephrine Research Articles

Hypothalamic monoamines in cold stress on the background of changes in the activity of the nitric oxide system

The effects of the NO donor sodium nitroprusside and the NO synthase blocker L-omega-N-nitroarginine (LNA) on body temperature, hypothalamic monoamines, and plasma corticosterone in conditions of cooling were studied in Male Wistar rats. Reductions in body temperature on cooling, both after administration of sodium nitroprusside and LNA, were no different from those seen without treatment. The basal corticosterone level after treatment with sodium nitroprusside increased from 5.3 +/- 2.2 to 29.1 +/- 1.8 microg%. Cooling led to a multiple increase in corticosterone levels in all animals, both in control conditions and after treatment with sodium nitroprusside and LNA. Sodium nitroprusside significantly decreased the basal hypothalamic noradrenaline level, by 37%. Cooling of the animals in these conditions led to an additional drop in the noradrenaline level. Noradrenaline levels 48 h after cold stress applied to animals cooled after treatment with LNA or sodium nitroprusside were significantly higher than in those cooled without treatment. No changes in serotonin and 5-hydroxyindoleacetic acid levels were seen in these experiments. The basal dihydroxyphenylacetic acid and dopamine levels increased after treatment with sodium nitroprusside, by 379% and 239% respectively. No dopamine response to cold was observed, though the dihydroxyphenylacetic acid level in the control group and animals treated with LNA increased. Thus, cold stress did not reveal differently directed directions for the actions of the NO donor and the NO synthase blocker, as seen with other types of stress.

Effects of exercise on plasma catecholamine levels in the toad, Bufo paracnemis: Role of the adrenals and neural control

Resting plasma epinephrine (E) and norepinephrine (N) concentrations for intact toads (Bufo paracnemis) were 5.57+/-1.0 and 0.88+/-0.38 ng/ml, respectively. Exercise induced a significant increase in heart rate, blood pressure and plasma epinephrine (about 4.3 times), whereas norepinephrine remained unchanged. The resting [E]/[N] ratio was 6.3 and increased to 32.9 during exercise. Adrenal denervation did not alter the basal plasma catecholamine or norepinephrine levels after exercise, but prevented the increase in epinephrine during exercise, suggesting that in the intact toad this increase is due to adrenal secretion whereas resting norepinephrine may be liberated by extra-adrenal chromaffin tissues. This also suggests that the adrenal glands can release selectively the two catecholamines. The increases in heart rate and blood pressure in denervated toads were not significantly different from those of intact animals, suggesting that during exercise the sympathetic nerves play the main role in inducing cardiovascular responses. Spinal transection induced a significant increase in basal norepinephrine levels, which remained elevated after exercise. Since spinal toads are unable to perform spontaneous movements it is possible that this increase may be caused by this stressful condition. The increases in heart rate and blood pressure observed in spinal toads during exercise may be due to direct mechanical effects of venous return on the heart.

Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone.

To evaluate the relationship between the development of obesity, nervous system activity, and insulin secretion and action, we tested the effect of a 2-mo high-fat diet in rats (HF rats) on glucose tolerance, glucose-induced insulin secretion (GIIS), and glucose turnover rate compared with chow-fed rats (C rats). Moreover, we measured pancreatic and hepatic norepinephrine (NE) turnover, as assessment of sympathetic tone, and performed hypothalamic microdialysis to quantify extracellular NE turnover. Baseline plasma triglyceride, free fatty acid, insulin, and glucose concentrations were similar in both groups. After 2 days of diet, GIIS was elevated more in HF than in C rats, whereas plasma glucose time course was similar. There was a significant increase in basal pancreatic NE level of HF rats, and a twofold decrease in the fractional turnover constant was observed, indicating a change in sympathetic tone. In ventromedian hypothalamus of HF rats, the decrease in NE extracellular concentration after a glucose challenge was lower compared with C rats, suggesting changes in overall activity. After 7 days, insulin hypersecretion persisted, and glucose intolerance appeared. Later (2 mo), there was no longer insulin hypersecretion, whereas glucose intolerance worsened. At all times, HF rats also displayed hepatic insulin resistance. On day 2 of HF diet, GIIS returned to normal after treatment with oxymetazoline, an alpha(2A)-adrenoreceptor agonist, thus suggesting the involvement of a low sympathetic tone in insulin hypersecretion in response to glucose in HF rats. In conclusion, the HF diet rapidly results in an increased GIIS, at least in part related to a decreased sympathetic tone, which can be the first step of a cascade of events leading to impaired glucose homeostasis.

The Role of the Anterodorsal Thalami Nuclei in the Regulation of Adrenal Medullary Function, Beta-adrenergic Cardiac Receptors and Anxiety Responses in Maternally Deprived Rats under Stressful Conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac β-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac β-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac β-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial β-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.

Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring

Background Early environment is a major determinant of long-term mental health, evidenced by the relationship between early-life neglect or abuse and chronically increased vulnerability to developmental psychopathology, including major depressive disorder (MDD). Animal studies can increase understanding of environmentally mediated causal risk processes. We describe how daily deprivation of biological parenting in primate infants disrupts development of homeostatic and reward systems central to MDD. Methods Nine breeding pairs of marmoset monkeys provided control twins (CON) and early-deprived twins (ED); the latter were socially isolated for 30–120 min/day on days 2–28. During the first year of life, basal urinary norepinephrine (NE) titers and cardiophysiologic activity were measured. At the end of year 1 (adolescence), automated neuropsychologic tests were conducted to measure responsiveness to changes in stimulus-reward association (simple/reversed visual discrimination learning) and to reward per se (progressive ratio [PR] reinforcement schedule). Results The ED monkeys exhibited increased basal urinary NE titers and increased systolic blood pressure relative to CON siblings. The ED monkeys required more sessions to reinstate stimulus-oriented behavior following reversal, suggesting increased vulnerability to perceived loss of environmental control; ED monkeys also performed less PR operant responses, indicating that reward was less of an incentive and that they were mildly anhedonic relative to CON. Conclusions In marmoset monkeys, neglect-like manipulation of ED leads to chronic changes in homeostatic systems, similar to those in children and adolescents exposed to early-life adversity and in MDD, and to responses to environmental stimuli similar to those that characterize MDD.

Diabetic cardiomyopathy: electromechanical cellular alterations.

Diabetic patients show a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death. However, although diabetic cardiomyopathy is a frequent and important complication of diabetes mellitus, its physiological basis is not completely known. The electrocardiogram of diabetic patients shows several alterations from normal patterns, most of them related to the QT interval and T wave. Recently, different alterations in cardiac ionic currents have been described in myocytes isolated from diabetic hearts, mainly a reduction in potassium repolarizing currents. Three different mechanisms could be involved in these alterations. First, direct metabolic alterations of the cardiac myocyte, such as impaired activity of protein kinases and phosphatases, intracellular pH regulation, intracellular calcium handling, and others. Second, impaired support of extra cardiac factors regulating cardiac activity, such as sympathetic regulation of heart rate and contractility. Thus, diabetic autonomic neuropathy leads to diminished noradrenaline release in cardiac ventricle in response to standing, exercise or cold stress. Besides, diabetic cardiomyopathy reduces cardiac myocyte response to acute noradrenaline exposure and finally, impairs support of different trophic factors responsible for the regulation of ionic channel expression. Thus, basal noradrenaline release in the ventricles, necessary to maintain adequate potassium channel expression, is reduced by sympathetic neuropathy. Moreover, the levels of insulin and other trophic factors required for the maintenance of adequate ionic channel expression are also altered in diabetic patients. Therefore, different physiopathological mechanisms are involved in diabetic cardiomyopathy. Thus, further research is needed in order to prevent the development of this long-term complication, and to improve the pharmacological management of diabetic patients.

Effects of real and simulated microgravity on response of sympathoadrenal system to various stress stimuli.

Changes in plasma levels of epinephrine (EPI) and norepinephrine (NE) were investigated in humans exposed to physical exercise (WL), to psychic stressor (mental arithmetic test, MAT), and to oral glucose administration (oGTT) before and during a stay in microgravity (real space flight, SF) or in simulated microgravity (head-down bed rest, HDBR). A permanent cannula inserted into the cubital vein and a special appliance, Plasma-03, were used for blood collection, plasma separation, and freezing of samples during SF. Plasma EPI, NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylalanine (DOPA) levels were measured by the high-pressure liquid chromatography (HPLC) method. Basal plasma EPI, NE, DHPG, and DOPA levels were found within the range of control values during SF. Preflight WL produced high increase in plasma NE and moderate elevation of plasma EPI, DHPG, and DOPA levels. Exaggerated exercise induced increases in plasma NE, DHPG, EPI, and DOPA levels were demonstrated in real microgravity. A return to preflight responses of sympathoadrenal system was seen after the landing. Plasma EPI, NE, and DHPG responses to MAT were relatively small, but increased during SF. During the oGTT the plasma EPI levels were slightly reduced in microgravity. Similarly as in SF, WL in HDBR was followed by significantly exaggerated responses of plasma catecholamines. These results show that both somatic and psychological stressors are able to induce an increased activation of sympathoadrenal system during SF or simulated microgravity in HDBR.

Increased endogenous noradrenaline and neuropeptide Y release from the hypothalamus of streptozotocin diabetic rats

Noradrenaline and neuropeptide Y (NPY) in the hypothalamus regulate a number of important endocrine and autonomic functions. Alterations in brain neurotransmitter content have been described in type 1 diabetes but there is little understanding of whether these changes affect neurotransmitter release. This study examined for the first time, region-specific co-release of NPY and noradrenaline from the hypothalamus of male Sprague–Dawley rats treated intravenously with 48 mg/kg streptozotocin (STZ) or vehicle. Five weeks later, the release of endogenous noradrenaline and NPY was monitored by in vitro superfusion of ventral and dorsal hypothalamus slices under basal and potassium-stimulated conditions. STZ-diabetes induced significant increases in basal noradrenaline and NPY overflow from the ventral hypothalamus ( P<0.05); only NPY overflow was increased in the dorsal hypothalamus ( P<0.05). Noradrenaline overflow increased similarly to potassium depolarisation in vehicle and STZ-diabetic rats, whereas diabetic rats showed a significantly increased NPY overflow response to potassium depolarisation compared to vehicle rats. These region-specific increases in endogenous noradrenaline and NPY overflow from the hypothalamus in diabetes suggest increased neuronal activity at rest and enhanced responses under some conditions. Increased hypothalamic NPY and noradrenaline overflow most likely contributes to diabetic hyperphagia.

Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study

Olfactory bulbectomy (OBX) in rats produces behavioral, physiological, and neurochemical changes that resemble symptoms of depression in humans. The procedure thus serves as a rodent model of affective disorder. Many of the behavioral effects of OBX resemble psychomotor agitation. The possible role of dysregulation of ventral striatal dopamine (DA) systems in this phenomenon was investigated. Basal levels of DA, norepinephrine (NE), homovanillic acid, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were examined in the striatum of OBX and sham-operated controls using in vivo microdialysis. OBX rats exhibited significantly higher basal DA levels (192%) and lower NE levels (12%) than sham-operated controls. Locomotor activity in response to novelty and footshock stress was elevated in OBX rats. The finding of higher DA levels in striatum may explain this “agitation-like” behavior, a commonly observed phenomenon in the OBX model.

The pattern of norepinephline release in the hypothalamic paraventricular nucleus in response to repeated peripheral nerve injury differs in the acute and chronic stage in conscious rats

We investigated the change in norepinephrine (NE) release in the hypothalamic paraventricular nucleus (PVN) in response to ligature of the median and ulnar nerves using a brain microdialysis technique in conscious rats. Primary ligature was performed of the right median and ulnar nerves, and then repeated injury was performed on the left nerves 6 h or 3 weeks after the primary ligature. Primary ligature of the nerves produced a significant increase that peaked at a mean 330% above basal NE release in the first 20 min. The NE release after reinjury 6 h later was significantly higher (a peak of 650%) than after primary nerve injury, although that at 3 weeks was significantly lower (a peak of 280%). The present study demonstrated that peripheral nerve injury induces an elevated response of the PVN, which is an integral center of the autonomic nervous system. NE release after reinjury differed in the acute and chronic stages.

Basal norepinephrine in depersonalization disorder

In contrast to the noradrenergic dysregulation described in PTSD, little is known regarding noradrenergic function in dissociative disorders. The purpose of this preliminary study was to investigate basal norepinephrine in depersonalization disorder (DPD). Nine subjects with DSM-IV DPD, without lifetime PTSD, were compared to nine healthy comparison (HC) subjects. Norepinephrine was measured via 24-h urine collection and three serial plasma determinations. Groups did not differ significantly in plasma norepinephrine levels. Compared to the HC group, the DPD group demonstrated significantly higher urinary norepinephrine, only prior to covarying for anxiety. The DPD group also demonstrated a highly significant inverse correlation between urinary norepinephrine and depersonalization severity ( r=−0.88). Norepinephrine and cortisol levels (reported in a prior study) were not intercorrelated. We concluded that although dissociation accompanied by anxiety was associated with heightened noradrenergic tone, there was a marked basal norepinephrine decline with increasing severity of dissociation. The findings are in concordance with the few reports on autonomic blunting in dissociation and merit further investigation.

Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice.

Epinephrine (E) and norepinephrine (NE) play a major role in regulating metabolism and cardiovascular physiology. Both are secreted in response to stress and their measurement in plasma allows the study of sympathoadrenal function. Several studies investigating sympathoadrenal physiology are conducted using mice. Review of the literature revealed that basal mouse NE and E plasma concentrations range within 4-140 nM depending on the blood sampling method. Such variability doesn't allow study comparison and may conceal catecholamine variations in response to stress. Therefore, our aim was to determine a reliable sampling method to measure mouse plasma catecholamine concentrations. Results showed that arterial catheterization is the most accurate sampling method: E and NE basal levels were similar to those found in humans (1.1+/-0.3 nM and 4.1+/-0.5 nM, respectively). Retro-orbital bleeding led to analogous results. On the contrary, decapitation was stressful for mice and consequently NE and E concentrations were high (24.6+/-2.7 nM and 27.3+/-3.8 nM, respectively). These different bleeding methods were compared in terms of their ability to detect sympathoadrenal system stimulation (cold-pressure test). With catheter and retro-orbital samplings the expected increase in NE and E levels was easily perceived. In contrast, with decapitation no significant change in E was detected. In conclusion, arterial-catheter and retro-orbital blood sampling methods appear to be the most accurate procedures for studying the sympathetic nervous system in mice in both unstressed and stressed conditions.

Androgen-induced norepinephrine release mediating guinea pig seminal vesicle smooth muscle proliferation: potential role of pre-synaptic alpha2-adrenoceptors.

Recent studies from our laboratory have demonstrated that androgen-induced basal norepinephrine (NE) release is responsible for the onset of proliferation in seminal vesicle smooth muscle (SVM) cells during early puberty. With subsequent sexual maturation, SVM was irreversibly differentiated to an androgen-resistant-amitotic state in which basal NE release remained elevated and resistant to androgen withdrawal or repletion. Based on these findings, we hypothesized that this irreversible elevation of basal NE release during pubertal development is caused, at least in part, by the down-regulation of pre-synaptic NE feedback inhibition, secondary to irreversible reduction in the expression of neuronal (pre-synaptic) alpha(2)-adrenoceptors. Functional alpha(2)-adrenoceptors are selectively localized to pre-synaptic sites in SVM. To test this hypothesis, we employed ligand binding techniques with [(3)H]RX821002, an antagonist which labeled all alpha(2)-adrenoceptor sub-types. Initial experiments focused on analysis of competitor specificity to identify the predominant alpha(2)-adrenoceptor sub-type in SVM. Subsequently, we quantified the changes in the receptor concentration (B(max)) for [(3)H]RX821002 at the point of maximal dihydrotestosterone (DHT)-induced change in basal NE release. Based on competitor specificity for [(3)H]RX821002, the alpha(2D)-adrenoceptor sub-type predominated in SVM. We treated pre-pubertal castrate animals with DHT for 7 days, which was previously demonstrated to maximally induce basal NE release. This treatment reduced the pre-synaptic alpha(2)-adrenoceptor B(max) 4-fold. In animals which had been castrated as adults, the B(max) for [(3)H]RX821002 remained irreversibly suppressed. The DHT-dependent reduction in the alpha(2)-adrenoceptor concentration is consistent with the developmental pattern of increased basal NE release. These findings support the hypothesis that the down-regulation of pre-synaptic NE feedback is mechanistically involved in the irreversible elevation of basal NE release. NE mediates proliferation in SVM in early pubertal development. Thus, the androgen-dependent pubertal growth of smooth muscle cells may be indirectly controlled at the level of neurotransmission.

Angiotensin II AT(1) and AT(2) receptors contribute to maintain basal adrenomedullary norepinephrine synthesis and tyrosine hydroxylase transcription.

Angiotensin II (Ang II) AT(1) receptors have been proposed to mediate the Ang II-dependent and the stress-stimulated adrenomedullary catecholamine synthesis and release. However, in this tissue, most of the Ang II receptors are of the AT(2) type. We asked the question whether AT(1) and AT(2) receptors regulate basal catecholamine synthesis. Long-term AT(1) receptor blockade decreased adrenomedullary AT(1) receptor binding, AT(2) receptor binding and AT(2) receptor protein, rat tyrosine hydroxylase (TH) mRNA, norepinephrine (NE) content, Fos-related antigen 2 (Fra-2) protein, phosphorylated cAMP response element binding protein (pCREB), and ERK2. Long-term AT(2) receptor blockade decreased AT(2) receptor binding, TH mRNA, NE content and Fra-2 protein, although not affecting AT(1) receptor binding or receptor protein, pCREB or ERK2. Angiotensin II colocalized with AT(1) and AT(2) receptors in ganglion cell bodies. AT(2) receptors were clearly localized to many, but not all, chromaffin cells. Our data support the hypothesis of an AT(1)/AT(2) receptor cross-talk in the adrenomedullary ganglion cells, and a role for both receptor types on the selective regulation of basal NE, but not epinephrine formation, and in the regulation of basal TH transcription. Whereas AT(1) and AT(2) receptors involve the Fos-related antigen Fra-2, AT(1) receptor transcriptional effects include pCREB and ERK2, indicating common as well as different regulatory mechanisms for each receptor type.

In vivo monitoring of norepinephrine and its metabolites in skeletal muscle

Although skeletal muscle sympathetic nerve activity plays an important role in the regulation of vascular tone and glucose metabolism, relatively little is known about regional norepinephrine (NE) kinetics in the skeletal muscle. With use of the dialysis technique, we implanted dialysis probes in the adductor muscle of anesthetized rabbits and examined whether dialysate NE and its metabolites were influenced by local administration of pharmacological agents through the dialysis probes. Dialysate dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured as two major metabolites of NE. The skeletal muscle dialysate NE, DHPG and MHPG were 11.7±1.2, 38.1±3.2, and 266.1±28.7 pg/ml, respectively. Basal dialysate NE levels were suppressed by tetrodotoxin (Na + channel blocker, 10 μM) (5.1±0.6 pg/ml), and augmented by desipramine (NE uptake blocker, 100 μM) (25.8±3.2 pg/ml). Basal dialysate DHPG levels were suppressed by pargyline (monoamine oxidase blocker, 1 mM) (24.3±4.6 pg/ml) and augmented by reserpine (vesicle NE transport blocker, 10 μM) (75.8±2.7 pg/ml). Basal dialysate MHPG levels were not affected by pargyline, reserpine, or desipramine. Addition of tyramine (sympathomimetic amine, 600 μM), KCl (100 mM), and ouabain (Na +–K + ATPase blocker, 100 μM) caused brisk increases in dialysate NE levels (200.9±14.2, 90.6±25.7, 285.3±46.8 pg/ml, respectively). Furthermore, increases in basal dialysate NE levels were correlated with locally administered desipramine (10, 100 μM). Thus, dialysate NE and its metabolite were affected by local administration of pharmacological agents that modified sympathetic nerve endings function in the skeletal muscle. Skeletal muscle microdialysis with local administration of a pharmacological agent provides information about NE release, uptake, vesicle uptake and degradation at skeletal muscle sympathetic nerve endings.

Norepinephrine release from the ischemic heart is greatly enhanced in mice lacking histamine H3 receptors.

We previously reported that histamine H(3) receptors (H(3)Rs) are present in cardiac sympathetic nerve endings (cSNE) of animals and humans, where they attenuate norepinephrine (NE) release in normal and hyperadrenergic states, such as myocardial ischemia. The recent creation of a transgenic line of mice lacking H(3)R provided us with the opportunity to assess the relevance of H(3)R in the ischemic heart. We isolated SNE from hearts of wild-type (H(3)R(+/+)) and knockout (H(3)R(-/-)) mice and found that basal NE release from H(3)R(-/-) cSNE was approximately 60% greater than that from H(3)R(+/+) cSNE. NE exocytosis evoked by K(+)-induced depolarization of cSNE from H(3)R(+/+) mice was attenuated by activation of either H(3)R or adenosine A(1) receptors (A(1)R). In contrast, NE release from cSNE of H(3)R(-/-) was unaffected by H(3)R agonists, but it was still attenuated by A(1)R activation. When isolated mouse hearts were subjected to ischemia for 20 min, NE overflow into the coronaries was 2-fold greater in the H(3)R(-/-) hearts than in those from H(3)R(+/+) mice. Furthermore, whereas stimulation of H(3)R or A(1)R reduced ischemic NE overflow from H(3)R(+/+) hearts by 50%, only A(1)R, but not H(3)R activation, reduced NE release in H(3)R(-/-). Our data demonstrate that NE release from cSNE can be modulated by various heteroinhibitory receptors (e.g., H(3)R and A(1)R) and that H(3)Rs are particularly important in modulating NE release in myocardial ischemia. Inasmuch as excessive NE release is clinically recognized as a major cause of arrhythmic cardiac dysfunction, our findings reveal a significant cardioprotective role of H(3)R on cSNE.

The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals.

Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release from sympathetic neurons and other neurosecretory cells. However, the actions of general anesthetics on NE release from central nervous system (CNS) neurons are unclear. We investigated the effects of representative IV and volatile anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were preloaded with [(3)H]NE and superfused with buffer containing pargyline (a monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the superfusate in the absence or presence of various anesthetics. Depolarization with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM) evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30 microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at larger concentrations, reduced stimulus-evoked release. The volatile anesthetic halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect stimulus-evoked release. These findings demonstrate drug-specific stimulation of basal NE release. Noradrenergic transmission may represent a presynaptic target for selected general anesthetics in the CNS. Given the contrasting effects of general anesthetics on the release of other CNS transmitters, the presynaptic actions of general anesthetics are both drug- and transmitter-specific. General anesthetics affect synaptic transmission both by altering neurotransmitter release and by modulating postsynaptic responses to transmitter. Anesthetics exert both drug-specific and transmitter-specific effects on transmitter release: therapeutic concentrations of some anesthetics stimulate basal, but not evoked, norepinephrine release, in contrast to evoked glutamate release, which is inhibited.

Vascular effects of singlet oxygen (1O2) generated by photo-excitation on adrenergic neurotransmission in isolated rabbit mesenteric vein

It has been suggested that reactive oxygen species (ROS) may be involved in the regulation of vascular tone. However, the nature of ROS effects on vascular sensitivity remains to be elucidated. The present study was designed to investigate the effects of ROS, especially 1O2, on neurotransmission at the sympathetic neurovascular junction. Basal noradrenaline (NA) release, release of NA induced by electrical stimulation (ES), and resting NA release at the sympathetic nerve terminals were determined using a superfusion technique. The amount of NA was determined by HPLC; isometric tension changes evoked by ES were also recorded simultaneously. 1O2 was generated from Rose Bengal by photo-activation. The generation of 1O2 in the superfusate was monitored by electron spin resonance (ESR) using the spin trap 2,2,6,6-tetramethyl-4-piperidinol throughout the experimental time course. The ESR results confirmed that 1O2 was generated by photo-activation of Rose Bengal via the formation of 2,2,6,6-tetramethyl-4-hydroxyl-piperidinyloxy. Exposure of helical strips of rabbit mesenteric vein to 1O2 induced a significant increase in tension and NA release during the basal period, but had no effect on ES-induced release. L-histidine, an 1O2 scavenger, significantly inhibited the observed effects on vascular tension and NA release in response to 1O2. These results suggest that 1O2 may induce NA-mediated vasoconstriction at the postjunctional site, and may be associated with Ca2+-independent NA release from the prejunctional site of adrenergic neurotransmission.

Impaired central stress-induced release of noradrenaline in rats with heart failure: a microdialysis study

Sympathetic hyperactivity in rats with heart failure is associated with increased extracellular noradrenaline in the hypothalamic paraventricular nucleus at rest. However, it is unknown how this nucleus responds to stressful stimuli. In the present study we therefore examined the basal and stress-induced release of noradrenaline in the paraventricular nucleus of conscious Sprague–Dawley rats with heart failure measured by in vivo microdialysis. Basal noradrenaline concentration in the paraventricular nucleus of rats with heart failure was more than double that in sham-operated controls. Immobilization stress decreases noradrenaline levels in the paraventricular nucleus of rats with heart failure to 57% of baseline, while it increased in sham-operated controls to 228%. However, serum corticosterone was similarly elevated at 30 and 90 min post-stress in both experimental groups. We have shown that heart failure causes an impairment of the central noradrenergic system’s response to acute sympatho-excitation but does not affect the hypothalamo–pituitary–adrenocortical response.

Acute Handling Stress Modulates Methylphenidate-induced Catecholamine Overflow in the Medial Prefrontal Cortex

Although stress is an extensively investigated phenomenon, the effects of specific stressors on the pharmacologic activity of routinely administered drugs are less well characterized. We designed the present study to investigate the effect of handling stress on catecholaminergic responsivity following an acute methylphenidate (MP, Ritalin) challenge in the medial prefrontal cortex (mPFC). Norepinephrine (NE) and dopamine (DA) levels were simultaneously measured in 15-min samples of PFC dialysate using HPLC coupled with electrochemical detection. Sprague-Dawley rats were handled for 15 min, which produced an increase from basal extracellular DA and NE levels. Handling stress attenuates the DA response when administered 2 h prior to IP MP, whereas handling stress enhances the DA response when administered simultaneously with IG MP. These findings suggest that persistent alterations in mesocorticolimbic DA-ergic activity are induced by a short exposure to restraint stress as evidenced by the altered response to MP challenge.