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PubMed1989

Effect of locally applied epinephrine and norepinephrine on blood flow and diameter in capillaries of rat mesentery.

Epinephrine (5.5 mM; quantity: 0.01-87 pmole) and norepinephrine (5.9 mM; quantity: 0.01-88 pmole) were applied to 144 and 26 mesenteric capillaries, respectively, in 39 rats. Neither of these agents had a significant effect on the mean capillary diameter (control diameter before epinephrine application: 9.6 +/- 3.6 microns SD; before norepinephrine application: 11.4 +/- 6.6 microns SD). Unexpectedly, in 36% of the epinephrine applications and 49% of the norepinephrine applications, capillary blood flow was either reduced (epinephrine: within 6-61 sec; norepinephrine: within 3-36 sec) or stopped completely (epinephrine: within 8-124 sec; norepinephrine: 11-124 sec). These reductions (duration: 12 sec-32 min for epinephrine; 21 sec-12 min for norepinephrine) were associated with flow reductions in all neighboring capillaries fed by a common supplying arteriole. In order to check the possible direct effect of drug diffusion norepinephrine was applied at increasing distances up to 400 microns from the arteriole. For all such distances arterioles constricted much quicker than predicted by diffusion. Fluorescent staining using glyoxylic acid showed the presence of adrenergic nerves around arterioles, along capillaries as well as in the avascular tissue. It is concluded that conduction along nerves, or possibly via endothelial cell-to-cell communication, could explain the intriguing retrograde effect of locally applied drugs on the supplying arteriole.

Animals↗

PubMed1980

The effects of prostaglandins E2 and I2, and arachidonic acid on vascular reactivity to norepinephrine in isolated rat mesenteric artery, hind limb and splenic artery.

The effects of prostaglandins E2 (PGE2) and I2 (PGI2), arachidonic acid, and indomethacin on the vascular reactivity to norepinephrine were tested in three different isolated rat vascular beds (mesenteric artery, hind limb and splenic artery) perfused with the Krebs bicarbonate solution. In these vascular beds PGE2 (0.25--16 ng/ml), PGI2 (0.1--100 ng/ml), arachidonic acid (0.1--10 micrograms/ml) or indomethacin (5--25 micrograms/ml) in the perfusate did not change the basal pressure. In the splenic artery, both PGE2 and PGI2 attenuated the vascular response to norepinephrine in a dose-related manner. In the mesenteric vascular bed and the hind limb, however, PGE2 potentiated the vascular response to norepinephrine, while PGI2 attenuated this response. Acahidonic acid, a prostaglandin precursor, potentiated the vasoconstrictor response to norepinephrine in the mesenteric artery and the hind limb, whereas in the splenic artery, attenuation of the response to norepinephrine occurred. In these three vascular beds, indomethacin, a prostaglandin synthetase inhibitor, attenutated the vascular response to norepinephrine. In the mesenteric artery and the hind limb, PGE2 and not PGI2 reversed the effect of indomethacin, while in the splenic artery, neither PGE2 nor PGI2 reversed the inhibitory effect of indomethacin. These results suggest that, at least in the rat mesenteric artery and the hind limb where the modulating effect of arachidonic acid is similar to that of PGE2, PGE2 and not PGI2 is a primary endogenous prostaglandin in determining the vascular reactivity to norepinephrine.

Animals↗

PubMedDate not supplied

Long-term hypoxia increases the number of norepinephrine-containing glomus cells in the rat carotid body: a correlative immunocytochemical and biochemical study.

A group of adult rats was divided into two subgroups: one was submitted to long-term normobaric hypoxia (10% O2, two weeks) while the other (control group) was kept in the same room, breathing air. Animals from each subgroup were used to study either the norepinephrine content of the carotid body by high pressure liquid chromatography or to localize norepinephrine-containing structures using an immunocytochemical procedure (peroxidase-labelled antibodies on cryostat sections). The biochemical study showed, as expected, a large increase in carotid body norepinephrine content (19-fold) and turnover (ten-fold) in hypoxic rats. The immunocytochemical study revealed only a few norepinephrine-immunopositive glomus cells in sections through the carotid body of normoxic rats, whereas the carotid body of hypoxic rats showed a very large number of norepinephrine-positive glomus cells. This increase was quantified, using an image analyser, and it was found to constitute a 61-fold increase in the number of immunopositive profiles per section and a 29-fold increase in the immunopositive profile area/section area ratio. It is concluded that long-term hypoxia increases rat carotid body norepinephrine content by inducing norepinephrine synthesis in glomus cells in which this amine was not detectable previously, before hypoxia.

Animals↗

PubMed1981

Interactions of norepinephrine and strophanthidin in cardiac Purkinje fibers.

The actions and interactions between strophanthidin and norepinephrine on electrical and mechanical events were studied in cardiac canine Purkinje fibers perfused in vitro. The results obtained show that norepinephrine (but not strophanthidin) shifts phase 1 and the beginning of the plateau to a more positive potential, an effect reduced by beta-receptor blockade. Norepinephrine increases the contractile force to the maximal value sooner than strophanthidin. In low Ca solution, the inotropic action of strophanthidin far exceeds that of norepinephrine. Norepinephrine does not cause spontaneous discharge in the driven fibers, whereas strophanthidin eventually induces fast spontaneous rhythms. When norepinephrine is given in the presence of strophanthidin (or vice versa) spontaneous activity is induced which consists either of a slow rhythm (characterized by large action potentials) or of a fast rhythm (characterized by small action potentials). The latter is typically induced by strophanthidin alone but occurs sooner in the presence of both agents. Propranolol prevents the onset of the slow rhythm but not that of the fast rhythm. It is concluded that norepinephrine and strophanthidin increase force by different mechanisms and that the potentiation between these agents in causing spontaneous discharge may involve an enhancement of diastolic depolarization(slow rhythm) or of the oscillatory potential (fast rhythm).

Action Potentials↗

PubMed1994

Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs.

These studies were conducted to evaluate effects of high dose norepinephrine infusion on left ventricular function in anesthetized and conscious dogs. Separate groups of pentobarbital anesthetized closed-chest dogs received norepinephrine infusion for 90 min followed by 1 h of recovery. Arterial pressure, electrocardiogram, two-dimensional echocardiogram and an equilibrium radionuclide angiogram were monitored. One hour following infusion of norepinephrine, left ventricular ejection fraction was reduced in a dose-dependent fashion. Fractional shortening was similarly reduced, with increased left ventricular systolic and diastolic dimensions also observed. Left ventricular end-systolic wall stress was increased at 60 min following infusion of norepinephrine but not saline: saline, 68 +/- 8, norepinephrine, 4 micrograms/kg/min, 113 +/- 8 g/cm2. The left ventricular end-systolic wall stress/fractional shortening relationship showed reduction of contractility. In 10 conscious dogs pretreated with morphine, norepinephrine at 5 micrograms/kg/min x 90 min produced similar changes to those seen in anesthetized animals. Ejection fraction was reduced from 0.69 +/- 0.3 to 0.36 +/- 0.04 at 60 min post infusion. Fractional shortening was also reduced. Left ventricular end-diastolic dimension was increased. However, when animals were followed for 1 week, complete recovery occurred within 48 h. Histology showed mild contraction band necrosis in acute experiments and mild perivascular fibrosis in chronic experiments. Therefore, norepinephrine cardiotoxicity produced significant left ventricular dilation and reduction of ejection phase indices of left ventricular function associated with reduced contractility. In chronic dogs, histologic changes were mild, and left ventricular dysfunction was reversible.

Anesthesia↗

PubMed1985

Exaggerated nicotine-induced norepinephrine release from atherosclerotic rabbit hearts.

Excessive cigarette smoking acts synergistically with atheromatous coronary artery disease to greatly enhance the risk of acute myocardial infarction. To explore a possible mechanism of this relation, the present study tested the hypotheses that diet-induced atherosclerosis in rabbits is associated with an increase in myocardial (-)-norepinephrine content and that the increased (-)-norepinephrine can be released by nicotine. Adult male rabbits were rendered atherosclerotic by feeding them a standard laboratory diet enriched with 2% cholesterol. After 12-13 weeks on the diet, hearts were excised and retroperfused according to the Langendorff technique. There were no differences between control and atherosclerotic animals in terms of baseline (-)-norepinephrine concentration in the coronary effluent. However, increases in effluent (-)-norepinephrine concentration provoked by 10 micrograms and 30 micrograms nicotine were significantly greater in atherosclerotic hearts than in controls. Similarly, myocardial tissue from atherosclerotic animals contained significantly more (-)-norepinephrine than controls. These observations suggest that diet-induced atherosclerosis in rabbits is associated with an increase in myocardial (-)-norepinephrine content and that the augmented (-)-norepinephrine pool can be mobilized by nicotine.

Animals↗

PubMed1985

Analgesia and tolerance to intrathecal morphine and norepinephrine infusion via implanted mini-osmotic pumps in the rat.

The objectives of this study were to investigate the duration of analgesia and the development of tolerance following continuous intrathecal administration of morphine and norepinephrine alone, and morphine followed by norepinephrine via mini-osmotic pumps in the rat. Analgesia was assessed by the tail-flick test. In single pump experiments morphine 1 microliter (10 micrograms)/h (7 days) and 0.5 microliter (10 micrograms)/h (14 days) produced analgesia with tolerance by days 5-7. Norepinephrine 1 microliter (15 micrograms)/h (7 days) produced analgesia equivalent to that of morphine with tolerance developing by day 3. Following continuous intrathecal morphine 1 microliter (10 micrograms)/h for 5 days, norepinephrine 1 microliter (15 micrograms)/h for 7 days failed to produce a significant increase in analgesia. This was in contrast to the increase in analgesia seen when the norepinephrine infusion followed a saline infusion. Determination of the norepinephrine concentration in the solution from the osmotic pumps verified that the norepinephrine is stable for the treatment period.

Analgesics↗

PubMed1992

Modulation of GABAA receptor-activated current by norepinephrine in cerebellar Purkinje cells.

Previous studies employing extracellular single-unit recording in the intact cerebellum have demonstrated that norepinephrine can potentiate GABA-induced suppression of Purkinje cell spike activity. However, many issues related to the nature of this modulatory phenomenon remain to be resolved. Using whole-cell patch clamp recording, the present study investigated the effect of norepinephrine on GABA-activated membrane currents (IGABA) in solitary Purkinje cells isolated from neonatal rat cerebella following acute dissociation. Exposure of Purkinje cells to norepinephrine at a concentration which, by itself, had no obvious effect on Purkinje cell membrane conductance, consistently augmented IGABA. The catecholamine also potentiated GABA-gated chloride currents as well as muscimol-induced currents in Purkinje cells. Thus, the facilitating effect of norepinephrine on IGABA was attributed to an interaction between norepinephrine and the GABAA receptor-mediated chloride conductance. The effect of norepinephrine could be mimicked by isoproterenol as well as by 8-bromo cAMP, suggesting that a beta-receptor-mediated, cAMP-dependent cascade may underlie the observed heteroreceptor interaction. Our results establish the existence of a postsynaptic mechanism by which norepinephrine, through activation of the beta-adrenoceptor, may modulate GABAA receptor function in cerebellar Purkinje cells. This study provides the groundwork for a detailed investigation into the cascade of membrane and intracellular events underlying such a synergistic modulatory interaction at the cellular and subcellular levels.

Animals↗

PubMedDate not supplied

Influence of external light conditions on norepinephrine levels in organs innervated by sympathetic nerves from different levels.

Rat tissues receiving their sympathetic innervation from different levels were studied for changes in their norepinephrine level after maintaining the animals for 2 weeks under various lighting conditions. Constant darkness resulted in a doubling of the norepinephrine concentration in iris and a significant increase also in the pia-arachnoid when compared to the tissues from animals kept in alternating light/darkness conditions. Also continuous light gave higher norepinephrine concentrations in the pia-arachnoid. None of the light conditions studied affected cardiac norepinephrine. Norepinephrine levels in vas deferens were reduced after constant light and increased after constant darkness, compared to light/dark conditions. It is concluded that norepinephrine only in tissues innervated from the superior cervical sympathetic ganglia is influenced by external light stimuli, and that the norepinephrine changes in vas deferens are secondary effects of the hormonal alterations produced by continuous light and darkness, respectively, and affecting the entire reproductive tract.

Adrenergic Fibers↗

PubMed1993

The effect of insulin on norepinephrine uptake by PC12 cells.

We have previously reported that insulin can enhance endogenous noradrenergic activity in vitro in the rat CNS. In the present study, we examined one potential mechanism underlying this effect: the ability of insulin to inhibit norepinephrine (NE) reuptake and secondarily increase its synaptic concentration. Acute (20 min) insulin treatment (0.1-10 nM) significantly inhibited specific 3H-norepinephrine uptake by rat hypothalamic slices. To ascertain whether this is a direct effect of insulin on cells that can synthesize and release norepinephrine, we studied NE uptake by the rat pheochromocytoma PC12 cell line. In PC12 cells, insulin (0.5-10 nM) inhibited NE uptake whereas the related peptide, insulin-like growth factor 1 (IGF-1), did not. Insulin did not compete with 3H-mazindol (a ligand for the NE reuptake transporter) binding to PC12 cell membranes. Thus, this effect of insulin is not due to interaction with either IGF-1 receptors or the norepinephrine transporter, but may be due to insulin interaction with its own receptor. Chronic (96-h) insulin treatment of PC12 cells also resulted in an inhibition of 3H-norepinephrine uptake, and membranes prepared from cells chronically treated with insulin bound less 3H-desipramine than control membranes. Thus, chronic insulin treatment may result in a decrease in the numbers of membrane-associated transporters. We conclude that insulin has a direct and physiological role in the modulation of synaptic norepinephrine levels by modulating reuptake by cells that synthesize and release norepinephrine.

Animals↗

PubMed1991

Plasma norepinephrine concentrations during resuscitation in the dog.

The objective of this study was to evaluate whether the adrenal glands contribute to the increase in plasma norepinephrine concentrations during cardiopulmonary resuscitation, by releasing norepinephrine and/or by secreting epinephrine that facilitates the release of norepinephrine from sympathetic nerve endings via stimulation of presynaptic beta receptors. The experiments were performed in adrenalectomized and in sham-operated dogs. In adrenalectomized dogs the increase in plasma norepinephrine concentrations during cardiopulmonary arrest and basic life support (BLS) was markedly smaller than in sham-operated dogs. Intravenous infusion of physiologic doses of epinephrine during BLS in adrenalectomized animals did not influence the plasma norepinephrine concentrations. These data indicate that, as suggested by others, the marked increase in plasma norepinephrine concentrations during BLS in dogs is mainly of adrenomedullary origin. They also suggest that presynaptic facilitation of norepinephrine release by epinephrine is not important, but further experiments using higher doses of epinephrine are necessary.

Adrenal Glands↗

PubMedDate not supplied

Ethanol-induced inhibition of norepinephrine release from brain slices obtained from LS and SS mice.

The effects of ethanol or prostaglandin E2 (PGE2) on K+-ion-stimulated or spontaneous (3H)-norepinephrine release were assessed in slices prepared from cortex and cerebellum of long-sleep (LS) and short-sleep (SS) mice. These lines were selectively bred for differences in ethanol-induced sleep time. Ethanol inhibited K+-stimulated release from LS cortical slices at lower concentrations than that required to inhibit release from SS cortical slices. Spontaneous release, on the other hand, was enhanced at lower ethanol concentrations in SS cortical slices. Ethanol inhibited K+-stimulated release equally in LS and SS cerebellar slices. Similarly, ethanol increased spontaneous release equally in LS and SS cerebellar slices. Thus, genotype and brain region influence the effect of ethanol on norepinephrine release. Since PGE2 has been reported to inhibit norepinephrine release, the effect of PGE2 on K+-stimulated norepinephrine release was examined in LS and SS cortical slices. PGE2 inhibited norepinephrine release equally in the two mouse lines. These data indicate that ethanol may elicit some of its depressant effects by altering norepinephrine release. The difference between the lines in inhibition of release probably does not involve differences in sensitivity to PGE2. Differences in ethanol-induced PGE2 production could, however, explain the differences in sensitivity of LS and SS cortical slices to ethanol-induced inhibition of K+-stimulated norepinephrine release.

Animals↗

PubMed1996

Effect of insulin on norepinephrine overflow at peripheral sympathetic nerve endings in young spontaneously hypertensive rats.

To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 +/- 5 mm Hg v 198 +/- 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 +/- 7 mm Hg v 104 +/- 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 +/- 0.079 ng/g) than in WKY (0.723 +/- 0.022 ng/g; P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (-18.4% +/- 4.0% v -32.0% +/- 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (-8.8% +/- 4.0%, P < .05), but not in WKY (-32.5% +/- 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na(+)-K+ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings.

Adrenergic alpha-Antagonists↗

PubMed2006

Contractile hyporesponsiveness to norepinephrine of forearm veins in chronic renal failure.

BACKGROUND: We recently reported that endothelium-dependent relaxation is impaired in forearm veins from patients with chronic renal failure. However, assessment of responses to norepinephrine remains controversial. We examined the contractile response to norepinephrine in forearm veins from patients on chronic hemodialysis and the role of nitric oxide (NO), prostanoids, and Ca(2+)-activated K(+) channels in this response. METHODS: Isometric contraction curves were obtained in rings of forearm vein from 21 dialyzed patients and 12 multiorgan donors in response to norepinephrine (1 nmol/L to 10 micromol/L) or KCl (5 to 100 mmol/L). RESULTS: Veins from uremic patients were markedly less responsive to norepinephrine (7.6 +/- 0.6 g) and KCl (6.0 +/- 0.3 g) than those from organ donors (12.0 +/- 0.7 g and 10.4 +/- 0.5 g, respectively, P < .05). Treatment with N(G)-monomethyl-l-arginine (100 micromol/L), an inhibitor of NO synthase, or indomethacin (10 micromol/L), an inhibitor of prostacyclin synthesis, increased the response to norepinephrine in veins from control subjects but not in veins from dialyzed patients. Additional blockade of Ca(2+)-activated K(+) channels did not correct the hyporesponsiveness. In veins incubated in Ca(2+)-free solution containing either 100 mmol/L KCl or 1 micromol/L norepinephrine, addition of calcium chloride (0.1 to 30 mmol/L) elicited contractile responses that were significantly lower in veins from dialyzed patients. CONCLUSIONS: The results demonstrate that norepinephrine-mediated contractions of forearm veins are markedly decreased in dialyzed patients. Endothelium-derived relaxing factors are not involved in this effect. The reduced contractile response is most likely caused by a decreased calcium entry through voltage- and receptor-dependent calcium channels.

Dose-Response Relationship, Drug↗

PubMed2006

Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients.

OBJECTIVE: Phosphodiesterase inhibitor is essential to the pharmacologic management of decompensated heart failure because it increases contractility and decreases afterload of right ventricle. It also improves hemodynamics and increases blood flow of the grafted internal mammary arteries and middle cerebral arteries during coronary artery bypass surgery. However, it induces vasodilation and necessitates the use of vasoconstrictors, such as norepinephrine. We hypothesized that vasopressin could recover hypotension induced by milrinone with less effect on pulmonary vascular resistance (PVR) compared to norepinephrine. METHODS: Fifty patients, undergoing coronary artery bypass graft (CABG) surgery, were assigned randomly in a double-blind manner to receive either vasopressin or norepinephrine. After baseline hemodynamic measurements, a loading dose of milrinone 50 microg/kg was infused slowly for 20 min followed by continuous infusion of 0.5 microg/(kg min). Immediately after the loading dose of milrinone, hemodynamic variables were measured, and vasopressin (VP group) or norepinephrine (NE groups) was infused. After being titrated until the mean arterial pressure was increased by 20%, hemodynamic variables were measured again. RESULTS: Milrinone infusion reduced both systemic vascular resistance (SVR, 1218+/-299 dynes/cm5 vs 838+/-209 dynes/cm5, 1345+/-299 dynes/cm5 vs 1011+/-195 dynes/cm5) and PVR (95+/-34 dynes/cm5 vs 72+/-30 dynes/cm5, 119+/-85 dynes/cm5 vs 87+/-33 dynes/cm5) in the VP and NE groups, respectively. Vasopressin and norepinephrine infusion increased both SVR (838+/-209 dynes/cm5 vs 1100+/-244 dynes/cm5, 1011+/-195 dynes/cm5 vs 1446+/-681 dynes/cm5, respectively) and PVR (72+/-30 dynes/cm5 vs 84+/-18 dynes/cm5, 87+/-33 dynes/cm5 vs 139+/-97 dynes/cm5, respectively). The PRV/SVR ratio was decreased after vasopressin infusion (0.10+/-0.03 vs 0.08+/-0.03), while no changes were found after norepinephrine infusion (0.09+/-0.02 vs 0.09+/-0.02). CONCLUSIONS: In the patients undergoing CABG surgery, both norepinephrine and low dose vasopressin were effective in restoring milrinone-induced decrease of SVR. However, only low-dose vasopressin decreased the PVR/SVR ratio that was increased by milrinone. Considering the importance of maintaining systemic perfusion pressure as well as reducing right heart afterload, milrinone-vasopressin may provide better hemodynamics than milrinone-norephinephrine during the management of right heart failure.

Aged↗

PubMed1999

Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder.

This review focuses on the role of norepinephrine (NE) in traumatic stress. The review is divided into three sections. The first section, "Norepinephrine and Arousal," describes preclinical studies related to norepinephrine's role in arousal, orienting to novel stimuli, selective attention and vigilance. It also contains a brief discussion of NE and its relationship to fear-provoking stimuli followed by preclinical and clinical studies that demonstrate heightened noradrenergic neuronal reactivity, increased alpha 2 receptor sensitivity and exaggerated arousal in organisms that have been exposed to chronic uncontrollable stress. The second section, "Norepinephrine and Memory," describes preclinical and clinical studies related to norepinephrine's role in enhanced encoding of memory for arousing and aversive events and in subsequent re-experiencing symptoms such as, intrusive memories and nightmares. The third section, "Norepinephrine and Pharmacologic Treatment," briefly discusses the use of adrenergic blockers, clonidine and propranol, as well as tricyclic and MAO inhibitors, for the treatment of PTSD. Finally, we attempt to synthesize trauma-related preclinical and clinical studies of norepinephrine. We do this, in part, by focusing on a series of yohimbine studies in subjects with PTSD because data from these studies allow for a discussion that brings together preclinical and clinical findings relevant to trauma-related alterations in arousal and memory.

Adrenergic alpha-Agonists↗

PubMed1996

Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus.

The present study was designed to determine the relationship between the discharge of noradrenergic locus coeruleus (LC) neurons and norepinephrine release in the medial prefrontal cortex, a target of LC projections. The LC was electrically stimulated at varying frequencies and patterns for 20 min and extracellular norepinephrine levels were measured in the medial prefrontal cortex of halothane-anesthetized rats using in vivo microdialysis. Electrical stimulation of the LC at 3-10 Hz with an evenly spaced pattern of pulses (tonic stimulation) increased cortical norepinephrine levels in a frequency-dependent manner, with 5- and 10-Hz stimulation increasing norepinephrine levels by 49 +/- 3% and 66 +/- 20%, respectively. The LC was also stimulated with bursts of pulses designed to deliver physiologically relevant phasic stimulation using the same number of stimuli in a 20-min period as delivered by tonic stimulation at 3 Hz. Results revealed that norepinephrine levels were significantly higher with phasic stimulation compared to tonic stimulation. The present findings indicate that both frequency and pattern of LC discharge are determinants of norepinephrine terminal release. Additionally, bursts of LC activity, similar to those that occur in behaving animals, may be more effective in increasing terminal norepinephrine release on a per spike basis than tonic increases in activity.

Animals↗

PubMed1999

Effect of intracerebral norepinephrine depletion on outcome from severe forebrain ischemia in the rat.

Manipulations of plasma catecholamine concentrations influence outcome from ischemic brain insults. It has been suggested that these effects are mediated by influences on brain catecholamine concentrations. This study examined whether major changes in brain norepinephrine concentrations can alter outcome from severe forebrain ischemia. Sprague-Dawley rats were administered 50 mg/kg i. p. N-(chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or were left untreated (control). One week later, these rats were subjected to either 7 or 8 min of normothermic forebrain ischemia (bilateral carotid occlusion and MABP=30 mmHg) and allowed to recover for 4 days. Histologic damage was then evaluated. In other control and DSP-4-treated animals, hippocampal microdialysate norepinephrine concentrations were measured before, during and after 8 min of forebrain ischemia. Norepinephrine concentrations were also determined in brain homogenates from non-ischemic DSP-treated and control rats. A 95% depletion of norepinephrine was observed in brain homogenates from non-ischemic DSP-4-treated rats compared with control. During ischemia, microdialysate norepinephrine concentrations increased in control but not in DSP-4-treated rats (P=0.002). For plasma, intra-ischemic epinephrine concentrations increased 8-10-fold and returned to baseline values post-ischemia with no differences between groups. Plasma norepinephrine values remained unchanged in both groups. Histologic damage resulting from either 7 or 8 min of ischemia in hippocampal structures, caudoputamen, and neocortex was similar between DSP-4-treated and control groups. This study could not identify any effect of major changes in brain norepinephrine concentrations on ischemic brain damage. These data indicate that peripheral catecholamine effects on near-complete forebrain ischemic outcome are unlikely to be mediated by effects on central catecholamine concentrations.

Animals↗