Showing papers on "Norepinephrine (medication) published in 2002"
TL;DR: It is concluded that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.
Abstract: Background: Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether shortterm vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion. Methods: Patients experiencing septic shock that required high-dose vasopressor support were randomized to a doubleblinded 4-h infusion of either norepinephrine (n 11) or vasopressin (n 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured. Results: Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 g/min to a blinded infusion of 17.0 g/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 g/min to 5.3 g/min a t4h( P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group. Conclusions: The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock. EFFECTIVE cardiovascular support plays an essential role in the management of patients with septic shock. Oxygen delivery must be maintained above a critical threshold, 1 and arterial pressure must exceed a level that al
546 citations
TL;DR: It is hypothesized that this combination of receptor variants, which results in increased synaptic norepinephrine release and enhanced receptor function at the myocyte, would predispose persons to heart failure.
Abstract: Background Sustained cardiac adrenergic stimulation has been implicated in the development and progression of heart failure. Release of norepinephrine is controlled by negative feedback from presynaptic α2-adrenergic receptors, and the targets of the released norepinephrine on myocytes are β1-adrenergic receptors. In transfected cells, a polymorphic α2C-adrenergic receptor (α2CDel322–325) has decreased function, and a variant of the β1-adrenergic receptor (β1Arg389) has increased function. We hypothesized that this combination of receptor variants, which results in increased synaptic norepinephrine release and enhanced receptor function at the myocyte, would predispose persons to heart failure. Methods Genotyping at these loci was performed in 159 patients with heart failure and 189 controls. Logistic-regression methods were used to determine the potential effect of each genotype and the interaction between them on the risk of heart failure. Results Among black subjects, the adjusted odds ratio for heart ...
530 citations
TL;DR: Terrlipressin seems to be an effective rescue therapy, which is able to restore blood pressure in patients with catecholamine-resistant septic shock, without obvious complication.
252 citations
TL;DR: In patients with septic shock, coupled plasmafiltration-adsorption combined with hemodialysis was associated with improved hemodynamics compared with continuous venovenous hemodiafiltration, suggesting a potential role for blood purification in the treatment of septicshock.
Abstract: Objective: To test the hypothesis that nonselective plasma adsorption by a hydrophobic resin (coupled plasmafiltration and adsorption) could improve hemodynamics and restore leukocyte responsiveness in patients with septic shock. Design: Prospective, pilot, crossover clinical trial. Setting: General intensive care unit in a teaching hospital. Subjects: Ten patients with hyperdynamic septic shock. Interventions: Patients were randomly allocated to 10 hrs of either coupled plasma filtration adsorption plus hemodialysis (treatment A) or continuous venovenous hemodiafiltration (treatment B) in random order. We measured the change in mean arterial pressure, norepinephrine requirements, and leukocyte tumor necrosis factor- (TNF-) production (both spontaneous and lipopolysaccharide-stimulated) after 10 hrs of each treatment. We also tested TNF- production from normal human adherent monocytes incubated with patients’ plasma obtained before and after the resin, both with or without incubation with an anti-interleukin-10 monoclonal antibody. Results: Mean arterial pressure increased after 10 hr by 11.8 mm Hg with treatment A and by 5.5 mm Hg with treatment B (p .001). There was an average decrease of norepinephrine requirement of 0.08 g/kg/min with treatment A and 0.0049 g/ kg/min with treatment B (p .003). All patients but one survived. Spontaneous and lipopolysaccharide-induced TNF- production from patients’ whole blood increased over time with treatment A. This increase was more marked in blood drawn after the device (plasmafiltrate-sorbent plus hemodialyzer) (p .009). Preresin plasma suppressed lipopolysaccharide-stimulated production of TNF- by 1 10 6 cultured adherent monocytes from healthy donors. This suppressive effect was significantly reduced after passage of plasma through the resin (p .019) and after incubation with anti-interleukin-10 monoclonal antibodies (p .028). Conclusions: In patients with septic shock, coupled plasmafiltration-adsorption combined with hemodialysis was associated with improved hemodynamics compared with continuous venovenous hemodiafiltration. This result might be related to its ability to restore leukocyte responsiveness to lipopolysaccharide. These findings suggest a potential role for blood purification in the treatment of septic shock. (Crit Care Med 2002; 30:1250 ‐1255)
244 citations
TL;DR: The degree of activation of the noradrenergic system within the amygdala in response to a novel, emotionally arousing experience predicts the extent of long‐term memory for that experience.
Abstract: Previous findings indicate that footshock and several drugs that modulate memory consolidation alter norepinephrine (noradrenaline) release in the amygdala, as assessed by in vivo microdialysis and high-performance liquid chromatography. Such findings suggest that norepinephrine release in the amygdala may be critical for regulating memory consolidation. The present study was the first to examine the relationship between norepinephrine release in the amygdala assessed after inhibitory avoidance training and 24-h retention performance within individual animals. Norepinephrine levels increased to > 300% of pretraining baseline 30 min after training and remained elevated for 2 h. In individual rats, the increase in norepinephrine levels after training correlated highly with 24-h retention performance. These findings indicate that the degree of activation of the noradrenergic system within the amygdala in response to a novel, emotionally arousing experience predicts the extent of long-term memory for that experience.
228 citations
TL;DR: It is suggested that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norpinephrine transporter.
Abstract: There is growing evidence of an interaction between dopamine and norepinephrine. To test the hypothesis that norepinephrine terminals are involved in the uptake and removal of dopamine from the extracellular space, the norepinephrine uptake blocker desmethylimipramine (DMI) was infused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrations of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic administration of haloperidol and the local infusion of DMI produced an augmented increase in extracellular dopamine in the cortex compared with the increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediated dopamine release produced by haloperidol and blockade of the norepinephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the alpha2-antagonist idazoxan also increased the extracellular concentrations of dopamine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concentrations of norepinephrine produced by these drugs, an increase in dopamine also was observed in lesioned rats that were depleted of norepinephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned controls. These results suggest that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.
219 citations
TL;DR: It is concluded that the α1D-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction by vasodilating the aorta and the pressor response of isolated perfused mesenteric arterial beds to α1-AR stimulation were markedly reduced inα1D ‐/‐ mice.
Abstract: To investigate the physiological role of the α1D-adrenergic receptor (α1D-AR) subtype, we created mice lacking the α1D-AR (α1D ‐/‐) by gene targeting and characterized their cardiovascular function. In α1D ‐/‐ mice, the RT-PCR did not detect any transcript of the α1D-AR in any tissue examined, and there was no apparent upregulation of other α1-AR subtypes. Radioligand binding studies showed that α1-AR binding capacity in the aorta was lost, while that in the heart was unaltered in α1D ‐/‐ mice. Non-anesthetized α1D ‐/‐ mice maintained significantly lower basal systolic and mean arterial blood pressure conditions, relative to wild-type mice, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30‐40% in α1D ‐/‐ mice. Furthermore, the contractile response of the aorta and the pressor response of isolated perfused mesenteric arterial beds to α1-AR stimulation were markedly reduced in α1D ‐/‐ mice. We conclude that the α1D-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction.
198 citations
TL;DR: An essential function is indicated in the prevention of heart failure progression in mice and human patients by the fact that heart failure patients with a dysfunctional variant of the &agr;2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography.
Abstract: Background— Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which α2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking α2-adrenoceptor subtypes (α2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of α2-adrenoceptors in human patients with chronic heart failure. Methods and Results— Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in α2A-KO (52%) and α2C-KO (47%) mice compared with wild-type and α2B-deficient (86%) animals. Excess mortality in α2A- and α2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importan...
181 citations
TL;DR: The results suggest that norepinephrine participates in the regulation of brain function at least partly by modulating the functions of microglia.
178 citations
TL;DR: It is concluded that the cold stress modulated the changes of catecholamines and cortisol and further depressed phagocytic activity and antibody levels in tilapia.
127 citations
TL;DR: Phenylephrine did not increase arterial blood pressure by more than 30% from baseline in one‐third of patients and decreased cardiac index without a significant decrease in ratio of pulmonary arterial pressure to systemic blood pressure.
Abstract: In this study the effect of phenylephrine and norepinephrine for the treatment of systemic hypotension were evaluated in patients with chronic pulmonary hypertension. When systemic hypotension (systolic arterial pressure < 100 mmHg) occurred following induction of anaesthesia, either phenylephrine or norepinephrine were infused in a random manner to raise the systolic blood pressure by 30% and 50% above baseline values. Norepinephrine decreased the ratio of pulmonary arterial pressure to systemic blood pressure without a change in cardiac index. However, phenylephrine did not increase arterial blood pressure by more than 30% from baseline in one-third of patients and decreased cardiac index without a significant decrease in ratio of pulmonary arterial pressure to systemic blood pressure. These vasoconstrictors showed different systemic and pulmonary haemodynamic effects in patients with chronic pulmonary hypertension as compared to acute pulmonary hypertension. Norepinephrine was considered to be preferable to phenylephrine for the treatment of hypotension in patients with chronic pulmonary hypertension.
TL;DR: The data demonstrate that the lack of &agr;1b-AR protects from the chronic increase of arterial blood pressure induced by norepinephrine and concomitantly prevents cardiovascular remodeling evoked by adrenergic activation independently of blood pressure levels.
Abstract: Background— The α1-adrenergic receptors (α1-ARs) play a key role in cardiovascular homeostasis. However, the functional role of α1-AR subtypes in vivo is still unclear. The aim of this study was to evaluate the cardiovascular influences of α1b-AR. Methods and Results— In transgenic mice lacking α1-AR (KO) and their wild-type controls (WT), we evaluated blood pressure profile and cardiovascular remodeling induced by the chronic administration (18 days via osmotic pumps) of norepinephrine, angiotensin II, and subpressor doses of phenylephrine. Our results indicate that norepinephrine induced an increase in blood pressure levels only in WT mice. In contrast, the hypertensive state induced by angiotensin II was comparable between WT and KO mice. Phenylephrine did not modify blood pressure levels in either WT or KO mice. The cardiac hypertrophy and eutrophic vascular remodeling evoked by norepinephrine was observed only in WT mice, and this effect was independent of the hypertensive state because it was simila...
TL;DR: The appetite-stimulating activity of ghrelin could be mediated by inhibited serotonin release, while the anorectic effects of amylin could involve inhibited release of dopamine in the hypothalamus.
TL;DR: This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease and suggests that NET inhibition might be useful in preventing vasovagal reactions.
Abstract: BACKGROUND: Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance METHODS AND RESULTS: We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects In a subset, we determined isoproterenol and phenylephrine sensitivities Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing In the supine position, heart rate was 65+/-2 bpm with placebo and 71+/-3 bpm with reboxetine At 75 degrees HUT, heart rate was 84+/-3 and 119+/-4 bpm with placebo and with reboxetine (P<00001) Mean arterial pressure was 85+/-2 with placebo and 91+/-2 mm Hg with reboxetine while supine (P<001) and 88+/-2 mm Hg and 90+/-3 mm Hg at 75 degrees HUT Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine CONCLUSIONS: Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions
TL;DR: This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys.
Abstract: This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18–20 nmol/min), produced mainly by the liver (17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7–9 nmol/min), produced largely by mesenteric organs (7 nmol/min), comprised 86–91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4-hydroxyphenylglycol.
TL;DR: There are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that are selective for either the 5- HT or NE system or both on lower urinary tract function.
TL;DR: POTS and NCS differ in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreasedRelease in the latter.
Abstract: Background— In postural tachycardia syndrome (POTS) and repeated neurocardiogenic presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic neurocirculatory failure. Whether these conditions involve abnormal cardiac sympathetic innervation or function has been unclear. Methods and Results— Patients with POTS or NCS underwent measurements of neurochemical indices of cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter norepinephrine based on entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), cardiac extraction of circulating 3H-norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement of left ventricular myocardial innervation density using 6-[18F]fluorodopamine positron emission tomographic scanning. Mean cardiac norepinephrine spillover in POTS (171±30 pmol/min, N=16) was higher and in NCS (62±9 pmol/min, N=20) was lower than in a large group of healthy volunteers (102±9 pmol/min, N=52) and in a...
Journal Article•
TL;DR: The CatCombi ELISA kit as an alternative to HPLC methods is very useful for clinical applications as well as for basic research where a simple, rapid, accurate and reproducible assay for epinephrine and norepinephrine determinations is required.
Abstract: SUMMARY Background: Measurement of the concentration of the free catecholamines epinephrine (adrenalin) and norepinephrine (noradrenalin) in humans is used for the diagnosis of pheochromocytoma and related diseases. Methods: A non-competitive enzyme-linked immunosorbent assay (CatCombi ELISA) kit for the measurement of epinephrine and norepinephrine concentrations in plasma and urine was developed and validated. The assay procedure consists of sample extraction, chemical and enzymatic derivatization and immunological reaction steps. A sample volume of 10 µL urine or 300 µL EDTA plasma is required for duplicate determinations of both catecholamines. For method comparison we used a reversed phase HPLC by Chromsystems after extraction by aluminium oxide with electrochemical detection for the determination of epinephrine and norepinephrine. Results: The CatCombi ELISA is accurate, sensitive, specific, and precise. Linear regression analysis of epinephrine and norepinephrine concentrations measured with the ELISA and with HPLC yielded highly significant correlations. Conclusions: The CatCombi ELISA kit as an alternative to HPLC methods is very useful for clinical applications as well as for basic research where a simple, rapid, accurate and reproducible assay for epinephrine and norepinephrine determinations is required. (Clin. Lab. 202;48:61-71)
TL;DR: The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects, and the inhibitory clonidine-like action of sibUTramine on thecentral nervous system attenuates the peripheral stimulatory effect.
Abstract: Background—Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. Methods and Results—In 11 healthy subjects (7 men, age 272 years, body mass index 23.10.7 kg/m 2 ), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 1133 mm Hg with placebo, 1213 mm Hg with sibutramine (P0.001 versus placebo), and 1112 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. Conclusions—The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered. (Circulation. 2002;106:2459-2465.)
TL;DR: A contribution of the increase in norepinephrine, but not serotonin, to the enhancement of dopamine after cocaine applied focally in the nucleus accumbens is suggested.
Abstract: Monoamine-uptake blockers were applied focally (0.1-1,000 microM) through a dialysis probe in the nucleus accumbens of freely moving rats, and the extracellular concentrations of dopamine, norepinephrine, and serotonin were measured. The selective dopamine-uptake blocker GBR 12935 increased dopamine preferentially with only a small effect on norepinephrine, whereas the selective serotonin-uptake blocker fluoxetine increased serotonin output preferentially. In contrast, the selective norepinephrine-uptake blockers desipramine and nisoxetine enhanced not only norepinephrine, but also serotonin and dopamine appreciably. Cocaine increased all three amines with the greatest effects on dopamine and serotonin. As in our previous study on the ventral tegmental area, there was a positive association between dopamine and norepinephrine output when all blocker data were taken together. The present results suggest a contribution of the increase in norepinephrine, but not serotonin, to the enhancement of dopamine after cocaine applied focally in the nucleus accumbens.
TL;DR: It is concluded that SNARE proteins are involved in exocytosis of NE from synaptic vesicles at low frequencies of stimulation but may not be essential for exocyTosis of NPY and NE from large vesicle at high stimulation frequencies.
Abstract: We examined effects of botulinum neurotoxin A (BoNTA) on sympathetic constrictions of the vena cava and uterine artery from guinea pigs to test the role of soluble NSF attachment protein receptor (...
01 Jan 2002
TL;DR: Acute mental stress may trigger a hypercoagulable state evidenced by increased thrombin activity and increased fibrin turnover and these mechanisms may help explain the adverse impact of mental stress on the cardiovascular system.
TL;DR: The dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure is investigated.
Abstract: Background— In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. Methods and Results— A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additi...
TL;DR: The present results suggest that controlled cortical impact brain injury produces disorder in the neuronal oxidative and norepinephrine metabolism.
Abstract: The recently developed controlled cortical impact model of brain injury in rats may be an excellent tool by which to attempt to understand the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral controlled cortical impact brain injury of low grade severity; their brains were frozen in situ at various times after injury to measure regional levels of lactate, high energy phosphates, and norepinephrine. Tissue lactate concentration in the injury site left cortex was increased in injured animals by sixfold at 30 min and twofold at 2.5 h and 24 h after injury (p < 0.05). At all postinjury times, lactate concentration was also increased in injured animals by about twofold in the cortex and hippocampus adjacent to the injury site (p < 0.05). No significant changes occurred in the levels of ATP and phosphocreatine in most of the brain regions of injured animals. However, in the primary site of injury (left cortex), phosphocreatine concentration was decreased by 40% in injured animals at 30 min after injury (p < 0.05). The norepinephrine concentration was decreased in the injury site left cortex of injured animals by 38% at 30 min, 29% at 2.5 h, and 30% at 24 h after injury (p < 0.05). The level of norepinephrine was also reduced by approximately 20% in the cortex adjacent to the injury site in injured animals. The present results suggest that controlled cortical impact brain injury produces disorder in the neuronal oxidative and norepinephrine metabolism.
TL;DR: Whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder is examined and this action may contribute to the broad therapeutic efficacy of parxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.
Abstract: Objective: The study examined whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder. Method: In an open-label, parallel-group, forced-titration study, 52 outpatients with DSM-IV major depressive disorder and a baseline Montgomery Asberg Depression Rating Scale score ≥20 were randomly assigned to treatment with paroxetine (to 60 mg/day) or desipramine (to 30 mg/ day) in a 3-to-1 ratio, respectively. Norepinephrine and 5-HT transporter function were assayed by using human transporter transfected cells in the presence of serum collected at baseline and the end of each treatment week. Data from 36 patients were analyzed. Results: Paroxetine decreased norepinephrine uptake to 73% of control (27% inhibition) at an average serum concentration of 100 ng/ml and 57% of control (43% inhibition) at 200 ng/ml. Uptake of 5-HT was decreased to less than 15% (greater than 85% inhibition) of control at these paroxetine concentrations. Desipramine decreased norepinephrine uptake to near maximal 15% of control (85% inhibition) at 100 ng/ml. Uptake of 5-HT was decreased to 82% of control (18% inhibition) at 100 ng/ml and 49% of control (51% inhibition) at 500 ng/ml. Conclusions: Paroxetine, currently classified as a selective 5-HT reuptake inhibitor, can act as a 5-HT/norepinephrine uptake inhibitor in vivo. The clinical significance of this action on norepinephrine uptake is currently unknown, but this action may contribute to the broad therapeutic efficacy of paroxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.
TL;DR: In this paper, presynatic histamine H3 receptors (H3R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions.
Abstract: Activation of presynatic histamine H3 receptors (H3R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of α2-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H3R-mediated antiexocytotic effects could result from a decreased Ca2+ influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H3R cDNA (SH-SY5Y-H3). We found that reducing Ca2+ influx in response to membrane depolarization by inhibiting N-type Ca2+ channels with ω-conotoxin (ω-CTX) greatly attenuated the exocytosis of [3H]norepinephrine from both SH-SY5Y and SH-SY5Y-H3 cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to ω-CTX, activation of H3R with the selective H3R-agonist imetit also reduced both the rise in intracellular Ca2+ concentration (Cai) and norepinephrine exocytosis in response to membrane depolarization. The selective H3R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H3R, imetit affected neither the rise in Cai nor [3H]norepinephrine exocytosis, demonstrating that the presence of H3R is a prerequisite for a decrease in Cai in response to imetit and that H3R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Cai. Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H3R agonists may offer a novel therapeutic approach to this condition.
TL;DR: These are the first in vivo studies demonstrating that norepinephrine is directly trophic for the vascular wall and augments injury-induced intimal lesion growth.
Abstract: Previous studies suggesting that norepinephrine is directly trophic for the vascular wall have been confounded by concomitant hemodynamic disturbances. Herein, a microcatheter connected to an osmot...
TL;DR: The available evidence comparing vasopressor agents in terms of safety and efficacy is limited, and when used at doses necessary to reverse distributive shock, less potent vasoconstrictors do not appear to be safer than more potent ones and do not seem to be as effective.
Abstract: Distributive shock is a common problem in intensive care. Systemic hypotension is a medical emergency and will cause end-organ injury if not reversed. There are relatively few medications available to treat distributive shock. Catecholamines are most widely used for this indication and work by stimulating alpha- and/or beta-adrenergic receptors. Vasopressin and corticosteroids may have a role in reversing refractory shock and work primary through nonadrenergic mechanisms. Shock is difficult to define using hemodynamic criteria, because the same hemodynamic values can be normal in one patient, yet represent shock in another. Thus, the appropriate therapeutic endpoints for vasopressor therapy are not uniform for all patients. Similarly, the available evidence comparing vasopressor agents in terms of safety and efficacy is limited. When used at doses necessary to reverse distributive shock, less potent vasoconstrictors (eg, dopamine) do not appear to be safer than more potent ones (eg, norepinephrine) and do not appear to be as effective.
TL;DR: The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock.
Abstract: Objective
In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock.
Methods
In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan-Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 μg/kg per minute, with 0.2 μg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 μg/kg per minute.
Results
Twenty-two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 ± 3 and 77 ± 5 mm Hg in the epinephrine and dobutamine-norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine-norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 ± 1.6 versus 4.2 ± 1.5 L/min per square meter; P = .078) and oxygen transport (617 ± 166 versus 481 ± 229 mL/min per square meter; P = .068). Epinephrine also induced significantly greater values of gastricmucosal blood flow (662 ± 210 versus 546 ± 200 units; P = .011) but did not modify indocyaninegreen clearance.
Conclusions
In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 μg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index.
Clinical Pharmacology & Therapeutics (2002) 71, 381–388; doi: 10.1067/mcp.2002.122471