Showing papers on "Norepinephrine (medication) published in 2010"

Comparison of Dopamine and Norepinephrine in the Treatment of Shock

Abstract: BACKGROUND Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other. METHODS In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 μg per kilogram of body weight per minute for dopamine or a dose of 0.19 μg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events. RESULTS The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P = 0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P = 0.03 for cardiogenic shock, P = 0.19 for septic shock, and P = 0.84 for hypovolemic shock, in Kaplan–Meier analyses). CONCLUSIONS Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. (ClinicalTrials.gov number, NCT00314704.)

The effects of vasopressin on acute kidney injury in septic shock.

Abstract: To compare the effects of vasopressin versus norepinephrine infusion on the outcome of kidney injury in septic shock Post-hoc analysis of the multi-center double-blind randomized controlled trial of vasopressin versus norepinephrine in adult patients who had septic shock (VASST) Seven hundred seventy-eight patients were randomized to receive a blinded infusion of either low-dose vasopressin (001–003 U/min) or norepinephrine infusion (5–15 μg/min) in addition to open-label vasopressors and were included in the outcome analysis All vasopressors were titrated and weaned to maintain a target blood pressure RIFLE criteria for acute kidney injury were used to compare the effects of vasopressin versus norepinephrine In view of multiple simultaneous comparisons, a p value of 001 was considered statistically significant Kidney injury was present in 464 patients (596%) at study entry In patients in the RIFLE “Risk” category (n = 106), vasopressin as compared with norepinephrine was associated with a trend to a lower rate of progression to renal “Failure” or “Loss” categories (208 vs 396%, respectively, p = 003), and a lower rate of use of renal replacement therapy (170 vs 377%, p = 002) Mortality rates in the “Risk” category patients treated with vasopressin compared to norepinephrine were 308 versus 547%, p = 001, but this did not reach significance in a multiple logistic regression analysis (OR = 033, 99% CI 010–109, p = 002) The interaction of treatment group and RIFLE category was significant in predicting mortality Vasopressin may reduce progression to renal failure and mortality in patients at risk of kidney injury who have septic shock

Monoamine Oxidase A–Mediated Enhanced Catabolism of Norepinephrine Contributes to Adverse Remodeling and Pump Failure in Hearts With Pressure Overload

Abstract: Rationale: Monoamine oxidases (MAOs) are mitochondrial enzymes that catabolize prohypertrophic neurotransmitters, such as norepinephrine and serotonin, generating hydrogen peroxide. Because excess reactive oxygen species and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAOs could play an important role in this process. Objective: Here, we investigated the role of MAO-A in maladaptive hypertrophy and heart failure. Methods and Results: We report that MAO-A activity is triggered in isolated neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. All of these in vitro changes occur, in part, independently from α- and β-adrenergic receptor–operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene reprogramming, metalloproteinase and caspase-3 activation, as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-A neo ), which were more protected against pressure overload than their wild-type littermates. Conclusions: In addition to adrenergic receptor–dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in augmented reactive oxygen species generation, contributing to maladaptive remodeling and left ventricular dysfunction in hearts subjected to chronic stress.

Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension.

Abstract: Introduction: We sought to examine the cardiac consequences of early administration of norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital. Methods: We included 105 septic-shock patients who already had received volume resuscitation. All received norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by norepinephrine when the achieved MAP was ≥65 mm Hg. Results: Norepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m 2 , stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m 2 , global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m 2 , and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with norepinephrine. Conclusions: Early administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.

Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients

Abstract: To examine the consequences of administration of norepinephrine on muscle tissue oxygenation in severely hypotensive septic shock patients. This was a prospective observational study conducted in a medical intensive care unit of a university hospital. We included 28 septic shock patients that received early volume resuscitation. All were eligible for receiving norepinephrine because of life-threatening hypotension and low diastolic arterial pressure. Muscle tissue oxygen saturation (StO2) and its changes during a vascular occlusion test were measured at the level of the thenar eminence using a near-infrared spectroscopy (NIRS) device. Transpulmonary thermodilution cardiac index (CI) and NIRS-derived variables were obtained before and after the mean arterial pressure (MAP) was increased by norepinephrine. The baseline StO2 and the vascular occlusion test-derived variables of 17 healthy volunteers were measured and served as controls. In healthy volunteers, StO2 ranged between 75 and 90% and StO2 recovery slopes ranged between 1.5 and 3.4%/s. Administration of norepinephrine, which was associated with an increase in MAP from 54 ± 8 to 77 ± 9 mmHg (p < 0.05), also induced increases in CI from 3.14 ± 1.03 to 3.61 ± 1.28 L/min/m2 (p < 0.05), in StO2 from 75 ± 9 to 78 ± 9% (p < 0.05) and in StO2 recovery slope from 1.0 ± 0.6 to 1.5 ± 0.7%/s (p < 0.05). Norepinephrine administration aimed at achieving a MAP higher than 65 mmHg in septic shock patients with life-threatening hypotension resulted in improvement of NIRS variables measured at the level of the thenar eminence.

Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial

Abstract: To compare the effects of two arginine vasopressin (AVP) dose regimens on the hemodynamic response, catecholamine requirements, AVP plasma concentrations, organ function and adverse events in advanced vasodilatory shock. In this prospective, controlled, open-label trial, patients with vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery requiring norepinephrine >0.6 μg/kg/min were randomized to receive a supplementary AVP infusion either at 0.033 IU/min (n = 25) or 0.067 IU/min (n = 25). The hemodynamic response, catecholamine doses, laboratory and organ function variables as well as adverse events (decrease in cardiac index or platelet count, increase in liver enzymes or bilirubin) were recorded before, 1, 12, 24 and 48 h after randomization. A linear mixed effects model was used for statistical analysis in order to account for drop-outs during the observation period. Heart rate and norepinephrine requirements decreased while MAP increased in both groups. Patients receiving AVP at 0.067 IU/min required less norepinephrine (P = 0.006) than those infused with AVP at 0.033 IU/min. Arterial lactate and base deficit decreased while arterial pH increased in both groups. During the observation period, AVP plasma levels increased in both groups (both P < 0.001), but were higher in the 0.067 IU/min group (P < 0.001) and in patients on concomitant hydrocortisone. The rate of adverse events and intensive care unit mortality was comparable between groups (0.033 IU/min, 52%; 0.067 IU/min, 52%; P = 1). A supplementary AVP infusion of 0.067 IU/min restores cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033 IU/min.

Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction

Abstract: In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated i...

Unveiling the Vasodilatory Actions and Mechanisms of Relaxin

Abstract: Relaxin is a 6-kDa peptide hormone that is secreted from the corpus luteum of the ovary and circulates in the blood during pregnancy in several species, including humans, rats, and mice1 (see Appendix for relaxin ligand and receptor nomenclature). Hisaw and colleagues,2,3⇓ who discovered the hormone, provided the first evidence, albeit structural in nature, that the vasculature is a relaxin target. In ovariectomized monkeys administered relaxin, they noted marked morphological changes in the endothelial cells of endometrial blood vessels consistent with hypertrophy and hyperplasia, as well as enlargement of arterioles and capillaries.4,5⇓ Functional evidence for a vasodilatory role of the hormone was initially reported by St-Louis and Massicotte,6 who demonstrated that chronic infusion of purified rat or porcine relaxin decreased systolic blood pressure in female spontaneously hypertensive rats but not Wistar-Kyoto rats. In another study, the same group of investigators showed that short-term administration of purified rat relaxin decreased mean arterial pressure in female spontaneously hypertensive rats as early as 8 hours after initiating the infusion, and the vasoconstrictor responses to norepinephrine and arginine vasopressin were blunted in the mesenteric circulation of these animals perfused in situ.7 Subsequently, some doubt about the physiological importance of the vascular role of relaxin was raised, when Ahokas et al8 found that the gestational decline in systolic blood pressure and decrease in vascular reactivity to angiotensin II were comparable in gravid spontaneously hypertensive rats with and without ovaries and, thus, with and without circulating relaxin. Further supportive evidence for vascular effects of relaxin was garnered by Bani-Sacchi et al,9 who reported that, in the Langendorff preparation, relaxin acutely increased coronary blood flow in rat and guinea pig hearts. This group also showed that the vasodilatory action of relaxin in the coronary circulation was prevented by …

Vasopressin and its immune effects in septic shock.

Abstract: Vasopressin is a stress hormone. However, vasopressin levels are inappropriately low in septic shock. Vasopressin stimulates AVPR1a, AVPR1b, AVPR2 and purinergic receptors. Vasopressin increases blood pressure by occupying AVPR1a receptors on vascular smooth muscle. An increase in ventricular afterload due to vasopressor administration limits ventricular systolic ejection, an effect that becomes increasingly important as systolic contractility is decreased. Stimulation of AVPR1a receptors may also decrease edemagenesis. Stimulation of AVPR1b by vasopressin releases ACTH and cortisol. AVPR2 stimulation increases retention of water by increasing cyclic AMP. Yet, vasopressin infusion may increase urine output, creatinine clearance and improve renal function in septic shock. Vasopressin has many effects on immune function such as altering cytokines, neuroimmunity, prostaglandins, humoral immunity and immune cells. For example, vasopressin decreases sepsis-induced pulmonary inflammation, could have renal anti-inflammatory effects and may decrease prostaglandin levels in a dose-dependent manner. Vasopressin may also modulate responses to stress by expression and release from immune cells. Interestingly, there are vasopressin receptors on immune cells. Many small clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases requirements for norepinephrine and improves renal function. However, vasopressin could decrease coronary, cerebral and mesenteric perfusion. A multicenter trial of vasopressin versus norepinephrine in septic shock found no overall difference in mortality. Vasopressin may decrease mortality in patients with less severe septic shock. Vasopressin plus corticosteroid treatment may decrease mortality compared to corticosteroids plus norepinephrine. Potential mechanisms are that vasopressin plus corticosteroids beneficially alter immunity in septic shock.

Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock.

Abstract: Objective:To compare the effects of a first-line therapy of combined arginine vasopressin, levosimendan, and norepinephrine with arginine vasopressin + norepinephrine or norepinephrine alone in ovine septic shock.Design:Prospective, randomized, controlled laboratory experiment.Setting:University ani

Psychological stress during exercise: immunoendocrine and oxidative responses.

Abstract: The purpose of this study was to examine the changes in catecholamines (epinephrine [EPI] and norepinephrine [NE]), interleukin-2 (IL-2) and a biomarker of oxidative stress (8-isoprostane) in healt...

A Glutamate Pathway to Faster-Acting Antidepressants?

Abstract: Depressive illness was described by Hippocrates in ancient Greece, but effective therapeutic agents did not emerge until the 1950s. Today, almost all antidepressant drugs in clinical use increase levels of certain neurotransmitters in the brain, in particular norepinephrine and serotonin. Although these medications are beneficial, a sizeable minority of patients remain resistant to their therapeutic effects ( 1 ). Moreover, in most patients, there is a delay of weeks to months before the drugs take full effect. As a result, there is an urgent need to develop faster-acting drugs ( 2 – 4 ).

EFFECTS OF A SELECTIVE iNOS INHIBITOR VERSUS NOREPINEPHRINE IN THE TREATMENT OF SEPTIC SHOCK

Abstract: Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.

Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia.

Abstract: Background Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia.

Norepinephrine causes a pressure-dependent plasma volume decrease in clinical vasodilatory shock.

Abstract: Background: Recent experimental studies have shown that a norepinephrine-induced increase in blood pressure induces a loss of plasma volume, particularly under increased microvascular permeability. We studied the effects of norepinephrine-induced variations in the mean arterial pressure (MAP) on plasma volume changes and systemic haemodynamics in patients with vasodilatory shock. Methods: Twenty-one mechanically ventilated patients who required norepinephrine to maintain MAP ≥ 70 mmHg because of septic/postcardiotomy vasodilatory shock were included. The norepinephrine dose was randomly titrated to target MAPs of 60, 75 and 90 mmHg. At each target MAP, data on systemic haemodynamics, haematocrit, arterial and mixed venous oxygen content and urine flow urine were measured. Changes in the plasma volume were calculated as 100 x (Hct pre /Hct post - 1)/(1 - Hct pre ), where Hct pre and Hct post are haematocrits before and after intervention. Results: Norepinephrine doses to obtain target MAPs of 60, 75 and 90 mmHg were 0.20 ± 0.18, 0.29 ± 0.18 and 0.42 ± 0.31 μg/kg/min, respectively. From 60 to 90 mmHg, increases in the cardiac index (15%), systemic oxygen delivery index (25%), central venous pressure (CVP) (20%) and pulmonary artery occlusion pressure (33%) were seen, while the intrapulmonary shunt fraction was unaffected by norepinehrine. Plasma volume decreased by 6.5% and 9.4% (P<0.0001) when blood pressure was increased from 60 to 75 and 90 mmHg, respectively. MAP (P<0.02) independently predicted the decrease in plasma volume with norepinephrine but not CVP (P = 0.19), cardiac index (P = 0.73), norepinephrine dose (P = 0.58) or urine flow (P = 0.64). Conclusions: Norepinephrine causes a pressure-dependent decrease in the plasma volume in patients with vasodilatory shock most likely caused by transcapillary fluid extravasation.

Histamine h3 inverse agonists and antagonists and methods of use thereof

Abstract: Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including, e.g., neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as, e.g., histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical compositions containing the compounds and their methods of use are also provided herein.

Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock

Abstract: Introduction: This study aims to compare two vasoconstrictors: - norepinephrine and phenylephrine - in the management of dopamine- resistant septic shock Materials and Methods: We performed a randomized, prospective, controlled trial in 54 septic shock patients, with persistent hypotension despite adequate volume resuscitation and continued dopamine infusion ~25μg/kg/h Patients were randomly allocated into two groups to receive either norepinephrine or phenylephrine infusion (n = 27 each) titrated to achieve a target of SBP > 90mm Hg, MAP > 75 mm Hg, SVRI > 1100 dyness/cm5m2, CI > 28 L/min/m2, DO2I > 550 ml/min/m2, and VO2I > 150 ml/min/m2 for continuous 6 h All the parameters were recorded every 30 min and increment in dose of studied drug was done in the specified dose range if targets were not achieved Data from pulmonary arterial and hepatic vein catheterization, thermodilution catheter, blood gas analysis, blood lactate levels, invasive blood pressure, and oxygen transport variables were compared with baseline values after achieving the targets of therapy Differences within and between groups were analyzed using a one-way analysis of variance test and Fischer's exact test Results: No difference was observed in any of the investigated parameters except for statistically significant reduction of heart rate (HR) ( P P Conclusions: Phenylephrine infusion is comparable to norepinephrine in reversing hemodynamic and metabolic abnormalities of sepsis patients, with an additional benefit of decrease in HR and improvement in SVI

Vasopressin in sepsis and septic shock.

Abstract: Arginine vasopressin (AVP) and its synthetic, long-acting analog terlipressin (TP) are potent alternative vasoconstrictors in the treatment of septic patients with catecholamine-refractive vasodilatatory shock. The results from one large randomized clinical trial suggest that AVP plus norepinephrine (NE) infusion is as safe and effective as treatment with NE alone in patients with septic shock. Because the desired effects of vasopressin analogs are basically related to their vasopressinergic effects via the V1a receptor, more selective V1 agonists, such as TP, may be more potent in reversing sepsis-related arterial hypotension. In this regard, recent evidence from small-scale studies suggests that continuous low-dose infusion rather than intermittent bolus injection of TP is associated with fewer side effects, such as depression of cardiac output and rebound arterial hypotension. However, because clinical data on the administration of TP in patients with sepsis are limited, it should not currently be used beyond the scope of controlled trials. The optimal time point for the initiation of therapy with vasopressin analogs has yet to be determined. While AVP and TP are commonly used as last-resort therapies in severe septic shock, some evidence supports the initiation of treatment in a less severe state of the disease.

Sympathetic α2-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload

Abstract: Aims α2-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of α2-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of α2A-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress. Methods and results Transgenic mice expressing α2A-adrenoceptors under control of the dopamine β-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the α2A- and α2C-adrenoceptor genes. α2AC-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-α2A transgene in sympathetic neurons prevented these effects. In contrast, Dbh-α2A receptors mediated only a minor part of the bradycardic and hypotensive effects of the α2-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-α2A transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, α2-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-α2A transgenic mice, norepinephrine and medetomidine induced endocytosis of α2A-adrenoceptors into neurite processes. Conclusion α2A-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.

Sympathetic Activation in Obesity: A Noninnocent Bystander

Abstract: The hypothesis that human obesity is associated with a state of adrenergic overdrive dates back to ≈50 years ago, when a group of American investigators noted that sympathetic function was indeed altered in the obese subject.1 Since then, many studies have attempted to investigate whether and to what extent sympathetic activation is a hallmark of the autonomic profile of the obese state. The results, which have also been included in a meta-analysis,2 although suggestive for a hyperadrenergic state, did not permit any definite conclusion on this issue to be drawn. Several factors may account for these inconclusive results. First, the data collected were mainly based on the biochemical assay of plasma norepinephrine or its urinary metabolites, that is, an approach known to have a limited reproducibility and sensitivity in detecting the adrenergic abnormalities characterizing a physiological or a pathophysiological state.3 Furthermore, plasma norepinephrine concentration relies on a variety of biological processes taking place both at a synaptic and at a postsynaptic level, such as the reuptake of the neurotransmitter by the adrenergic nerve terminals and the tissue clearance process of norepinephrine, as well as its functional role as a cotransmitter with epinephrine.3 These complex steps make hard to establish whether and to what extent an elevation in circulating levels of norepinephrine (or its urinary metabolites) mirrors a true increase in central adrenergic outflow or whether it rather reflects an impairment of the physiological processes mentioned above taking place at a peripheral neural level. More stringent evidence on the adrenergic overdrive characterizing the obese state …

The diverse effects of vasopressors on the fetoplacental circulation of the dual perfused human placenta.

Abstract: BACKGROUND:We studied the effects of 5 vasopressors on fetal arterial perfusion pressure (FAP) in vitro using the dual perfused, single isolated cotyledon, human placental model.METHODS:In 29 separate experiments, epinephrine (75 mg), norepinephrine (75 mg), ephedrine (50 mg), phenylephrine (2 mg),

Role of β1–3-Adrenoceptors in Blood Pressure Control at Rest and During Tyramine-Induced Norepinephrine Release in Spontaneously Hypertensive Rats

Abstract: β-Adrenoceptors contribute to hypertension in spite of the fact that β-adrenoceptor agonists lower blood pressure. We aimed to differentiate between these functions and to identify differences between spontaneously hypertensive and normotensive rats. β-Adrenoceptor antagonists with different subtype selectivity or the ability to cross the blood-brain barrier were used to demonstrate β-adrenoceptor involvement in resting blood pressure and the response to tyramine-induced peripheral norepinephrine release. The centrally acting propranolol (β 1+2[+3] ), CGP20712A (β 1 ), ICI-118551 (β 2 ), and SR59230A (β 3 ), as well as peripherally restricted nadolol (β 1+2 ) and atenolol (β 1 ), were administered intravenously, separately, or in combinations. Blood pressure, cardiac output, heart rate, total peripheral vascular resistance, and plasma catecholamine concentrations were evaluated. β-Adrenoceptor antagonists had little effect on cardiovascular baselines in normotensive rats. In hypertensive rats, antagonist-induced hypotension paralleled reductions in resistance, except for atenolol, which reduced cardiac output. The resistance reduction involved primarily neuronal catecholamine, central β 1 -adrenoceptors, and peripheral β 2 -adrenoceptors. Tyramine induced a transient, prazosin-sensitive vascular resistance increase. Inhibition of nerve-activated, peripheral β 1/3 -adrenoceptors enhanced this α 1 -adrenoceptor–dependent vasoconstriction in normotensive but not hypertensive rats. In hypertensive rats, return to baseline was eliminated after inhibition of the central β 1 -adrenoceptor, epinephrine release (acute adrenalectomy), and peripheral β 2/3 -adrenoceptors. Adrenalectomy eliminated β-adrenoceptor–mediated vasodilation in hypertensive rats, and tyramine induced a prazosin-sensitive vasoconstriction, which was inhibited by combined blockade of central β 1 - and peripheral β 2 -adrenoceptors. In conclusion, nerve-activated β 1 - and β 3 -adrenoceptor–mediated vasodilation was not present in hypertensive rats, whereas epinephrine-activated β 2 - and β 3 -adrenoceptor–mediated vasodilation was upregulated. There was also a hypertensive, nerve-activated vasoconstrictory mechanism present in hypertensive rats, involving central β 1 - and peripheral β 2 -adrenoceptors combined.

The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis.

Abstract: BACKGROUND: The use of vasoactive drugs to restore arterial blood pressure in patients with septic shock remains a cornerstone of intensive care medicine. However, vasopressors can accentuate the hypoperfusion of the gut during septic shock, allowing bacterial translocation and endotoxemia. In this study, we compared the effects of different vasoactive drugs on intestinal microcirculation and tissue oxygenation, independent of the effects of fluid therapy, in a rat model of endotoxemic shock. METHODS: Pentobarbital-anesthetized Wistar Kyoto rats were submitted to endotoxemic shock induced by Escherichia coli lipopolysaccharide (2 mg/kg IV). Arterial blood pressure was normalized by a continuous infusion of different vasoactive drugs, including epinephrine, norepinephrine, phenylephrine, dopamine, dobutamine, or a combination of dobutamine and norepinephrine. The functional capillary density (FCD) of the muscular layer of the small intestine was evaluated by intravital video-microscopy. Mesenteric venous blood gases and lactate concentrations were also analyzed. RESULTS: FCD decreased by approximately 25% to 60% after the IV infusion of epinephrine, norepinephrine, and phenylephrine. Administration of dopamine, dobutamine, and the combination of dobutamine and norepinephrine did not induce significant alterations in gut FCD. In addition, the mesenteric venous lactate concentration increased in the presence of phenylephrine and showed a tendency to increase after the administration of epinephrine and norepinephrine, whereas there was no observable increase after the administration of dopamine, dobutamine, and the combination of dobutamine with norepinephrine. CONCLUSION: This study confirms dissociation of the systemic hemodynamic and microvascular alterations in an experimental model of septic shock. Moreover, the results indicate that the use of dopamine, dobutamine, and dobutamine in combination with norepinephrine yields a protective effect on the microcirculation of the intestinal muscular layer in endotoxemic rats.

Venlafaxine-associated nocturnal bruxism in a depressive patient successfully treated with buspirone.

Abstract: Bruxism, which is characterized by clenching and/or grinding of the dentition, is a common condition affecting approximately 8-21% of the population. It may be common during therapy with psychotropic medications, including antipsychotics and antidepressants. Bruxism associated with drugs can be destructive, resulting in severe consequences to health that include destruction of tooth structure, irreversible harm to the temporomandibular joint, severe myofascial pain, and muscle contraction headaches (Winocur, et al., 2003). Although selective serotonin reuptake inhibitor (SSRI)-associated bruxism has often been described in the literature (Gerber and Lynd, 1998; Winocur, et al., 2003), to our knowledge there are only two case reports describing venlafaxine-induced bruxism (Jaffee and Bostwick 2000; Brown and Hong, 1999). Here, we report a case of nocturnal bruxism likely induced by the antidepressant venlafaxine and successfully treated with buspirone. Mrs G was a 31-year-old separated woman with a primary school education admitted to our inpatient clinic. Upon examination, she was found to suffer from severe pervasive sadness, anhedonia, insomnia, moderate psychomotor retardation, feelings of worthlessness, distractibility, occasional passive suicidal ideation and decreased energy, concentration and self-esteem. She experienced these symptoms on most days and nearly every day during the month before admission. She stayed in bed most of the time, rarely took care of herself, and could not work at all. She had no personal history of substance abuse and no family history of mental illness. In addition, the patient started smoking cigarettes at an age of 25 and smoked 20 cigarettes per day. Also, she had not stopped smoking after being admitted into the hospital. She was diagnosed with major depressive disorder based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision) (DSMIV-TR) (American Psychiatric Association, 2000). Initially, her 17-item Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960) total score was 27. Subsequently, extendedrelease (XR) venlafaxine was started at a dosage of 37.5 mg/day, which was titrated up to 150 mg/day. After a week of treatment with venlafaxine, she reported severe nocturnal bruxism. Her complaints included masseter tightness, headaches, tooth pain, and nocturnal tooth grinding. Her roommates reported loud nocturnal grinding noises. All the laboratory investigations were in the normal range and all the potential organic contributors to depression and to bruxism were excluded. In the past three years, she had two depressive episodes that required the use of antidepressant medications, including escitalopram (10 mg/day) and fluoxetine (20 mg/day). The patient and her family reported nocturnal bruxism symptoms associated with both of these medications. In addition, the patient indicated that her bruxism symptoms were similar to those she experienced with previous antidepressant medications, including escitalopram and fluoxetine. In an attempt to control the bruxism, clonazepam was initiated at a dose of 2 mg/day. At the end of the third week after hospitalization, there was no improvement in her bruxism, although her depressive symptoms partially remitted. Subsequently, clonezapam was gradually stopped, and buspirone was started at a dose of 10 mg/day, which was increased to 20 mg/day. She reported full resolution of headaches and bruxism within 10 days of the initiation of buspirone. At the fifth week after hospitalization, there was significant improvement of both depressive symptoms and bruxism symptoms. The patient’s total score on the HAM-D on the last week of admission was 5. Also, during the follow-up, there was no further appearance of nocturnal bruxism with venlafaxine and buspirone treatment. The neurochemical mechanisms underlying bruxism are little understood at present. Recent pharmacologic evidence suggests that the central dopaminergic system, especially within the mesocortical tract, may be involved in the pathophysiology Letter to the Editors

Inhibitory effects of angiotensin-(1-7) on the nerve stimulation-induced release of norepinephrine and neuropeptide Y from the mesenteric arterial bed

Abstract: Neuropeptide Y (NPY) is a cotransmitter with norepinephrine (NE) and ATP in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin-angiotensin ...

Role of nifedipine-sensitive sympathetic vasoconstriction in maintenance of high blood pressure in spontaneously hypertensive rats: effect of Gi-protein inactivation by pertussis toxin.

Abstract: Background High blood pressure (BP) in spontaneously hypertensive rats (SHRs) is attributed to excessive activity of sympathetic nervous system (SNS) and relative nitric oxide deficiency. An important part of SNS hypertensive action is exerted by calcium influx through L-type of voltage-dependent calcium channels (L-VDCC). The overexpression of pertussis toxin (PTX)-sensitive inhibitory G-proteins (Gi) participating in the development and maintenance of high BP in SHRs suggested us to study Gi-protein involvement in the pathway through which noradrenergic vasoconstriction and calcium influx can be coupled. Method The participation of main vasoactive systems (angiotensin II, norepinephrine, nitric oxide) in BP maintenance was investigated in conscious SHR and WKY rats (half of them being pretreated with PTX, 10 μg/kg i.v., 48 h before the experiment). To evaluate the contribution of Gi-proteins and L-VDCC to vasoconstriction induced by exogenous norepinephrine, dose–response curves were determined before and after acute nifedipine administration. Results PTX pretreatment of SHRs significantly decreased BP and reduced sympathetic vasoconstriction, which was partially substituted by enhanced angiotensin II-dependent vasoconstriction. PTX pretreatment also reduced nitric oxide-dependent vasodilation in both rat strains. PTX pretreatment of SHRs decreased BP component sensitive to acute blockade of calcium entry by nifedipine. In both strains, PTX pretreatment as well as acute nifedipine administration caused substantial rightward shift of norepinephrine dose–response curves (without additive effects of both treatments). Conclusion The enhanced contribution of SNS to hypertension maintenance in SHRs is mediated by Gi-protein-coupled pathway controlling calcium influx through L-VDCC.