交感神经递质及其受体在小鼠血吸虫肝纤维化中的作用

目的 研究交感神经递质及其受体在正常小鼠及血吸虫病肝纤维化小鼠体内的变化情况.方法 应用腹部敷贴尾蚴法制备血吸虫病小鼠模型.30只昆明小鼠随机分为正常对照组和肝纤维化模型组.采用HE和Van Gieson染色,光镜观察肝组织病理学改变及纤维化程度,免疫荧光组织化学染色结合激光共聚焦扫描检测肝组织中α1A、β2肾上腺素能受体表达情况,同时用高效液相色谱-电化学法检测血浆中去甲肾上腺素和多巴胺的水平. 结果 正常组α1A、β2肾上腺素能受体散在表达于肝细胞胞质和肝窦内,模型组在门静脉和虫卵结节周围肝细胞胞质中阳性表达明显增加(α1A受体的平均灰度值分别为18.28±7.56、30.53±8.88,β2受体的平均灰度值分别为28.67±6.42、42.29±4.56,t值分别为-2.888和-6.648,P值均＜0.05);血吸虫肝纤维化小鼠和正常小鼠去甲肾上腺素含量分别为(7.83±4.36)、(2.72±0.94)ng/ml,多巴胺的含量分别为(6.97±4.33)、(0.74±0.34)ng/ml,t值分别为-3.372和-4.428,P值均＜0.05.结论 交感神经递质及其受体表达的上调可能是血吸虫肝纤维化发展的作用机制之一.     

Effects of 5,7–Dihydroxytryptamine Lesions of the Prefrontal Cortex on Consumption of Sucrose-Ethanol Solutions: Relationship to Prefrontal Monoamines

Thirty adult male Wistar rats received 8 μg bilaterally of 5,7–dihy-droxytryptamine into the medial prefrontal cortex (mPFC). Rats were then trained, via a sucrose fading paradigm, to consume increasing concentrations of alcohol. After death, dopamine (DA), norepineph-rine (NE), serotonin (5–HT), and their metabolites were measured in the mPFC, nucleus accumbens (NA), and raphe nucleus. The le-sioned group demonstrated a reduction in 5–hydroxyindoleacetic acid (5–HIAA), DA, and NE in the mPFC ( p < 0.05), and a trend toward reduction of 5–HT in the NA. In comparison with controls, lesioned animals consumed less of all solutions containing sucrose and alcohol. On regression analyses, monoamines in the mPFC (i.e., 5–HIAA, dihydrophenylacetic acid and NE) predicted consumption of the 5% ethanol solution ( p = 0.00S), 10% ethanol solution ( p = 0.0006), and the 5% sucrose solutions ( p = 0.0006), but not the 20% sucrose solutions. In each case, monoamine levels were positively correlated with consumption. No relationships were seen between monoamine levels in the NA and raphe, and in consummatory behavior.     

Hypoxia does not activate ATP-sensitive K+ channels in arteriolar muscle cells

OBJECTIVE: To test the hypothesis that hypoxia activates ATP-sensitive K+ (KATP) channels in cremasteric arteriolar muscle cells, resulting in membrane hyperpolarization and inhibition of norepinephrine-induced contraction. METHODS: Arteriolar muscle cells were isolated enzymatically from second- and third-order arterioles that were surgically removed from hamster cremaster muscles. The effects of hypoxia (PO2 = 12-15 mm Hg) were then examined on norepinephrine-induced contraction, membrane currents, and membrane potential in these cells at room temperature. Whole-cell currents and membrane potential were recorded using the perforated patch technique. RESULTS: Hypoxia (12-15 mm Hg PO2) reversibly inhibited norepinephrine-induced contraction to 52 +/- 6% of the response in normoxic solutions (156 mm Hg, n = 12 digests, p < 0.05). These effects of hypoxia could be prevented by superfusion of the cells with either solutions containing the KATP channel antagonist glibenclamide (1 microM) or solutions containing 35 mM K+ to reduce the electrochemical gradient for K+ diffusion. Cromakalim, an activator of KATP channels, also inhibited norepinephrine-induced contraction to a similar extent as hypoxia, and in a glibenclamide and 35 mM K(+)-sensitive manner. These results are consistent with the KATP channel hypothesis. In contrast, hypoxia had no effect on estimated whole-cell membrane conductance between -40 and -90 mV in voltage-clamp experiments; on holding current measured at -60 mV in cells superfused with 143 mM K+ under voltage-clamp conditions; or on membrane potential in current-clamp experiments, despite positive effects of cromakalim in all three protocols. These electrophysiological data lead to rejection of the hypothesis that hypoxia activates KATP channels. CONCLUSIONS: Hypoxia inhibits norepinephrine-induced contraction of cremasteric arteriolar muscle cells by a mechanism that does not involve KATP channels. It is speculated that the inhibitory effects of glibenclamide and 35 mM K+ on the effects of hypoxia on contraction resulted from depolarization induced by these treatments rather than specific inhibition of KATP channels.     

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.     

From facial mimicry to emotional empathy: A role for norepinephrine ?

Tendency to mimic others' emotional facial expressions predicts empathy and may represent a physiological marker of psychopathy. Anatomical connectivity between amygdala, cingulate motor cortex (M3, M4), and facial nucleus demonstrates a potential neuroanatomical substrate for mimicry, though pharmacological influences are largely unknown. Norepinephrine modulation selectively impairs negative emotion recognition, reflecting a potential role in processing empathy-eliciting facial expressions. We examined effects of single doses of propranolol (beta-adrenoceptor blocker) and reboxetine (selective norepinephrine reuptake inhibitor) on automatic facial mimicry of sadness, anger, and happiness, and the relationship between mimicry and empathy. Forty-five healthy volunteers were randomized to 40 mg propranolol or 4 mg reboxetine. Two hours after drug subjects viewed and rated facial expressions of sadness, anger, and happiness, while corrugator, zygomatic, and mentalis EMG were recorded. Trait emotional empathy was measured using the Balanced Emotional Empathy Scale. EMG confirmed emotion-specific mimicry and the relationship between corrugator mimicry and empathy. Norepinephrine modulation did not alter mimicry to any expression or influence the relationship between mimicry and empathy. Corrugator but not zygomaticus mimicry predicts trait empathy, consistent with greater anatomical connectivity between amygdala and M3 coding upper facial muscle representations. Although influencing emotion perception, norepinephrine does not influence emotional facial mimicry or its relationship with trait empathy.     

Clobenpropit,a histamine H3 receptor antagonist/inverse agonist,inhibits [3H]-dopamine uptake by human neuroblastoma SH-SY5Y cells and rat brain synaptosomes

Background

Clobenpropit, a potent antagonist/inverse agonist at the histamine H₃ receptor (H₃R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H₃R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport.

Intraoperative Continuous Norepinephrine Infusion Combined with Restrictive Deferred Hydration Significantly Reduces the Need for Blood Transfusion in Patients Undergoing Open Radical Cystectomy: Results of a Prospective Randomised Trial

Background

Open radical cystectomy (ORC) is associated with substantial blood loss and a high incidence of perioperative blood transfusions. Strategies to reduce blood loss and blood transfusion are warranted.

Objective

To determine whether continuous norepinephrine administration combined with intraoperative restrictive hydration with Ringer's maleate solution can reduce blood loss and the need for blood transfusion.

Design, setting, and participants

This was a double-blind, randomised, parallel-group, single-centre trial including 166 consecutive patients undergoing ORC with urinary diversion (UD). Exclusion criteria were severe hepatic or renal dysfunction, congestive heart failure, and contraindications to epidural analgesia.

Intervention

Patients were randomly allocated to continuous norepinephrine administration starting with 2 μg/kg per hour combined with 1 ml/kg per hour until the bladder was removed, then to 3 ml/kg per hour of Ringer's maleate solution (norepinephrine/low-volume group) or 6 ml/kg per hour of Ringer's maleate solution throughout surgery (control group).

Outcome measurements and statistical analysis

Intraoperative blood loss and the percentage of patients requiring blood transfusions perioperatively were assessed. Data were analysed using nonparametric statistical models.

Results and limitations

Total median blood loss was 800 ml (range: 300–1700) in the norepinephrine/low-volume group versus 1200 ml (range: 400–2800) in the control group (p < 0.0001). In the norepinephrine/low-volume group, 27 of 83 patients (33%) required an average of 1.8 U (±0.8) of packed red blood cells (PRBCs). In the control group, 50 of 83 patients (60%) required an average of 2.9 U (±2.1) of PRBCs during hospitalisation (relative risk: 0.54; 95% confidence interval [CI], 0.38–0.77; p = 0.0006). The absolute reduction in transfusion rate throughout hospitalisation was 28% (95% CI, 12–45). In this study, surgery was performed by three high-volume surgeons using a standardised technique, so whether these significant results are reproducible in other centres needs to be shown.

Conclusions

Continuous norepinephrine administration combined with restrictive hydration significantly reduces intraoperative blood loss, the rate of blood transfusions, and the number of PRBC units required per patient undergoing ORC with UD.     

Effects of Milrinone continuous intravenous infusion on global cerebral oxygenation and cerebral vasospasm after cerebral aneurysm surgical clipping

BackgroundCerebral vasospasm (CVS) is a disabling disease with high morbidity and mortality risk. Milrinone (phosphodiesterase III inhibitor) has inotropic and vasodilator effects, noninvasive transcranial cerebral oximetry (rSO2%) useful in estimating the effect of triple-H therapy preventive measures against CVS.ObjectiveThe objective of the study is to clarify the value of the use of Milrinone continuous IV infusion as a cerebral vasodilator in post-clipping spasm prevention during the period of maximum vasospasm incidence, guided by noninvasive rSO2%.MethodsPost-clipping all patients extubated in the operative room, shifted to Neurosurgical ICU, and fully monitored. Then, in the period from 4th till the 11th day post-clipping, they were divided into two groups 15 patients each: Group 1: control group, given Norepinephrine continuous IV infusion alone in a dose ranges from 0.05 to 0.2 μg/kg/min. Group 2: given Norepinephrine continuous IV infusion 0.05–0.2 μg/kg/min, Plus Milrinone starting with 50 μg/kg bolus dose, followed by IV infusion at a rate of [0.5–0.75 μg/kg/min]. IMAP, ICP and CPP, GCS, Norepinephrine dose, rSO2%, were recorded every 6 h for the next 168 h. Any attack of cerebral vascular spasm recorded as number and % in each group as an incident.ResultsMBP, rSO2%, ICP, CPP, Norepinephrine Infusion dose, and GCS were significantly increased in Group (2) in comparison with Group (1) mostly during the period of the study. CVS occurrence was significantly lower in group (2), i.e., (20%) cases compared to (46.6%) in group (1).ConclusionsMilrinone improved significantly the global cerebral oxygenation and reduced the incidence of cerebral vasospasm during the dangerous period of cerebral spasm after cerebral aneurysm clipping.     

Antagonistic influences of dibutyryl cyclic AMP and dibutyryl cyclic GMP on the beating rate of cultured mouse myocardial cells.

Cultured myocardial cells obtained from neonatal mouse ventricles beat spontaneously and rhythmically. Norepinephrine and dibutyryl cyclic AMP accelerated the rate of spontaneous beating. Dibutyryl cyclic GMP slightly decreased the rate of spontaneous beating. The acceleration of the beating rate of cultured myocardial cells by norepinephrine or dibutyryl cyclic AMP was counteracted by dibutyryl cyclic GMP. Preincubation of cultured myocardial cells with dibutyryl cyclic GMP prevented the positive chronotropic effect of dibutyryl cyclic AMP.