The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.     

糖尿病、高血压与血脂紊乱对心率变异性的影响

目的 探讨糖尿病、高血压、血脂紊乱对心率变异性（HRV）的影响。方法 对单纯33例糖尿病、30例高血压及76例血脂紊乱患者，进行24h HRV时域、频域分析，同时与34例无明显临床疾病、肥胖或超重及血脂异常的正常成人进行HRV的差异比较。结果 1．糖尿病和高血压组与正常组比较HRV各指标除FL／HL均降低（P〈0．05）；血脂异常组HRV各指标除FL／HL也均低于正常组，但仅HF有统计学差异（P〈0．05）。2．血脂异常组与糖尿病及高血压组比：反映交感神经张力的SDNN，SDANN，SDNNindex，LH均降低（P均〈0．05），而反映迷走神经张力的RMSSD、PNN50及HF也降低，仅糖尿病与血脂异常组HF有统计学意义（P〈0．05）；3．糖尿病组HRV各指标均低于高血压组，但无统计学差异。校正年龄、性别、吸烟、We，SBP，DBP，FPG，UA，FATc，Te，TG，HDL-c，LDL-c后上述差异仍存在。结论 糖尿病、高血压与血脂异常、正常人间存在HRV差异。糖尿病和高血压血脂紊乱HRV各指标减低，提示存在交感神经活性增加，迷走神经活性降低，自主神经的功能紊乱可能是糖尿病、高血压血脂紊乱患者心血管事件增加的原因之一。     

Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus.

Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA(3) pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT(1B) autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 microg/kg, i.v.), which assesses alpha(2)-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT(1A) receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT(1A) receptors might be attributable in part to a desensitization of alpha(2)-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.     

Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression

Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the (S,S)-(+)- and (R,R)-(-)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding. The pharmacokinetics of reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins. The primary route of reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. A number of metabolites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. In vitro studies show that reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, reboxetine should be used with caution, and a dosage reduction is indicated. Ketoconazole decreases the clearance of reboxetine, so that the dosage of reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.     

气腹对老年高血压患者自主神经功能的影响

目的 :探讨老年高血压患者在腹腔镜手术过程中气腹对自主神经系统功能的影响。方法 :应用心率变异性 (heartratevariability,HRV)对20例择期高血压老年患者 (Ⅱ组 )和20例择期无高血压老年患者 (Ⅰ组 )行腹腔镜手术中麻醉前、气腹前、气腹后5分钟、气腹后30分钟的心率变异性改变进行分析。结果 :气腹后HR、MAP显著升高 ;LF、LF/HF、TF相对于气腹前也明显升高。组间比较 ,Ⅰ组MAPHR、LF、LF/HF及TF升高幅度显著大于Ⅱ组。结论 :老年高血压患者气腹后交感神经活性和自主神经张力明显高于无高血压的老年患者 ,老年高血压患者气腹时心血管反应明显     

心率变异分析与运动试验对病理性室性早搏诊断价值的研究

目的探讨心率变异性分析与小儿脚踏车运动试验联合应用对判定小儿病理性室性早搏的应用价值。方法根据临床症状、体征及辅助检查将86例确诊室性早搏儿童分为有器质性心脏病组（A组）54例和无器质性心脏病组（B组）32例,分别对其进行心率变异（HRV）分析与脚踏车运动试验检查,所得结果应用统计学方法处理。结果两组儿童HRV比较,A组较B组心率变异性降低,差异有显著性（P〈0.05）。两组儿童脚踏车运动试验结果比较,A组阳性率高于B组,差异有显著性（P〈0.05）。结论病理性室性早搏多与自主神经功能受损有关,心率变异性分析与运动试验均可用于病理性室性早搏的诊断,二者联合应用可更有效辅助病理性早搏的鉴别诊断,并且对判定室性早搏的危险程度及选择治疗方案有一定的应用价值。     

The influence of cocaine and desipramine on the cardiac responses to exogenous and endogenous norepinephrine

In open-chest, anesthetized dogs, cocaine and desipramine potentiated the pressor, chronotropic, inotropic and coronary sinus blood flow responses to norepinephrine (NE) infusions. The chronotropic and inotropic responses were also prolonged, the former more markedly than the later and the extraction of exogenous NE from the coronary blood stream was diminished. Cocaine and desipramine also potentiated the pressor and coronary sinus blood flow responses, but not the chronotropic or inotropic responses, to stimulation of the left ansa subclavia. The inotropic response was slightly prolonged, however, and the chronotropic response was markedly prolonged. The overflow of NE into the coronary sinus blood was not increased by either neuronal uptake blocking agent. It is proposed that cocaine and desipramine, at the doses employed, diminish the release of NE from the cardiac nerve endings at the same time that they inhibit reuptake of the neurotransmitter. Their mechanisms of action and their side effects on the circulatory system do not appear to differ significantly.     

Effect of cardiac vagal outflow on complexity and fractal correlation properties of heart rate dynamics

1. Cardiac vagal outflow is the major factor determining the magnitude of heart rate (HR) variability analysed by traditional time and frequency domain methods. New analysis techniques, such as fractal and complexity methods, have been developed to probe non-linear features in HR behaviour that may not be detectable by traditional methods. 2. We investigated the effects of vagal blockade (glycopyrrolate i.v. 5 microg kg-1 h-1 for 2 h, n = 8 vs. unmedicated control group, n = 8) and various breathing patterns (n = 12) on two non-linear measures of HR variability--detrended fluctuation analysis (DFA) and approximate entropy (ApEn)--in healthy male volunteers. 3. Glycopyrrolate decreased the mean (+/-SD) ApEn from 1.46 +/- 0.18 to 0.85 +/- 0.24 (P = 0.001 in comparison with the control group), and increased the short-term (alpha 1) and intermediate-term (alpha 2) fractal scaling exponents of DFA, alpha 1 from 0.96 +/- 0.19 to 1.43 +/- 0.29 (P = 0.003) and alpha 2 from 1.13 +/- 0.10 to 1.34 +/- 0.14 (P < 0.001). 4. Decrease in fixed respiration rate from 15 to 6 breaths min-1 increased alpha 1 from 0.83 +/- 0.25 to 1.18 +/- 0.27 (P < 0.001), but decreased alpha 2 from 0.88 +/- 0.09 to 0.45 +/- 0.17 (P < 0.001) and ApEn from 1.26 +/- 0.12 to 1.10 +/- 0.14 (P = 0.028). Rapid breathing (24 min-1) had no influence on these non-linear measures of HR variability. Hyperventilation (15 min-1, tidal volume increased voluntarily by 0.5 l) decreased alpha 1 from 0.83 +/- 0.25 to 0.66 +/- 0.28 (P = 0.002) but did not affect alpha 2 or ApEn. 5. To conclude, vagal blockade alters the fractal scaling properties of R-R intervals (alpha 1, alpha 2) and reduces the complexity (ApEn) of HR behaviour. Both the fractal and complexity measures of HR variability can also be influenced by changes in the breathing pattern.     

老年2型糖尿病心脏自主神经功能与心率变异性关系的研究

目的探讨耱尿病患者的心率变异性(HRV)及其在诊断自主神经病变(ANP)方面的意义。方法设观察组(糖尿病组)和对照组(非糖尿病组)各30例。两组均测定时域分析的各参数。结果糖尿病组的心率变异性比非糖尿病组显著降低。结论检测糖尿病的心率变异性可早期敏感诊断老年2型糖尿病患者心脏自主神经功能病变。     

A meta-analysis of clinical trials comparing reboxetine, a norepinephrine reuptake inhibitor, with selective serotonin reuptake inhibitors for the treatment of major depressive disorder.

The goal of the present work was to conduct a meta-analysis comparing reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n=2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and reboxetine (59.2%)-treated groups (p=0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p=0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p=0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD.     

Alcohol and tobacco use and heart rate reactivity to a psychosocial stressor in an adolescent population

Background

Few studies have investigated physiological stress (re)activity in relation to substance use, especially in adolescents. Using substances is one way to stimulate physiological arousal, therefore inherent hypo-arousal may be associated with substance use in adolescents. The purpose of this study was to examine the relation of autonomic nervous system (ANS) activity with alcohol and tobacco use in adolescents.

Methods

ANS activity and perceived stress during a social stress procedure were examined in relation to substance use. 275 Dutch adolescents from a general population study provided complete data. Heart rate was recorded continuously during a pre-task rest period, a stressful task period and a post-task recovery period. Alcohol and tobacco use were self-reported.

Results

Adolescents who consumed a medium and high number of alcoholic drinks per week (more than two) exhibited lower heart rates during the entire stress procedure as compared to those who consumed a low number of alcoholic drinks. Adolescents who smoked every day portrayed blunted heart rate reactivity to stress as compared to adolescents who smoked less frequently or not at all. Perceived stress was not related to alcohol or tobacco use.

Conclusions

Overall lower heart rate in adolescents who drank more and blunted heart rate reactivity to stress in those who used tobacco every day may indicate inherent hypo-arousal of the ANS system in those vulnerable to use substances more often. These adolescents may actively seek out substances in order to achieve a more normalized state of arousal.     

Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats: a characterization with alpha/beta-adrenoceptor subtype selective ligands, antidepressants, and antagonists at neuropeptide receptors

Although little information is available concerning discriminative stimulus (DS) properties of antidepressants, rats can be trained to recognize the selective norepinephrine (NE) reuptake inhibitor, reboxetine (2.5 mg/kg i.p.). By analogy to reboxetine (effective dose50, 1.1), 'full' (80%) substitution dose50 was obtained with the NE reuptake inhibitors, nisoxetine (4.9), nomifensine (0.5) and BW1555,U88 (1.0). Full substitution was also attained with the NE/serotonin (5-HT) reuptake inhibitors, S33005 (0.3), venlafaxine (4.8) and duloxetine (26.8), and the tricyclics, imipramine (2.5) and clomipramine (2.9). In contrast, the 5-HT reuptake inhibitors, citalopram, sertraline and paroxetine (all >2.5), and the 5-HT reuptake inhibitors/5-HT2 receptor antagonists, nefazodone and trazodone (both >10.0), did not substitute for reboxetine. The 'atypical' antidepressants, mirtazapine (>10.0) and mianserin (>2.5), similarly failed to substitute. DS properties of reboxetine were dose-dependently blocked by the alpha1-adrenoceptor (AR) antagonists, prazosin (inhibitory dose50, 0.3) and WB4101 (0.5), but resistant to the alpha2-AR antagonists, atipamezole (>0.63), idazoxan (>2.5) and RX821,002 (>0.08), and to the beta1-AR and beta2-AR antagonists, betaxolol (>2.5) and ICI118,551 (>10.0). Interestingly, the neurokinin-1 receptor antagonist, GR205,171, stereospecifically substituted for reboxetine (1.1) compared to its less active isomer, GR226,206 (>10.0). The corticotrophin-releasing factor-1 antagonists, DMP695 (>40), CP154,526 (>10.0) and SN003 (>40.0), and the melanin-concentrating hormone-1 antagonist, SNAP-7941 (>40.0), failed to substitute for reboxetine. In conclusion, DS properties of reboxetine are mimicked by antidepressants recognizing NE transporters, and require functionally intact alpha1-ARs for their expression. The neurokinin-1 antagonist, GR205,171, mimics the interoceptive properties of reboxetine, possibly reflecting its elevation of extracellular levels of NE in corticolimbic structures.     

Dual activation of cardiac sympathetic and parasympathetic components during conditioned fear to context in the rat

1. The present study investigates the contribution of the sympathetic and vagal parasympathetic systems to the tachycardic response of long-lasting (40 min) conditioned fear responses to context. 2. The conditioned fear response evoked by re-exposure to a footshock chamber was tested 10 min after intravenous injection of the beta-adrenoceptor antagonist propranolol (2 mg/kg) or the muscarinic antagonist atropine methyl nitrate (2 mg/kg) in rats implanted with radiotelemetric probes. 3. Compared with saline controls, the drugs did not change the behavioural component of the response (freezing, 22 kHz ultrasonic vocalizations) or its pressor component (+28 mmHg). 4. Propranolol abolished the tachycardic response of fear, whereas atropine more than doubled it (from +75 to +175 b.p.m. above resting baseline). 5. The results demonstrate that both sympathetic and vagal parasympathetic outflows to the heart are strongly activated during conditioned fear. The vagal activation may act to hold back cardiac acceleration while the animal waits for the aversive stimulus to come.     

Miotic tolerance to sarin vapor exposure: role of the sympathetic and parasympathetic nervous systems.

O-isopropyl methylphosphonofluoridate, also known as sarin or GB, is a highly toxic organophosphorous compound that exerts its effect by inhibiting the enzyme acetylcholinesterase. While the effects of a single exposure to GB vapor are well characterized, the effects of multiple exposures to GB vapor are less clear. Previous studies in the rat and guinea pig have demonstrated that multiple exposures result in tolerance to the miotic effect of nerve agents. The aim of the present study was to examine potential mechanisms responsible for tolerance to the miotic effect of GB vapor that has been observed in the rat after multiple exposures. Multiple whole-body inhalation exposures to GB vapor were conducted in a dynamic airflow chamber. Exposures lasted 60 min and each of the three exposures occurred at 24-h intervals. The results of the present study demonstrate that the alpha-adrenergic antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol did not affect the development of tolerance to the miotic effect of GB vapor, suggesting that enhanced sympathetic tone to the eye is not responsible for the observed tolerance. Administration of atropine before the first exposure prevented the tolerance to the miotic effect of GB vapor after the third exposure, suggesting that the tolerance is the result of muscarinic receptor desensitization secondary to receptor stimulation. The present study extends the findings of previous studies to strengthen the hypothesis that the miotic tolerance observed in the rat upon repeated exposure to nerve agents is due to desensitization of muscarinic acetylcholine receptors located on the pupillary sphincter.     

美托洛尔对老年患者心功能及心率变异性的影响

目的评价美托洛尔对老年患者心功能及心率变异性(HRV)的影响。方法心血管病老年患者426例,年龄≥70岁,口服美托洛尔治疗12个月。观察治疗前、治疗12个月后BP、HR、HRV(340例窦性心律患者)、左室收缩末期容积(LVESV)和舒张末期容积(LVEDV)、左室射血分数(LVEF)和心排血量(CO)的变化。结果与治疗前比较,治疗后BP、HR明显降低(P<0.05),LVEDV及LVESV明显降低[(173.22±45.42)ml vs.(158.55±40.34)ml和(150.34±54.14)mlvs.(134.65±44.02)ml](P<0.05)],而LVEF和CO明显增加[(56.16±3.26)%vs.(60.25±4.05)%和(4.2±1.2)L vs.(5.4±1.9)L](P<0.05)]。HRV各参数均较治疗前明显升高。药物相关的不良反应无明显增加。结论对老年患者,美托洛尔降低心率和血压的同时,明显改善HRV及心功能。     

The effect of hepatic or renal impairment on the pharmacokinetics of edivoxetine, a selective norepinephrine transporter reuptake inhibitor

Purpose

To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine.

Methods

Two separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child–Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft–Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration–time data.

Results

In the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h?×?ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of C_max was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events.

Conclusions

PK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.     

Efectsofmoxonidineinjectedintorostralventrolateralmedulaonbloodpressure,heartrate,andrenalsympatheticnerveactivityinrats

目的：观察延髓腹外侧头端（ＲＶＬＭ）注射莫索尼定（Ｍｏｘ）对麻醉大鼠血压（ＢＰ）、心率（ＨＲ）及肾交感神经放电（ＲＳＮＡ）的影响．方法：麻醉大鼠ＲＶＬＭ注射１μＬＭｏｘ１，１０，１００μｍｏｌ·Ｌ－１，同步记录ＢＰ，ＨＲ及ＲＳＮＡ．结果：Ｍｏｘ１，１０，１００μｍｏｌ·Ｌ－１分别使ＢＰ从１３９±１０ｋＰａ降至１３０±１７ｋＰａ（Ｐ＜００５），１３８±１８ｋＰａ至１１４±１５ｋＰａ（Ｐ＜００１），ａｎｄ１３９±１９ｋＰａ至９４±１７ｋＰａ（Ｐ＜００１）．Ｍｏｘ不影响ＨＲ．Ｍｏｘ１μｍｏｌ·Ｌ－１增加ＲＳＮＡ５０％（Ｐ＜００５），１０μｍｏｌ·Ｌ－１对ＲＳＮＡ无影响（Ｐ＞００５），１００μｍｏｌ·Ｌ－１则降低ＲＳＮＡ２３％（Ｐ＜００５）．在缓冲神经切断大鼠，Ｍｏｘ１０μｍｏｌ·Ｌ－１抑制ＲＳＮＡ５０％（Ｐ＜００５），明显不同于缓冲神经完整的动物（Ｐ＜００１）．结论：麻醉大鼠ＲＶＬＭ注射Ｍｏｘ可降低ＢＰ，但不影响ＨＲ，且ＲＳＮＡ变化与其降压作用并不平行     

The effects of reboxetine,a noradrenaline reuptake inhibitor,on the plasma noradrenaline response to a cold pressor test in healthy volunteers

Previous studies have shown peripheral abnormalities in noradrenergic activity in depressed melancholic patients. These abnormalities have a relationship with short-term and long-term outcome. Little is known about the effects of antidepressant treatment on these peripheral measures such as plasma noradrenaline (NA) and the plasma NA response to a laboratory stressor, the cold pressor test (CPT). The present study examines the effects of the antidepressant reboxetine, a noradrenaline reuptake inhibitor, on baseline plasma NA and the plasma NA response to a CPT, in nine healthy volunteers compared to placebo. A double-blind crossover design was used, with each agent given for 4 weeks with a 4-week washout period. There was no effect of reboxetine on baseline plasma NA. The plasma NA response to reboxetine, with a CPT, was blunted 3 days after commencing treatment. Reboxetine alters the plasma NA response to a CPT independent of baseline plasma NA.     

The acute effects of inhaled salbutamol on the beat-to-beat variability of heart rate and blood pressure assessed by spectral analysis

Aims We wanted to study the effects of a 600  μg inhaled salbutamol dose on the cardiovascular and respiratory autonomic nervous regulation in eight children suffering from bronchial asthma.
Methods In this randomized, double-blind, placebo-controlled, crossover study we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline as well as 20  min and 2  h after the drug inhalation. The R–R interval (the time between successive heart beats) and SAP variabilities were assessed by using spectral analysis. Baroreflex sensitivity was assessed by using cross-spectral analysis.
Results Salbutamol significantly decreased the total and low frequency (LF) variability of R–R intervals as well as the high frequency (HF) variability of R–R intervals and of SAP. Salbutamol significantly increased the LF/HF ratio of R–R intervals and of SAP, minute ventilation, heart rate and forced pulmonary function in comparison with placebo. The weight of the subjects significantly correlated positively with baroreflex sensitivity and negatively with heart rate after the salbutamol inhalation.
Conclusions We conclude that the acute salbutamol inhalation decreases cardiovagal nervous responsiveness, increases sympathetic dominance in the cardiovascular autonomic balance, and has a tendency to decrease baroreflex sensitivity in addition to improved pulmonary function.     

Inhibition of sympathetic transmission in rat heart by clonidine: The roles of stimulation frequency,endogenous feedback and noradrenaline re-uptake

Summary The inhibitory effects of clonidine were compared with other procedures which reduce the effector response to sympathetic cardioaccelerator nerve stimulation in the pithed rat. The effect of clonidine was most marked against responses to stimulation with relatively short trains of pulses and/or low frequencies of stimulation but a similar effect could be achieved by stimulating fewer fibres, by pretreating the rats with reserpine or by acute administration of guanethidine or propranolol. Unlike the other procedures, however, clonidine did not abolish responses. The effects of clonidine were similar whether or not endogenous -adrenoceptor-mediated feedback could be demonstrated. After blockade with cocaine of the neuronal re-uptake of transmitter noradrenaline, the inhibitory effect of clonidine was undiminished when the effect of cocaine on the frequency/response curve was taken into account. It is concluded that with frequencies and train lengths within the physiological range relative resistance to the inhibitory effect of clonidine is more dependent on post-junctional summation than on the development of pre-junctional facilitation or feedback mechanisms. Even with a single stimulus, however, the inhibitory effect of clonidine was limited suggesting that a portion of transmitter release is inaccessible to such blockade.