The depolarizing action of 5-hydroxytryptamine on rabbit vagal primary afferent and sympathetic neurones and its selective blockade by MDL 72222

Summary MDL 72222 (1H,3,5H-tropan-3-yl-3,5-dichlorobenzoate) is a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones. In the present study, the sucrose-gap technique has been used to record depolarizing responses to 5-HT from the cells of the rabbit nodose and superior cervical ganglia and to investigate the potency and selectivity of MDL 72222 as an antagonist of these responses.On nodose ganglia, responses to 5-HT were inhibited surmountably by MDL 72222 at concentrations up to 100 nmol/l. The threshold for antagonism was 2–10 nmol/l and the apparent pA₂ value (Schild 1947) was 7.7±0.2,n=10. Blockade was selective since responses to GABA and noradrenaline were unaffected by MDL 72222, 100 nmol/l. With concentrations of MDL 7222 higher than 100 nmol/l, antagonism was concentration-related but not in a manner consistent with simple competitive antagonism and even a concentration of 1 mol/l failed to abolish the response to 5-HT.The results from the superior cervical ganglion were essentially similar to those obtained from the nodose ganglion. The threshold concentration of MDL 72222 for inhibition of 5-HT was 1–10 nmol/l and blockade was selective in that depolarizing responses to dimethylphenylpiperazinium (DMPP) was unaffected by a concentration of MDL 72222 of 1 mol/l.The data provide direct evidence that MDL 72222 is a potent and selective antagonist of the receptors for 5-HT which mediate depolarizing responses in vagal primary afferent cell bodies and in sympathetic ganglion cells.     

MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors

Summary The properties of MDL 72222 (1H,3,5H-tropan-3-yl-3,5-dichlorobenzoate), a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones, are described.On the rabbit isolated heart, MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sympathetic fibres. The threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED₅₀ of 5-HT to that of the ED₅₀ was 9.27. MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimethylphenylpiperazinum iodine (DMPP), were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT.In the anaesthetised rat, MDL 72222 produced marked blockade of the Bezold-Jarisch effect of 5-HT. Again, inhibition was selective since much higher doses of MDL 72222 failed to alter the response to electrical stimulation of the efferent vagus nerves. In contrast, MDL 72222 proved only a weak and essentially non-selective antagonist of responses mediated by the 5-HT M-receptor present on the cholinergic nerves of the guinea-pig ileum.MDL 72222 does not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholinoceptors or histamine H₁-receptors except at relatively high concentrations. Similarly, in a number of radioligand binding assays carried out using brain tissue membranes, the displacing effects of MDL 72222 were absent or weak at sites identifying compounds with activity at ₁, ₂ or -adrenoceptors, 5-HT₁ or 5-HT₂ receptors, benzodiazepine receptors or histamine H₁-receptors.MDL 72222 is the first reported selective and potent antagonist of responses mediated through the 5-HT receptors present on the terminal sympathetic neurones of the rabbit heart and on the neurones subserving the afferent limb of the Bezold-Jarisch reflex. The compound should provide a useful means by which responses mediated through such sites can be distinguished.     

Effects of participatory workplace improvement program on stress-related biomarkers and self-reported stress among university hospital nurses: a preliminary study

Although participatory workplace improvement programs are known to provide favorable effects on high stress occupations like nursing, no studies have confirmed its effect using biomarkers. The aim of this study was to determine whether a participatory workplace improvement program would decrease stress-related symptoms as evaluated by biomarkers and self-reported stress among hospital nurses. Three actions to alleviate job stress, which were determined through focus group interviews and voting, were undertaken for two months. A total of 31 female Japanese nurses underwent measurement of inflammatory markers, autonomic nervous activity (ANA), and perceived job stress (PJS) at three-time points; before the program (T1), within a week after the completion of the program (T2), and three months after the program (T3). A series of inflammatory markers (Interferon-γ, Interleukin (IL)-6, and IL-12/23p40) decreased significantly at T2, and IL-12/23p40 and IL-15 significantly decreased at T3 compared to T1, while ANA and PJS remained unchanged. Our participatory program exerted beneficial effects in reducing inflammatory responses, but not for ANA and PJS. Further investigations with a better study design, i.e., a randomized controlled trial, and a larger sample size are warranted to determine what exerted beneficial effects on inflammatory markers and why other outcomes remained unchanged.     

慢性肾衰患者心率变异性改变

目的　通过心率变异性 (HRV)变化测定 ,探讨慢性肾功能衰竭 (CRF)患者的自主神经活动状况。方法　用2 4小时动态心电图分析系统 ,对 2 0例健康者 ,77例CRF患者 (其中 30例氮质血症 ,4 7例尿毒症 )心率变异性的时域指标进行对比研究。结果　CRF患者心率变异性的测定结果为 :SDNN 85 .2 8± 19.96 ,SDANN 75 .5 5± 2 2 .4 7,r-MSSD19.2 2± 11.82 ,PNN50 6 .7± 14 .79,各项指标均明显低于健康者 (P <0 .0 1)。氮质血症期与尿毒症期心率变异性无明显差别。结论　通过HRV时域分析发现 ,CRF患者有自主神经调节功能紊乱。CRF氮质血症期患者已出现HRV下降 ,提示CRF患者早期就存在自主神经功能损害。     

Immunogenicity and tumor-inhibiting effects of HSP-antigen peptide complex in melanoma B16 cells in mice

目的 :黑色素瘤 B1 6细胞热休克蛋白 -抗原肽复合物 (HACs)及其粗提物 (HAC- CEs)的制备 ,以及它们的免疫原性和抑瘤效应的研究。方法 :应用 Sephacryl S- 2 0 0凝胶过滤制备HAC- CEs,应用亲和层析纯化 HACs,并测其免疫功能和抑瘤效应。结果 :应用凝胶过滤制备的HAC- CE3、HAC- CE4、HAC- CE5和应用亲和层析纯化的 HAC60 ,HAC75和 HAC97均不同程度地降低肿瘤发生率、延迟肿瘤发生时间和减少移植黑色素瘤 C57BL/6J小鼠死亡率 ;同时 ,伴有小鼠脾细胞 IFN-γ和 IL- 2分泌活性及 CTL杀伤率的增加。结论 :分子量为 60 0 0 0～ 970 0 0的 HACs具有免疫原性和抑瘤效应 ,本研究为制备肿瘤疫苗提供重要的实验依据。     

经皮腔内冠状动脉成形术对心脏自主神经活动的影响

目的：观察经皮腔内冠状动脉成形术（ＰＴＣＡ）后心率变异（ＨＲＶ）的变化,探讨ＰＴＣＡ和ＨＲＶ的影响。方法：ＰＴＣＡ患者１２０例,２４ｈ动态心电图（ＤＣＧ）记录ＰＴＣＡ术前１周、术后１周、术后６个月的心电信息并进行ＨＲＶ分析。结果：ＰＴＣＡ术后６个月ＨＲＶ指标中的２４ＲＲ间期标准差（ＳＤＮＮ（和高频段的功率谱密度（ＨＦＰ）较术前明显增高（Ｐ分别不小于０．０５及０．０１）;ＰＴＣＡ术后冠状动脉再狭窄患     

吸毒成瘾者免疫功能变化的研究

目的：测定吸毒者体液免疫和细胞免疫的各项指标,从而研究其免疫功能的改变。方法：取25例吸毒者及28例健康成人外周血,用ELISA法和免疫比浊法测其血清中抗体和补体;免疫荧光法和酶联免疫斑点法(ELISPOT)测其T细胞亚群和Th细胞亚群。结果：吸毒者IgG增高,C3下降,IgA、IgM和IgE与正常人无显著差异。吸毒者CD3、CD4^ 、CD4^ ／CD8^ 、Th1^ 和Th1／Th2低于正常人,而CD8^ 、CD20^ 和Th2与正常人相差不大。淋巴细胞转化试验吸毒者显著低于正常对照组。结论：吸毒者细胞免疫功能降低,而体液免疫变化不大。     

Observations on the arterial baroreflex in neurally mediated vasodepressor syncope

The arterial baroreflex was studied in subjects who had recently had an episode of vasodepressor syncope. This was determined using 2–3 mcg/kg intravenous boluses of phenylephrine and assessing the bradycardic response. The values were measured in ms/mmHg and expressed as the angular coefficient of the regression line between the increase in R—R interval on the electrocardiograph and the systolic arterial pressure. In subjects examined immediately after the vasodepressor syncope episode the bradycardic response was much more marked than in controls (p < 0.01) and in the subjects themselves 6 months after the episode, provided that they were symptom-free (p < 0.01). It is concluded that in vasodepressor syncope there is a phase in which the baroreflex is highly sensitive and that this is due not to a lowering of the stimulation threshold but to a gain in the efferent arc, which explains a vagotonic response.     

Behavioral and autonomic responses to intermittent social stress: differential protection by clonidine and metoprolol

The present study investigated physiological and pharmacological characteristics of socially stressed animals. Specifically, we examined (1) to what degree autonomic and behavioral stress reactions during intermittent confrontations between an intruder male adult Long-Evans rat with an aggressive resident undergo habituation, and (2) to what extent the defeat-experienced animal can be protected against these stress reactions with clonidine or metoprolol, two adrenergic agents with clinical anxiolytic effects. We developed an acute social stress situation that consisted of initially placing an experimental rat as an intruder into the homecage of a resident while the resident was not present, thereafter permitting brief physical agonistic interactions with the reintroduced resident until the intruder was forced into a submissive supine posture and emitted ultrasonic vocalizations (USV), and eventually exposing the intruder to the resident's threats for one hour, while being shielded from potentially injurious attacks (threat encounter). Over the course of the initial 4-weekly threat encounters the acute tachycardia but not the hyperthermic stress responses decreased in magnitude. Following the first three threat encounters core temperature (T_c) was significantly elevated for at least 3 h. The T_c was already elevated when the repeatedly defeated intruder was confronted with the olfactory cues of the resident's cage. This conditioned anticipatory hyperthermia developed in the course of the first three confrontations and was paralleled by a decrease in exploratory and motor behavior and by an increase in defensive behaviors and in both types of USV emitted in the low (20–30 kHz) and the high (31–70 kHz) frequency range. Clonidine (0.01–0.1 mg/kg, IP), an ₂-adrenergic agonist and metoprolol, a -adrenergic blocker (1.0–10.0 mg/kg, IP), dose-dependently prevented the tachycardic response to stress. Only clonidine, but not metoprolol, also attenuated the rise in T₀ during the 1-h agonistic interaction. Clonidine decreased those aspects of motor behavior (e.g. rearing, walking) that are of lesser cost for the individual but maintained high levels of defensive reactions and increased the duration of low USV. The high doses of clonidine (0.06, 0.1 mg/kg) attenuated the homeostatic regulation and sedated the intruder while exposed to threats during a social confrontation. The absence of attenuation of the high level of defensive behavior and the prolonged low USV suggest a stress intensification by the higher doses of clonidine. In conclusion, after the fourth encounter, the autonomic, behavioral and vocal response pattern prior to and during repeated weekly confrontations show no evidence for habituation for the following 6 weeks. Moreover, adrenergic therapeutic agents that are applied to treat symptoms of anxiety block the tachycardic response but may actually intensify defensive behavior and certain stress vocalizations.     

Good exercise capacity at hospital discharge predicts recovery of baroreflex sensitivity after myocardial infarction

Myocardial infarction results in depressed baroreflex sensitivity,which has been shown to be associated with increased risk ofventricular arrhythmias and sudden death. We measured baroreflexsensitivity in 37 patients with acute myocardial infarctionbefore hospital discharge and 3 months after the infarctionto find out whether the baroreflex sensitivity recovers duringthat period. In addition, baroreflex sensitivity was assessedin 15 healthy controls. Baroreflex sensitivity was assessedfrom the regression line relating the change in R-R intervalto the change in systolic blood pressure following an intravenousbolus injection of phenylephrine. There was a wide inter-individualvariation in the change of baroreflex sensitivity (Abaroreflexsensitivity) in infarction patients, but the average baroreflexsensitivity showed no significant change during the 3-monthfollow-up (10.2 +5.6 to 11.8 ± 7.5 ms. mmHg ^–1,ns) and remained lower than the baroreflex sensitivity of thecontrols (16.4 ± 9.7 ms. mmHg^–1, P<0.05). Baroreflexsensitivity correlated significantly with exercise capacitymeasured before hospital discharge. When the patients were dividedinto tertiles according to the baroreflex sensitivity ( –3.3 ± 1.5 ms. mmHg^–1 in the lowest tertile, 1.0± 1.0 ms. mmHg^–1 in the middle tertile and 7.5± 40 ms. mmHg^–1 in the highest tertile) the exercisecapacity was found to increase from the lowest to the highesttertile (exercise time 357 ± 115 s, 418 ± 126s and 461 ± 141 s, respectively; P<0.05 lowest vshighest tertile). Patients with a low exercise tolerance (exercisetime <360 s) showed a significantly smaller Abaroreflex sensitivitythan patients with a good exercise tolerance (exercise time480s) ( – 0.5±4.4 vs 5.3 ± 5.4ms. mmHg^–1,P<0.05), respectively. Baroreflex sensitivity was not relatedto the location or type of infarction, thrombolytic therapy,presence of angina pectoris or left ventricular function atthe time of discharge. In conclusion, exercise capacity assessedbefore hospital discharge seems to be a predictor of baroreflexsensitivity recovery in patients with a recent myocardial infarction.