Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(1-(α-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4- tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca²⁺-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca²⁺-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 μM) shifted the EC₅₀ of Ca²⁺ for contractile activation of skinned fibers of pig heart from 2.41 μM to 0.73 μM, whereas [-]-EMD 60264 (30 μM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35 % of pre-drug control with [+]-EMD 60263 in comparison to 113 % with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component I_Kr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define I_Kr. It is concluded, that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca²⁺-sensitizing effect. The accompanying prolongation in action potential duration is caused by block of the I_Kr component of the delayed rectifier. While the inotropic effects are stereoselective, most of the electrophysiological actions are clearly independent of sterical configuration. The combination of Ca²⁺-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic use. Received: 7 January 1997 / Accepted: 25 February 1997     

Subtype determination of soma-dendritic α2-autoreceptors in slices of rat locus coeruleus

The aim of the study was to subclassify the soma-dendritic α₂-autoreceptors in the locus coeruleus (LC) of the rat by means of antagonists. To this end, the frequency of spontaneous action potentials was recorded extracellularly from single LC neurones in brain slices. The neurones fired spontaneously at an average rate of 1 Hz. The selective α₂-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) and noradrenaline decreased the action potential discharge with IC₅₀ values of 5 and 510 nM, respectively. The concentration-inhibition curves of UK 14,304 and noradrenaline were shifted to the right by phentolamine (0.15 μM) and rauwolscine (0.15 μM) but not by prazosin (1 μM). Apparent K _d values of phentolamine were 17 nM (against UK 14,304) and 20 nM (against noradrenaline). Apparent K _d values of rauwolscine were 47 nM (against UK 14,304) and 70 nM (against noradrenaline). (+)-Oxaprotiline (1 μM) suppressed the firing of the neurones within 10 to 33 min. In the continued presence of oxaprotiline, phentolamine and rauwolscine restored firing with EC₅₀ values of 120 and 250 nM, respectively. Prazosin (1 μM) again was ineffective. All three antagonist affinity estimates – against UK 14,304, exogenous noradrenaline and endogenous noradrenaline (that accumulates in the extracellular space in the presence of oxaprotiline) – yield an affinity order phentolamine > rauwolscine >> prazosin, prazosin being ineffective even at a concentration of 1 μM. These findings identify the soma-dendritic α₂-autoreceptors of the LC as the rat variant of the α_2A/D-adrenoceptor, i.e. α_2D. Not only presynaptic but also soma-dendritic α₂-autoreceptors may at least predominantly be α_2A/D throughout the nervous system. Received: 3 March 1997 / Accepted: 21 April 1997     

Action Research: a valuable research technique for service delivery development

The evaluation of healthcare practice and service delivery is fraught with difficulties. Service development and / or delivery occurs within socially dynamic settings which are in a continual state of change. Service development also often involves large elements of improvisation. The action research approach is useful for health service research, as it supports collaboration between researchers and practitioners, and not only allows but makes explicit that the action researcher has both roles within the setting being studied. This paper discusses action research methodology and offers insight into principles that favor its use for service delivery development. This includes consideration of the interactive variables within studies of health care systems and the importance of evaluating relationships between stakeholders to understand how these factors or variables, which cannot be controlled for, are responsible for successful development of the service. Action research facilitates change and helps bridge the heory--practice gap. With the current dynamic changes within both the pharmacy profession and national health services, researchers may find the action research technique of value when considering new roles and innovative ways of engaging in collaborative, multi-disciplinary working to improve delivery of patient care.Accepted july 2004     

Health promotion training needs analysis: an integral role for clinical nurses in Lanarkshire,Scotland*

Training needs analysis is considered essential to professional and organizational development, for continuing education and for incorporation into professional practice. Increasingly, nurses are encouraged to develop their health promotion role. Despite this there has been relatively little research in Scotland into the health promotion role of the hospital nurse. This study describes the results of a health promotion training needs analysis undertaken on qualified, hospital-based nurses in Lanarkshire, Scotland. Information on the nurses' current health promotion practices, their attitudes and beliefs, their views on role development and priorities for further training were collated, analysed and discussed within the framework of the Health Action Model. This model was originally designed to assist understanding of the gap that exists between an individual intention to act and the eventual health action. However, in this study the ways in which ‘cognitive factors’ (knowledge and beliefs) and ‘motivational factors’ (considering values, attitudes and drives) and pressures from social norms and significant others assisted in the understanding of the nurse's orientation to, and beliefs about, health promotion practice. Fifty-seven per cent of nurses in the study considered health promotion activities to be emerging in clinical care and 4% considered them to be advanced. The interest respondents have in role development and the further integration of health promotion activities into nursing practice was explored by ascertaining the nurses' attitudes and beliefs about their own health promotion role. Of 107 respondents, a majority 72 (67%) agreed health promotion interventions to be an important function of the nurse with 29 (27%) strongly agreeing (n=107). Sixty per cent stated they would be interested in developing their role and 30% were very strongly interested. Recommendations are therefore made for future planning and development strategies for the health promotion role of hospital nurses.     

青滕碱对豚鼠心肌动作电位和收缩力的影响

青藤碱2.7μmol/L以上,呈浓度依赖性地降低豚鼠乳头肌收缩力,延长动作电位时程和有效不应期。小剂量时,青藤碱能降低动作电位0相上升最大速率;较大剂量时,动作电位幅度也降低。用TTX处理豚鼠乳头肌所致的慢反应电位,青藤碱能够抑制。此外,青藤碱能对抗乙酰胆碱缩短豚鼠左房肌动作电位时程的作用。结果提示:青藤碱对Na⁺,Ca²⁺和K⁺的跨膜转运均有抑制作用。     

大豆总皂甙对培养心肌细胞自发性搏动与动作电位的影响

培养Wistar大鼠乳鼠的心室肌细胞,向培养基中分别加入浓度为1.56μg/ml至50μg/ml的大豆皂甙,可使心肌细胞群落的自发性搏动呈剂量依赖性抑制。洗脱大豆皂甙或向培养基中再加入10μg/ml肾上腺素均能使自发性搏动恢复。向培养基中加入大豆皂甙5μg/ml使心肌细胞动作电位的波幅、波宽、超射、最大舒张电位、阈电位、最大除极速度等各电参数立即减小。Ca~(2+)80μg/ml能使动作电位的抑制逆转。上述结果表明大豆皂甙对培养的鼠心肌细胞具有钙通道阻滞用。     

维生素D_3与心肌细胞电活动关系的实验研究

本实验利用标准玻璃微电极技术和微机系统的实时应用,在离体豚鼠右心室乳头肌上观察维生素D_3对其细胞电活动的影响。结果表明维生素D_3可使心肌细胞动作电位和零相最大去极化速率发生明显改变,其变化主要是由于通过细胞膜慢通道有大量的Ca~(2+)内流,使细胞内Ca~(2+)超负荷来实现的。     

Pharmacology of KB‐R7943: A Na+–Ca2+ exchange inhibitor

The Na⁺–Ca²⁺ exchange (NCX) system plays a pivotal role in regulating intracellular Ca²⁺ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca²⁺‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.     

NGD及NRF对大鼠坐骨神经缺损修复的电生理学检测

目的 :观察神经生长液 ( NGD)及神经再生素 ( NRF)修复大鼠坐骨神经缺损的效果。方法 :用生理盐水( NS)、NRF桥接以及 NRF桥接 +口服 NGD修复大鼠坐骨神经缺损 ,术后 12周检测大鼠坐骨神经干动作电位传导速度及肌电图。结果 :行为方面 NGD+ NRF组比 NS组恢复早 ,NS组、NRF组、NRF+ NGD组神经干动作电位传导速度的平均值分别为 5 .72 0 m/ s、16 .5 14 m/ s、2 1.310 m/ s。NS组与 NGD+ NRF组的神经干动作电位传导速度经统计学分析有显著性差异 ( P<0 .0 1)。NGD+ NRF组与 NS组的肌电图比较 ,前者的潜伏期短、峰谷值大、运动神经传导速度快。结论 :NGD+ NRF具有良好促进神经再生作用     

Self-perception and action in infancy

By 2–3 months, infants engage in exploration of their own body as it moves and acts in the environment. They babble and touch their own body, attracted and actively involved in investigating the rich intermodal redundancies, temporal contingencies, and spatial congruence of self-perception. Recent research is presented, which investigats the spatial and temporal determinants of self-perception and action infancy. This research shows that, in the course of the first weeks of life, infants develop an ability to detect intermodal invariants and regularities in their sensorimotor experience, which specify themselves as separate entities agent in the environment. Recent observations on the detection of intermodal invariants regarding self-produced leg movements and auditory feedback of sucking by young infants are reported. These observations demonstrate that, early in development and long before mirror self-recognition, infants develop a perceptual ability to specify themselves. It is tentatively proposed that young infants’ propensity to engage in self-perception and systematic exploration of the perceptual consequences of their own action plays an important role in the intermodal calibration of the body and is probably at the origin of an early sense of self: the ecological self.