Block of the endplate acetylcholine receptor channel by the sympathomimetic agents ephedrine, pseudoephedrine, and albuterol

Recent observations suggest that some patients with congenital myasthenic syndromes respond favorably to ephedrine, pseudoephedrine, or albuterol. Conventional microelectrode studies, however, provide no clear explanation for a beneficial effect of ephedrine in endplate diseases. To gain further insight into how these drugs affect neuromuscular transmission, we investigated their effects on the kinetic properties of the acetylcholine (ACh) receptor. Single channel currents were recorded from rat lumbrical muscles endplates using low concentrations of ACh and 2.5–100 μM of drugs. Between 10–100 μM, each drug progressively increased the rate of channel closure in a concentration dependent manner, consistent with an open-channel block. Albuterol acted as a sequential fast-acting channel blocker, increasing the mean burst duration in a concentration dependent manner without altering the total open time per burst or the duration of intraburst blockages. Increasing concentrations of ephedrine and pseudoephedrine also increased the number of intraburst closures but decreased the total open time per burst. None of the drugs altered single channel conductance. The channel blocking effects of ephedrine and pseudoephedrine might reduce the synaptic overactivity that occurs in the slow-channel myasthenic syndromes or in endplate ACh esterase deficiency, but these effects occur at concentrations not attainable in clinical practice.     

The effects of an intracellular calcium antagonist HA 1077 on delayed cerebral vasospasm in dogs

Summary The effectiveness of calcium antagonists on a chronic cerebral vasospasm after an SAH is still under debate. Calcium channel blockers such as nimodipine, nefedipine etc. can dilate spastic arteries by intrathecal administration, but not by systemic (iv or po) use. HA 1077 is a novel and potent calcium antagonist vasodilator which is considered to act by employing different mechanisms from the usual calcium channel blockers since it inhibits 1. calcium ionophore A 23187 induced contraction in arterial strips and 2. phenylephrine induced contraction in calcium free media, suggesting that its site of action is in the intracellular space. HA 1077 is water soluble and relatively stable in light.In the present study, the efficacy of HA 1077 was evaluated on dogs by using the spiral arterial strips in vitro and by angiography in vivo. In the arterial strips from the control dogs, a 50% relaxation of KCl (15 mM) induced contraction was obtained by a 10^–6 M HA 1077 for the intracranial basilar and middle cerebral arteries, while a 10^–5 M was needed to obtain the same effect for the extracranial common carotid and vertebral arteries, indicating that HA 1077 is more effective for the intracranial arteries. A vasospasm was produced by the two haemorrhage model of Varsoset al. The average angiographic diameter of the basilar artery was reduced to 60% of the control on SAH day 7. Intravenous infusion of HA 1077 (0.5–3 mg/kg/30 min) significantly dilated the spastic basilar artery (up to 20–30%), for over 2 hours. A fall in the systemic BP remained less than 20% during this time. Such spasmolytic effects by intravenous administration could not have been obtained with the usual calcium channel blockers. HA 1077 may be suitable for the treatment of a vasospasm in humans as well.     

Effects of trapidil-derivatives on calcium channel currents in isolated ventricular cells from mice

Summary A single glass micropipette voltage clamp technique with intracellular dialysis was used to study the effects of the trapidil derivatives AR 12–456 and AR 12–463 on Ca channel currents carried by Bat+ in isolated ventricular cells from mice hearts. Inspite of a more potent inhibition of the cAMP phosphodiesterase from heart (Bartel et al. 1985) a reversible Ca channel blocking action of both compounds could be observed. The concentration of half maximal block was calculated to about 50 mol/l for both derivatives tested. Neither a shift in the current-voltage relationships nor a significant change in the potential for half maximal activation was found. The maximal Ba²⁺ -conductance was reduced. The steady state inactivation was shifted towards more negative potentials by application of 100 mol/l AR 12–463. The decay of the Ba currents was accelerated in the range of the applied test potentials between –20 and +20 mV. It is concluded that the new trapidil derivatives with more potent inhibitory action on cardiac phosphodiesterase than trapidil can block myocardial Ca channels. Send offprint requests to B. Nilius     

Computerized axial tomo-epidurographic and radiographic documentation of unilateral epidural analgesia

A 23-year-old primigravid patient who received epidural analgesia for pain of labour presented with persistent, apparently irremediable, unilateral analgesia. Computerized axial tomo-epidurography demonstrated absence of circumferential spread due to lateral placement of the catheter. Transforaminal escape of contrast medium into the paravertebral area had occurred and anterior and posterior midline partitioning of the epidural space was obvious. All the usual measures to promote contralateral analgesia, except re-insertion of the catheter, had been tried without success.     

Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by<Emphasis Type="Italic"> LMNA</Emphasis> gene defects

Mutations of the LMNA gene encoding the lamin A and C nuclear envelope proteins cause an autosomal dominant form of dilated cardiomyopathy (DCM) with atrioventricular block (AVB). The aim of this study was to investigate ultrastructural nuclear membrane changes by conventional electron microscopy and protein expression by immuno-electron microscopy in the heart of patients with DCM and AVB due to LMNA gene mutations. Four immunohistochemical techniques were used: pre-embedding and post-embedding in Epon-Araldite resin and London Resin White (LRW), with and without silver enhancement. Parallel light microscopy immunohistochemistry studies were performed. Conventional electron microscopy showed a loss of integrity of the myocyte nuclei with blebs of the nuclear membrane, herniations and delamination of the nuclear lamina and nuclear pore clustering. Post-embedding LRW was the most informative technique for morphology and immuno-labelling. Immuno-labelling was almost absent in the nuclear envelope of patients with LMNA gene mutations, but intensely present in controls. The loss of labelling selectively affected myocyte nuclei; the endothelial cell nuclei were immunostained in patients and controls. Light immunohistochemistry confirmed the results. These findings confirm the hypothesis that LMNA gene defects are associated with a loss of protein expression in the selective compartment of non-cycling myocyte nuclei.     

Agarose cell block: innovated technique for the processing of urine cytology for electron microscopy examination

Easy manipulation and preservation of cells in suspension through the different steps of sample processing for electron microscopy examination is essential for proper diagnosis. The author used agarose gel as an embedding media for processing cells in suspension for electron microscopic examination. The AgarCyto cell block procedure of Kerstens et al. (J Histochem Cytochem. 2000; 48: 709—718) was used to begin electron microscopic processing of exfoliated urothelial cells in voided urine or cells in suspension. Processing of agarose cell block simultaneously for light and electron microscopic examination represents a great advantage offered by this innovated technique.     

Unidirectional block in a computer model of partially coupled segments of cardiac Purkinje tissue

The initiation of a reentrant circuit requires a zone of slow conduction and a zone of unidirectional block. This study used computer model conditions under which partial coupling between segments of cardiac Purkinje tissue resulted in unidirectional block. The structure used was one-dimensional and divided into three segments: a middle segment of variable length coupled to two long (semi-infinite in concept) segments. The DiFrancesco-Noble equations represented the ionic currents of the membrane. The results show that the possibility of unidirectional block depends on the size of the middle segment and the coupling resistances between the segments. No combination of coupling resistances allowed unidirectional block for middle segments with a length of two space constants (4 mm) or longer. Unidirectional block occurred for many combinations of coupling resistances as the length of the middle segment decreased to around half a space constant (1 mm). The number of length combinations that caused unidirectional block decreased again as segment length further decreased. These results provide a possible mechanism of unidirectional block for situations where islands of viable tissue are connected through nonviable tissue, such as in a healed myocardial infarction.     

A way of preventing the free fatty acid concentration in the serum of rabbits from rising

A scheme of administration of nicotinic acid by mouth is suggested in order to prevent any increase in the free fatty acid concentration in the serum after intravenous injection of heparin or triiodothyronine, prolonged starvation, and thyroid feeding.Laboratory of Pathological Physiology, Institute of Experimental Endocrinology and Hormone Chemistry, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Yudaev.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 78, No. 8, pp. 122–125, August, 1974.     

Diblock Copolymers Based on 1,4‐Dioxan‐2‐one and ε‐Caprolactone: Characterization and Thermal Properties

Summary: Various poly(ε‐caprolactone‐block‐1,4‐dioxan‐2‐one) (P(CL‐block‐PDX)) block copolymers were prepared according to the living/controlled ring‐opening polymerization (ROP) of 1,4‐dioxan‐2‐one (PDX) as initiated by in situ generated ω‐aluminium alkoxides poly(ε‐caprolactone) (PCL) chains in toluene at 25 °C. 1 ¹H NMR, PCS and TEM measurements have attested for the formation of colloids attributed to a growing PPDX core surrounded by a solvating PCL shell during the polymerization of PDX promoted by ω‐Al alkoxide PCL chains in toluene. The thermal behavior of the P(CL‐block‐PDX) copolymers was studied by DSC; showing two distinct melting temperatures (as well as two glass transition temperatures) similar to those of the respective homopolyesters. Finally, the thermal degradation of the P(CL‐block‐PDX) block copolymers was investigated by TGA simultaneously coupled to a FT‐IR spectrometer and a mass spectrometer for evolved gas analysis (EGA). The degradation occurred in two consecutive steps involving a first unzipping depolymerization of the PPDX blocks followed by the degradation of the PCL blocks via both ester pyrolysis and unzipping reactions.

TEM observation of P(CL‐block‐PDX) block copolyesters ( = 11 600 and = 22 100) as formed by vaporization starting from a diluted suspension in toluene/TCE mixture solvent (50/50 v/v).