The effect of trimethyltin on acetylcholine release in the guinea-pig trachea

The purpose of the present work was to characterise the effects of trimethyltin on the release of acetylcholine from parasympathetic nerves and its effect on the postjunctional cholinergic stimulation of a smooth muscle. The guinea-pig trachea has been used as a model. Prejunctionally, trimethyltin (3.0 × 10⁻³ M) significantly enhanced in a reversible manner the high K⁺ (75 mM) evoked release of endogenous acetylcholine and [³H]acetylcholine. The evoked release of endogenous acetylcholine and [³H]acetylcholine was released from a pool of acetylcholine being independent of extraneuronal Ca²⁺ in the presence, but not in the absence of trimethyltin. The effect of trimethyltin on the release was not inhibited by low Ca²⁺ (0 mM and 1.0 × 10⁻⁴ M) or by Ca²⁺ channel blockers (verapamil, 1.0 × 10⁻⁴ M, flunarizine, 1.0 × 10⁻⁴ M, ω-conotoxin GVIA, 2.0 × 10⁻⁷ M and ω-agatoxin, 2.0 × 10⁻⁷ M). The present results also demonstrate that trimethyltin induce emptying of a non-vesicular, probably a cytoplasmic storage pool of acetylcholine, since AH5183 (2.0 × 10⁻⁵ M), an inhibitor of the translocation of acetylcholine into synaptic vesicles, and -latrotoxin (1.0 × 10⁻⁸ M), a toxin from black widow spider venom inducing vesicle depletion, had no inhibitory effects on the release of [³H]acetylcholine evoked by trimethyltin (3.0 × 10⁻³ M). The release of [³H]acetylcholine was moreover enhanced by trimethyltin when the vesicular uptake of [³H]acetylcholine was inhibited by AH5183, probably as a result of a higher cytoplasmic concentration of [³H]acetylcholine. Trimethyltin also reduced the neuronal uptake of [³H]choline and this was probably due to a depolarising effect of trimethyltin on the cholinergic nerve terminals. A similar depolarisation induced by trimethyltin was observed during patch clamping of GH₄ C₁ neuronal cells. Postjunctionally, trimethyltin had no effect by itself or on the carbachol-induced smooth muscle contraction, indicating that trimethyltin did not have a general depolarising effect on smooth muscle cells or an effect on muscarinic receptors. Furthermore, the reduced electrical field-induced contraction and the subsequent increase in the basal smooth muscle tension that was observed by addition of trimethyltin was activity-dependent, and was most probably due to emptying of a nervous non-vesicular storage pool of acetylcholine, followed by rapid hydrolysis of acetylcholine by acetyl- and pseudocholinesterases.     

Alpha-motoneuron excitability at high altitude

Summary It has been hypothesized that chronic hypobaric hypoxia could lead to inhibition of the-motoneuron pool, thus limiting the maximal activation of working skeletal muscles. To test this hypothesis six subjects [32 (SEM 2) years] were evaluated in resting conditions, at sea level and after acclimatization at 5,050 m. The recruitment curves of the Hofmann-reflex (H-) and the direct muscle-response (M-) of the right soleus muscle were obtained by stimulating the posterior tibeal nerve with different intensities while recording the electromyogram of the soleus muscle. From the recorded data the net-motoneuron excitability (ratio of maximal H-reflex to M-response H_max : M_max ratio), the threshold and gain for both responses, obtained from linear regressions through the rising phase of the recruitment curves of both responses, as well as the latency times of both responses were determined. The latency times and the H_max :M_max ratio were unchanged at altitude. The thresholds of both responses and the gain of the M-response were unaltered. The gain of the H-response was significantly higher at altitude when compared to sea level. It is concluded that in the acclimatized subjects at rest the signal conduction velocity through the different parts of both pathways was unaltered and therefore nerve and muscle conduction velocity as well as synaptic and muscle end-plate transmission were unchanged, that the recruitment of the H-reflex was slightly facilitated after acclimatization to high altitude suggesting increased excitability of the-motoneurons, through either postsynaptic facilitatory changes in the soma or a different descending drive, and that the unchanged H_max:M_max ratio indicated no change in the net excitatory and inhibitory influences on the-motoneuron pool. The above hypothesis is thus not strengthened by the results that were, however, obtained in resting conditions.     

Selective strategies in food webs

Food webs are described as control systems where the controlsare chosen according to given myopic strategies. In particular,strategies describing selective feeding and selective escapeare defined. The existence of optimal myopic solutions and theiruniqueness are discussed. Computer simulations modelling ‘switching’are given for a one-predator—two-prey system.     

Ondine's curse and neurally mediated syncope -- a new and important association

A 6-year-old boy with congenital central hypoventilation syndrome(Ondine's curse) presented with presyncope. Investigation revealeda diagnosis of neurally mediated syncope. This previously unreportedassociation provides strong evidence that autonomic dysfunctionis implicated in both these conditions.     

Type I familial amyloid polyneuropathy and pontine haemorrhage

A Portuguese female, aged 47 years, who had emigrated to Spain, was admitted to the hospital in 1991 for pontine haematoma. The patient, four siblings and her father were affected by a peripheral neuropathy, indicating autosomal dominant inheritance. The patient presented in the 2nd decade with sensory and motor neuropathy beginning in the lower extremities. Alternating constipation and diarrhoea, and urinary incontinence became uncontrollable. She had to be colostomised, and, eventually, confined to a wheelchair from the age of 43. Neurological examination showed bilateral facial involvement, and severe signs of sensory and motor peripheral neuropathy, and later right hemiplegia. There were abnormalities of atrial rhythm and left bundle branch block. Computerised axial tomography and magnetic resonance images demonstrated left-sided pontine haemorrhage. Nerve conduction studies revealed severe diminution of motor conduction velocity and absence or reduction of amplitude of sensory and motor action potentials. Inanition and a respiratory infection led to her death. Clinical diagnosis was type I familial amyloid polyneuropathy (FAP). Postmortem examination demonstrated amyloid deposits in peripheral nerves, including spinal roots and cranial nerves, leptomeninges, thyroid, breasts, heart, adrenal glands, kidneys, intestines, pancreas, and meningeal and some pontine vascular structures. Advanced pontine haematoma was verified. Cerebral haemorrhage usually occurs with cerebrovascular amyloidosis, but exceptionally with FAP. A minority of patients presenting with CNS haemorrhage showed arteriovenous malformation or embolism [Da Silva Horta and Dias Coelho (1960) Arch de Vecchi Anal Patol Med Clin 31=163–172]. However, amyloid deposition in some small pontine vessels could have played a role in the pathogenesis of haemorrhage in the present case.     

Role of disturbance of ependymal ciliary movement in development of hydrocephalus in rats

We have developed a new in vitro method of quantitatively analyzing ciliary movement in the ependymal wall of the aqueduct in rats. An axial slice of the midbrain containing ependymal wall was placed in a culture dish filled with a culture medium containing latex beads 1 m in diameter at a concentration of 10⁷ beads/ml. The movement of the beads caused by flow of culture medium generated by the to-and-fro ciliary movement was recorded by a high speed video system attached to an inverted phase-contrast microscope. Ciliary movement was expressed by the speed of the latex beads (m/s). Aqueductal ciliary movement in congenitally hydrocephalic HTX rats, congenitally hydrocephalic WIC-Hyd rats, and other normal rats was evaluated. The results suggest that in congenitally hydrocephalic WIC-Hyd rats the degree of hydrocephalus related strongly to the degree of ciliary dyskinesia, but in congenitally hydrocephalic HTX rats it did not. Considering this discrepancy, we attempted to see whether or not hydrocephalus was caused by artificial disturbance of ependymal ciliary movement in vivo. We found that continuous infusion of metavana date, an inhibitor of ciliary movement, into the III ventricle of normal Sprague-Dawley rats for 7 days induced dilatation of the ventricular system. Although the question whether or not disturbance of aqueductal ependymal ciliary movement is related to the development of human congenital hydrocephalus is debatable, the results of the present in vitro and in vivo experimental investigations appear to suggest that the disturbance of ciliary movement in the aqueduct could at least be one of the factors contributing to the inducement of hydrocephalus in experimental conditions.     

Structural and steric requirements for β-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in the rat limbic forebrain

Summary The present studies were undertaken to assess the structural and steric requirements for -phenethylamines as agonists of the noradrenergic cyclic AMP generating system in slices of the rat limbic forebrain. Significant agonist activity of -phenethylamines requires a -3,4-dihydroxyphenethylamine with a -hydroxyl group in the R configuration. Thus, dopamine did not stimulate the system at concentrations up to 10^–3 M. Moreover, -hydroxyphenethylamines without a 3,4-catechol group (octopamine, phenylephrine, p-hydroxynorephedrine, metaraminol and methoxamine)-though exerting -agonist activity in peripheral tissues-lack agonist activity in this particular cyclic AMP generating system. The effects of (R)-norepinephrine and (R)-isoproterenol at maximal concentrations were not additive. The results lend further support to the view that the cyclic AMP generating system in slices of the limbic forebrain is part of a norepinephrine receptor coupled adenylate cyclase system with a subpopulation of receptors that are in nature.     

Hexachlorophene and the central nervous system

Summary A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or splitting developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutancous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in humans and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.