Modulation of neurotransmission in the guinea-pig vas deferens by capsaicin: involvement of calcitonin gene-related peptide and substance P.

1. The effects of capsaicin, calcitonin gene-related peptide and substance P were studied via three parameters in the guinea-pig vas deferens: the overflow of ATP and of tritiated noradrenaline, the mechanical responses to field stimulation and the mechanical responses to exogenous noradrenaline and alpha, beta-methylene ATP. 2. At 2 Hz, capsaicin inhibited the stimulus-evoked release of ATP, whereas it was without effect on the release of noradrenaline. At 20 Hz capsaicin did not affect the release of either of the cotransmitters. Capsaicin enhanced responses to alpha, beta-methylene ATP, but not to exogenous noradrenaline. 3. Calcitonin gene-related peptide, like capsaicin, inhibited the release of ATP, but not noradrenaline at 2 Hz and was without effect on release at 20 Hz. However, calcitonin gene related peptide inhibited responses to alpha, beta-methylene ATP and was without effect on responses to exogenous noradrenaline. 4. Substance P had no effect on the release of either noradrenaline or ATP at either frequency. However, like capsaicin it enhanced responses to alpha, beta-methylene ATP and was without effect on exogenous noradrenaline. 5. These results suggest that the actions of capsaicin on the guinea-pig isolated vas deferens are mediated via the release of both calcitonin gene-related peptide and substance P. Furthermore, as capsaicin and calcitonin gene-related peptide prejunctionally modulate purinergic, but not noradrenergic transmission, this suggests that the mechanisms for the storage and release of the sympathetic co-transmitters noradrenaline and ATP may not be the same.     

大鼠下丘脑室旁核及其邻近区域至室管膜的传出联系

用20只Wistar大鼠以PHA—L免疫组织化学顺行追踪技术研究了下丘脑室旁核及其邻近区域对脑室系统室管膜的传出联系。在脑室系统某些部位的室管膜层或其下方见有丰富的标记纤维并见许多膨结和终末膨突。这些纤维似乎参与形成室管膜上、下丛,构成脑—脑脊液神经体液回路的重要环节。     

Effect of food on enoxacin absorption.

Fifteen subjects received a single 400-mg oral dose of enoxacin in the fasting state and after carbohydrate and high-fat meals. The carbohydrate meal delayed the time to peak enoxacin concentration in plasma by an average of 0.92 h. The extent of enoxacin absorption was not altered by food.     

The influence of food on the pharmacokinetics of ''biphasic'' nifedipine at steady state in normal subjects.

Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a 'biphasic' formulation comprising 'rapid' and 'retarded' drug release components. Fifteen normal subjects took 20 mg 'biphasic' nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from 'biphasic' tablets.     

Immune complexes in CSF and serum in various neurological diseases

A technique whereby immune complexes (ICs) are detected in the CSF and serum from their inhibitory effect on the agglutination of IgG-coated latex particles by rheumatoid factor (RF) has been applied to patients with the following neurological diseases: multiple sclerosis (MS), inflammatory diseases, extradural peripheral neuropathies (EPN), CNS tumors, dementia, and a control group of other neurological diseases (OND). The groups did not differ significantly in respect of IC positivity either in CSF or serum. The MS group was tested for correlations between percentage of IC positives and CSF IgG/Albumin ratio on the one hand and presence of oligoclonal bands on isoelectric focusing on the other. The specificity of ICs to the dysimmune condition is discussed.

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Sommario È stata applicata una tecnica di inibizione della reazione di agglutinazione del Fattore Reumatoide (RF) su particelle di latice, ricoperte di immunoglobuline umane, per il dosaggio degli immunocomplessi (ICs) nel liquor e net siero di pazienti affetti da malattie neurologiche. Sono stati considerati 5 gruppi di malattie neurologiche, rappresentate da: sclerosi multipla (MS), malattie infiammatorie, polinevriti, tumori del SNC, demenza ed un gruppo di controllo composto da malattie neurologiche miste (OND).Non sono state riscontrate differenze significative tra le percentuali di positività nei diversi gruppi esaminati, compreso il gruppo di controllo, tanto sul liquor che su siero.Particolare attenzione è stata posta allo studio della MS, ove la percentuale di positività degli ICs è stata raffrontata con il rapporto IgG/Albumina liquorale e con la presenza di bande oligoclonali IgG all'isoelectrofocusing (IEF).La specificità della formazione degli ICs in relazione alla situazione disimmune è stata inoltre discussa.

     

Human peripheral monocytes express putative receptors for neuroexcitatory amino acids.

Human peripheral mononuclear cells responded chemotactically to 4-carboxyl-L-glutamic acid. The maximal chemotactic response occurred at 0.1 nM. No chemotactic response was found with neutrophils or fetal bovine fibroblasts. Glutamic acid, a neuroexcitatory dicarboxylic amino acid and the parent compound of 4-carboxyglutamic acid, did not stimulate chemotaxis in any of the cells tested. However, it functioned as an antagonist to 4-carboxyglutamic acid (ED50 approximately 2 pM; ED100 approximately 10 pM). In contrast to the lack of response to glutamic acid, its dicarboxylic cyclic analogue, kainic acid, excited a chemotactic response in mononuclear cells. The data suggest that mononuclear phagocytes have receptors for dicarboxylic neuroexcitatory amino acids, and we speculate that 4-carboxyglutamic acid, a tricarboxylic acid, may have a previously unrecognized role as a neuroexcitatory amino acid.     

Separable evoked retinal and cortical potentials from each major visual pathway: preliminary results.

Single cell experiments in primates show that there are two major parallel pathways named after the lamination in the lateral geniculate nucleus. Each of these systems can be preferentially excited by appropriate stimuli. Here we report that in man the polarity of the evoked potentials both in retina and in cortex depends on which of these pathways is stimulated. The identification of the resulting waveforms is thereby simplified--a matter of practical importance. The fact that at retina and cortex there are characteristic potentials may reflect the different cell biology of the two pathways.     

Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype.

1. Under voltage-clamp dissociated adult and foetal rat superior cervical ganglion (s.c.g.) cells exhibited a non-inactivating voltage- and time-dependent component of K+ current termed the M-current (IM). IM was detected and measured from the current decay during hyperpolarizing voltage steps applied from potentials where IM was pre-activated. 2. Neither the resting membrane current nor the amplitude of these current decay relaxations were reduced by omitting Ca from the bathing fluid, showing that the M-current was not a 'Ca-activated' K-current dependent on a primary Ca-influx. Concentrations of (+)-tubocurarine sufficient to block the slow Ca-activated K-current IAHP did not inhibit IM or antagonize the effect of muscarinic agonists on IM, showing that IM was not contaminated by IAHP. Tetraethylammonium (1 mM), which blocks the fast Ca-activated K-current IC, produced a small inhibition of IM. This was not due to contamination of IM by IC since muscarinic agonists did not consistently block IC. 3. The muscarinic agonists muscarine, oxotremorine, McN-A-343 and methacholine reversibly suppressed IM, resulting in an inward (depolarizing) current. The rank order of potency was: oxotremorine greater than or equal to muscarine greater than McN-A-343 greater than methacholine. 4. The suppression of IM by muscarine was similar in cultured cells derived from adult and foetal tissue to that seen in the intact ganglia. 5. IM-suppression by muscarine was inhibited by pirenzepine (Pz) and AF-DX 116 with mean pKB values of 7.53 +/- 0.13 (n = 3) and 6.02 +/- 0.13 (n = 4) respectively. 6. The suppression of IM by muscarinic agonists was not affected by gallamine (10-30 microM). 4-Diphenylacetoxy-N-methylpiperidine methiodide inhibited the response at 300 nM. 7. Pirenzepine inhibited the contractions of the guinea-pig isolated ileum produced by muscarine with a mean pKB of 6.37 +/- 0.03 (n = 8). 8. These results suggest that the receptors mediating suppression of the M-current accord with those designated pharmacologically as M1 and that these receptors reach maturity at a very early stage in the development of the rat s.c.g.     

Early cardiovascular changes with ibopamine: evidence for a biphasic haemodynamic action.

1. The haemodynamic effects of ibopamine, an oral dopamine derivative, were studied in eight patients with left ventricular dysfunction using invasive catheterisation techniques. 2. An early rise was seen in the mean right atrial pressure (P less than 0.05), the mean capillary wedge pressure (P less than 0.01) and the mean pulmonary arterial pressure (P less than 0.001) which occurred at 15 min and persisted for 30 min. 3. A second, later, positive chronotropic effect was seen as an increase in the heart rate (P less than 0.05) at 45 min with an increased cardiac output (P less than 0.05) persisting above baseline values at 1 h, but with no change in stroke volume. 4. These results support a biphasic mode of action for ibopamine which may be explained by a time phase difference in alpha- and beta-adrenoceptor stimulatory effects.