Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs

This minireview is concerned with a re-examination of the locus of action and the possible peripheral mechanisms involved in the gastrointestinal (GI) stimulant effects of metoclopramide. Such a re-evaluation is opportune given the increasing use of this drug in the therapy of certain GI tract disorders. To provide an orientation on this subject the location in the GI tract and function of several relevant receptor types have been reviewed. In the past metoclopramide has been reported to enhance contractions of a variety of GI preparations to electrical stimulation, acetylcholine, carbachol and ganglion stimulants, to inhibit responses to alpha 2-adrenoreceptor agonists and 5-hydroxytryptamine, as well as blocking those to dopamine. Also in such preparations metoclopramide facilitates the release of acetylcholine to transmural stimulation. One important question is whether this effect is mediated via a specific prejunctional receptor. In this respect 2 suggestions have been made. Firstly that the drug may act as a preferential, prejunctional muscarinic antagonist thus inhibiting the negative feedback inhibition of acetylcholine release and secondly that metoclopramide may be a prejunctional agonist (partial) at 5-hydroxy-tryptamine receptors. Although the latter possibility appears most tenable at present, the involvement of a specific receptor remains to be confirmed. The important finding that dopamine receptors are probably not involved in the local stimulant effects of metoclopramide has important implications for future research orientated towards the discovery of a new generation of GI drugs lacking the side effects associated with central dopamine receptor blockade. Several compounds (cinitapride, BRL 20627A and cisapride) are now in the early stages of clinical evaluation.     

Group-selective reagent modification of the sodium- and chloride-coupled glycine transporter under native and reconstituted conditions.

Glycine transporter from rat brain stem and spinal cord is inactivated by specific sulfhydryl reagents. Modification of lysine residues also promotes a decrease of the transporter activity but in a lesser extent than that promoted by thiol group reagents. Mercurials showed a more marked inhibitory effect than maleimide derivatives. SH groups display a similar reactivity for p-chloromercuribenzenesulfonate (pCMBS) and mersalyl in synaptosomal membrane vesicles and proteoliposomes reconstituted with the solubilized transporter. However, different reactivity is observed with N-ethylmaleimide (MalNEt), the greatest effect being attained in membrane vesicles. The rate of inactivation by pCMBS and MalNEt is pseudo-first-order showing time- and concentration-dependence. pCMBS and MalNEt decrease the Vmax for glycine transport and to a lesser extent act on the apparent Km. Treatment with dithiothreitol (DTT) of the transporter modified by pCMBS results in a complete restoration of transporter activity indicating that the effect exercised by the reagent is specific for cysteine residues on the protein. It is concluded that SH groups are involved in the glycine transporter function and that these critical residues are mostly located in a relatively hydrophilic environment of the protein.     

Mesocyclops longisetus effects on survivorship of Aedes aegypti immature stages in car tyres

Abstract .The effect of the introduction of the entomophagous copepod Mesocyclops longisetus (Acuacultura F.C.B. strain) on the survival of Aedes aegypti immature stages in car tyres was evaluated under semi-natural conditions in the municipality of Merida, Yucatan, Mexico. Life tables were constructed for the immature stages of the mosquito in the presence and absence of M. longisetus , and the survival data were compared using log–linear models. The data set was adjusted using the GLIM statistical package and the quality of adjustment was evaluated with a chi-squared test . Survivorship curves were constructed for each treatment.
In the absence of M. longisetus , the survivorship of Ae. aegypti immature stages averaged 9%. The highest mortality rate was observed during the fourth larval instar (54%) and the resulting survival pattern corresponded to a type II survivorship curve. The mortality rate of Ae. aegypti first-instar larvae (fifty per tyre) increased more than 200-fold in the presence of M. longisetus (twenty per tyre) and the highest mortality was during the first two larval instars, where it reached 98.9%, with a resulting survivorship of 0.2%. Overall mortality was sixfold greater in the presence of the copepod than in its absence. The survival pattern of immature stages of Ae. aegypti in the presence of the copepod corresponded to a type III survivorship curve. As M. longisetus was so effective against Ae. aegypti immature stages in tyres under semi-natural conditions, its long-term effectiveness should be evaluated under socially and ecologically realistic field conditions in Mexico.     

Restriction mapping of the rRNA genes from Artemia larvae

A restriction endonuclease analysis of the genes coding for the ribosomal RNA from Artemia larvae has shown that these genes consist of a repeat unit of 16.2 kilobase pairs (10.7 Mdaltons) and that the repeat unit seems to be homogeneous in size.     

On the purification of beta-bungarotoxin

It has recently been claimed that our beta-bungarotoxin preparation contained three contaminants, including a postsynaptic toxin. We have extended our purification procedure and found no evidence of such contaminants.     

De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase.

Recent observations support the importance of ceramide synthesis de novo in the induction of apoptosis. However, the downstream targets of de novo-synthesized ceramide are unknown. Here we show that palmitate incorporated into ceramide and induced apoptotic DNA fragmentation in astrocytes. These effects of palmitate were exacerbated when fatty acid breakdown was uncoupled and were not evident in neurons, which show a very low capacity to take up and metabolize palmitate. Palmitate-induced apoptosis of astrocytes was prevented by L-cycloserine and fumonisin B1, two inhibitors of ceramide synthesis de novo, and by PD098059, an inhibitor of the extracellular signal-regulated kinase (ERK) cascade. Accordingly, palmitate activated ERK by a process that was dependent on ceramide synthesis de novo and Raf-1, but independent of kinase suppressor of Ras. Other potential targets of ceramide in the control of cell fate, namely, c-Jun amino-terminal kinase, p38 mitogen-activated protein kinase, and protein kinase B, were not significantly affected in astrocytes exposed to palmitate. Results show that the Raf-1/ERK cascade is the selective downstream target of de novo-synthesized ceramide in the induction of apoptosis in astrocytes and also highlight the importance of ceramide synthesis de novo in apoptosis of astrocytes, which might have pathophysiological relevance.