Acta physiologica, pharmacologica et therapeutica latinoamericana : organo de la Asociacion Latinoamericana de Ciencias Fisiologicas y [de] la Asociacion Latinoamericana de Farmacologia最新文献

The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed.

In the present work we have investigated the presence of the membrane proteins Syntaxin-1 and synaptosomal-associated protein (SNAP-25) by immunohistochemistry in the different parts of the pituitary of mouse, guinea pig and cat. We have demonstrated Syntaxin-1 and SNAP-25 immunoreactivity in the adenohypophysis as well as in the neurohypophysis but not in intermediate lobe. The results suggest that Syntaxin-1 and SNAP-25 are involved in the hormonal secretary process of adenohypophysis as well as neurohypophysis of these animals.

The 13C-UBT has been demonstrated to be a reliable method for the evaluation of Helicobacter pylori infection. The aim of our work is to determine the cut-off point of the 13C-UBT for samples collected as gas or collected in a solution of triethanolamine. For this purpose, patients fasted for at least 6 hours were able to collect basal samples before the administration of 65 mg of 13C-urea solution. Breath samples were taken 10, 30 and 60 minutes after the administration of the labeled solution. All the samples were collected in gas collectors and in glass vials containing 1 ml of a 7% triethanolamine solution. The cut-off points for gas collected samples were established in 4.0/1000, 4.6/1000 and 4.4/1000 for 10, 30 and 60 minutes samples, respectively, while for the samples collected in triethanolamine solution, cut-off points were established in 5.0/1000, for the 10 minutes samples, in 3.5/1000 for the 30 minutes samples and 4.7/1000 for the 60 minutes samples. We found that this test has a sensitivity of 100% and a specificity of 100% for H. pylori detection in both experimental conditions, when multiple breath samples are taken. If we considered only the 30 minutes time, sensitivity and specificity diminish for the gas collected samples. We conclude that the collection of breath samples in triethanolamine solution allows a better differentiation between H. pylori infected and non infected patients than gas collected samples.

During last years considerable interest has been devoted to understand the role of oxygen radicals in the ischemia induced cell injury associated with reperfusion. In the brain and in others tissues, free radicals play a role as modulators of vascular tone as well as a cytotoxic role as part of the ischemia associated pathology. This review discusses methods for free radical detection in brain and in other tissues, mechanisms of radical production in the course of the ischemia reperfusion process, and the efficacy of potential antioxidant agents in post ischemia therapy, especially with respect to allopurinol, an inhibitor of xanthine oxidase, and the role of taurine and its derivatives as antioxidants in different organs including the brain.

The mechanisms of UTP-induced tension in human and rat skinned fibers were investigated using isometric tension recordings, electrophysiological techniques and biochemical methods. In fast-type fibers from rat extensor digitorum longus (EDL) the UTP-induced tension: a) required previous loading of Ca2+ into the sarcoplasmic reticulum (SR); b) was inhibited by previous exposure to caffeine; c) was abolished by functional disruption of the SR; d) was not affected by blockade of the SR Ca(2+)-release channels by ruthenium red or heparin; e) was prevented by spermidine. These data point to the SR as the target of UTP action and suggest a pathway of UTP-induced Ca(2+)-release independent of the ryanodine- or the IP3-sensitive Ca(2+)-release channels. Accordingly, UTP failed to stimulate the electrophysiological activity of ryanodine-sensitive channels, incorporated into lipid bilayers. We suggest that UTP-induced Ca(2+)-release might occur via the channel form of the SR Ca(2+)-ATPase. The UTP-induced tension in human slow-type fibers was not affected by the SR Ca2+ content or by disruption of the SR, but was accompanied by changes in the tension-pCa relationship, namely increase in maximum Ca(2+)-activated tension, and in apparent Ca(2+)-affinity of troponin. The UTP-induced tension in slow-type fibers from rat soleus was partially inhibited by Ca(2+)-depletion from, or by disruption of the SR, and was accompanied by changes in tension/pCa relationship, similar to those observed in human fibers. Both in skinned fibers and in isolated SR vesicles, UTP was less effective than ATP as a substrate for the SR Ca(2+)-ATPase. This effect might contribute to the UTP-induced tension.

Since the original observation of Vital Brazil and Corrado (1957) concerning the antibiotic induced neuromuscular block produced by streptomycin, there has been considerable interest in the mechanisms responsible for not only neuromuscular block but also the effects of antibiotics on different systems. We used the voltage clamped end-plate of transacted skeletal muscle to examine the concentration-dependent actions of several groups of antibiotics. The aminoglycoside antibiotics, neomycin and streptomycin, were both more effective at reducing quantal release of acetylcholine (ACh) than interacting with the postjunctional ACh receptor-channel complex. Neomycin was approximately 10 X more potent prejunctionally than streptomycin and the prejunctional effects of each antibiotic were reversed competitively by raising extracellular calcium. Both neomycin and streptomycin also had postjunctional actions at higher concentrations. Neomycin interacted with the open state of the ACh receptor ion channel complex while streptomycin blocks the ACh receptor. The lincosamide antibiotics, lincomycin and clindamycin produced their neuromuscular block postjunctionally by interacting with the open state of the ACh-receptor channel complex. Clindamycin is approximately 20 X more effective at blocking the open channel than was lincomycin. Using cell attached patch clamp recordings in cultured rat myotubes, we demonstrated a lincosamide-induced block of open ion channels with clindamycin having a much slower unblocking rate than lincomycin. Using epimers of the lincosamides, we demonstrated that lipophilicity of the molecule, rather than stereochemical considerations, is important for open channel blockade affecting primarily the "off" rate of channel blocking. This mechanism appears important for not only the lincosamide antibiotics but also for the postjunctional actions of the aminoglycoside antibiotics, particularly neomycin.

The existence of a modulatory system controlling the acetylcholine (ACh) release was first proposed for the nicotinic subtype in 1962. Following the first observation of a possible positive feedback loop activated by the released Ach, many studies were oriented in the investigation of the involved presynaptic autoreceptors. Most of the data have been obtained at the motor end-plate, commonly defined as the simplest model of peripheral synapse. The characterization of the chemical transmission since its first proposal showed a more complex pattern involving both the cholinergic and the adrenergic systems. It is now evident that this regulation is widespread both in the central and in the peripheral nervous system. The evidence that the release of ACh can be up- or down-regulated by the transmitter itself (autoregulation) or other neuromediators (heteroregulation) is now proved. In the last decades the attention was focused to the identification of the receptor subtypes located on the releasing nerve terminal. For the purpose, different techniques were used in the various laboratories. The functional approach was based mainly on the electrophysiological characterization of the events evolved prior, during and after the activation of the motor endplate nicotinic receptor. On the other hand, the overflow studies were carried out using radiolabeled ACh (rACh) obtained treating muscle fibers with radioactive choline (rCh). Many scientific papers proposed common data indicating a clear positive (nicotinic) or negative (muscarinic) modulation of the ACh release. Temporally, the description of the muscarinic regulation followed the discovery of the nicotinic one. However, by a pure pharmacological point of view it represents a challenge due to the more complex organization and function. In the peripheral nervous system, i.e. neuromuscular, the meaning of both the muscarinic and nicotinic modulations may appear as free of function. Conversely, in the central systems some effects, such as antinociception and others, could represent the basis of a functional activity such as proposed by Corrado group. The complete characterization of this phenomenon by a physiological and a pharmacological point of view could represents the goal for future uses and therapeutic potential. The present review illustrates the know how and the efforts in the characterisation of the muscarinic regulation of transmitter release from the beginning of its discovery trying to order the numerous scientific data published in this field. Furthermore, our personal data obtained with the Loose Patch Clamp (LPC) technique will be briefly presented and discussed. Our work was built up using agonists and antagonists of the muscarinic receptor subtype in the aim of better characterize the modulation function of the mediator Ach. We used carbachol (Cch), oxotremorine (Oxo) and dl-muscarine as agonists and 1-hyoscyamine, pirenzepine, ipratropium, 11[[2-1[(diethylamino) methyl-1-piperidinyl

The present study describes the use of nose-poke habituation as a memory task in mice and demonstrates that it is sensitive to oxytocin (OT) and an oxytocin receptor antagonist (AOT) administered after the learning trial. Habituation of nose-poke behavior of mice was defined as a reduction in number of nose-pokes compared to baseline, and was measured in a hole-board apparatus to which male Swiss mice were exposed on two consecutive days for 5 min, respectively. Immediate post-training subcutaneous administration of OT (2.00 micrograms/kg) impaired retention performance, whereas AOT (0.20 microgram/kg) enhanced it. Neither the impairing effects of OT (2.00 micrograms/kg) nor the enhancing effects of AOT (0.20 microgram/kg) were seen when the training treatment interval was 180 min, suggesting that both treatments influenced the storage of recently acquired information. The effects of OT (2.00 micrograms/kg) on retention were prevented by AOT (0.02 microgram/kg) administered immediately after training but 10 min prior OT treatment. This dose of antagonist did not affect retention by itself which suggest that impairing effects of OT on retention are probably due to an interaction of the neuropeptide with specific receptors. The actions of OT and AOT on retention were not due to enduring proactive effects of the compounds on performance during the retention test, since when given to untrained mice did not modify their spontaneous activities in the hole-board when recorded 24 h later. We suggest that nose-poke habituation learning can be a suitable method to investigate the mnestic effects of drugs, and that oxytocin negatively modulates memory storage of this form of learning elicited by stimuli repeatedly presented without reinforcement.

There is a paucity of experimental data on the actual mechanism of insulin-induced changes on the myocardial function. In the present study we investigated the myocardial contractile, response to an oral glucose load using echocardiography. Fifteen healthy volunteers were studied after overnight fast and 150 minutes after the oral load of 75 g glucose. Oral glucose load caused an increase in plasma glucose and insulin levels, which was accompanied by a significant increase in left ventricular shortening (from 35.2 +/- 0.7% at baseline, to 38.5 +/- 0.6% and 39 +/- 0.9% at 30 and 60 minutes post glucose load, respectively [P < 0.05 vs baseline]; ejection fraction rose from 0.73% +/- 0.01 to 0.77% +/- 0.01 (P < 0.05); pressure rate product increased from 7.29 +/- 0.2 to 8.31 +/- 0.3 mmHg x beats per min (P < 0.007) and heart rate enhanced from 68.3 +/- 1.9 to 74 +/- 1.6 (P < 0.034) and 75.3 +/- 1.5 beats per min (P < 0.008) at 60 and 90 minutes after glucose, respectively. Meanwhile, mean arterial pressure decreased significantly (10 +/- 1.5%, P < 0.018) when compared to basal values. These results indicate a significant change in the myocardial contractile response to an oral glucose load, probably related to baroreceptor reflex response as well as an overridden by a potent vasodilator action of insulin. Nevertheless, we could not rule out that the cardiac effects may also be due an insulin-induced sympathetic activation or a direct myocardial effect.

Effects of calcium channel blocker flunarizine on spinal monosynaptic reflexes were investigated in spinal cats. Flunarizine was administered locally into the spinal cord (10, 50, 100 microM) and intraperitoneally (5, 10, 20 mg/kg). Adult cats (n = 10), weighing 1.5-3 kg were anesthetized with ketamine (50 mg/kg, i.m.) and artificially ventilated. Animals were spinalized at C1 level. A laminectomy was performed in the lumbosacral region. The ventral and dorsal roots of segment L5 were isolated and a pouch of skin was formed at the site of the dissection to allow the exposed tissues to be covered with liquid paraffin. The temperature was kept at 38.5 degrees C with a heating pad. A polyethylene cannula was introduced into the left carotid artery to monitor blood pressure, which was kept above 100 mmHg. The dorsal root of segment L5 was placed on a silver-silver chloride wire electrode for stimulation through an isolation unit. The reflex potentials were recorded from the ipsilateral L5 ventral root, mounted on a silver-silver chloride wire electrode. The systemic (5, 10, 20 mg/kg) and local (50 and 100 microM) dosages of cinnarizin derivative flunarizine significantly decreased the amplitude of reflex response (p < 0.05). Moreover, the latency of the monosynaptic reflexes was increased after administration of the drug (p < 0.05). Voltage-dependent calcium channels in the spinal cord may play an important role to regulate reflex respond.