Nicotine induces calcium spikes in single nerve terminal varicosities: a role for intracellular calcium stores

We have previously shown that a large part of the D-amphetamine-induced release of dopamine in the nucleus accumbens is not associated with an increase in locomotor activity, and that "functional" dopamine release (i.e. release of dopamine associated with locomotor activity) requires the distal facilitation of noradrenergic transmission through alpha1-adrenergic receptors in the prefrontal cortex. To determine the role of monosynaptic or polysynaptic projections from the prefrontal cortex to the nucleus accumbens in these amphetamine responses, either AMPA/kainate (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, 300microM), N-methyl-D-aspartate (D(-)-2-amino-5-phosphono-pentanoic acid, APV, 500microM) or metabotropic [(+)-alpha-methyl-4-carboxy-phenylglycine, MCPG, 10mM] glutamate receptor antagonists were infused through a dialysis probe in the rat nucleus accumbens. CNQX and MCPG but not APV reduced the "non-functional" release of dopamine evoked by local (3microM) and systemic D-amphetamine (2mg/kg i.p.) treatments. However, the locomotor hyperactivity and functional dopamine release induced by systemic D-amphetamine were abolished by MCPG, but neither by CNQX nor by APV. MCPG treatment also abolished the hyperlocomotor activity and functional dopamine release evoked by bilateral morphine injection into the ventral tegmental area. The dopamine release evoked by this morphine treatment was 16-fold lower than that induced by the systemic D-amphetamine injection, although similar behavioral activations were observed. Altogether, our results further aid the discrimination of functional and non-functional release of dopamine. We suggest that the activation of metabotropic glutamate receptors in the nucleus accumbens is required for functional dopamine release following systemic D-amphetamine injection.     

活血化瘀药对脑梗塞患者血液流变学的影响

为探讨活血化瘀药治疗脑梗塞的作用机理，对31例住院患者进行血液流变学治疗前后的检测，以发现多项血液流变学指标变化的规律。运用活血化瘀药治疗前后进行血液流变学指标：全血比黏度（低切、高切）、红细胞聚集指数、血浆比黏度、还原比黏度纤维蛋白原的测定并予以统计分析。结果：红细胞聚集指数治疗前后有非常显著差异（P＜0．001）、全血比黏度（低切）治疗前后有比较显著差异（P＜0．01）、血浆比黏度、还原比黏度有显著差异（P＜0．05）、全血比黏度（高切）、纤维蛋白原治疗前后无显著差异。提示活血化瘀药可以改善脑梗塞患者血液流变学指标和临床症状。     

Metabolic evolution suggests an explanation for the weakness of antioxidant defences in beta-cells

The lack of an effective antioxidant system in beta-cells, which renders them susceptible to oxidative stress, is to date without explanation. The particular weakness of beta-cells in females, in both humans and mice, is another unexplained observation. We hypothesise that reactive oxygen species (ROS) in beta-cells, by their negative effect on insulin synthesis/secretion, play a fitness-enhancing role for the whole organism. Under stress conditions, the release of stress hormones produces insulin resistance and, owing to ROS preventing beta-cells from secreting insulin at the level required to maintain homeostasis, diverts glucose to insulin-independent tissues such as the brain and the foetus. We suggest that pancreatic beta-cells lost part of their antioxidant defence in association with brain evolution, and lost even more in females when placental mammals evolved. The unusual antioxidant status of beta-cells may thus be explained as an instance of co-evolution of the brain, cortisol and corticosteroid receptors, and beta-cells in the endocrine pancreas.     

Effects of 17β-oestradiol on rat detrusor smooth muscle contractility

The aim of this study was to investigate the effect of 17β-oestradiol (E₂) on detrusor smooth muscle contractility and its possible neuroprotective role against ischaemic-like condition, which could arise during overactive bladder disease. The effect of E₂ was investigated on rat detrusor muscle strips stimulated with carbachol, KCl and electrically, in the absence or presence of a selective oestrogen receptor antagonist (ICI 182,780) and, by using confocal Ca²⁺ imaging technique, measuring the amplitude (Δ F / F ₀) and the frequency of spontaneous whole cell Ca²⁺ flashes. Moreover, the effect of 1 and 2 h of anoxia–glucopenia and reperfusion (A-G/R), in the absence or presence of the hormone, was evaluated in rat detrusor strips perfused with Krebs solution which underwent electrical field stimulation to stimulate intrinsic nerves; the amplitude and the frequency of Ca²⁺ flashes were also measured. 17β-Oestradiol exhibited antispasmogenic activity assessed on detrusor strips depolarized with 60 m m KCl at two different Ca²⁺ concentrations. 17β-Oestradiol at the highest concentration tested (30 μ m ) significantly decreased detrusor contractions induced by all the stimuli applied. In addition, the amplitude and the frequency of spontaneous Ca²⁺ flashes were significantly decreased in the presence of E₂ (10 and 30 μ m ) compared with control detrusor strips. In strips subjected to A-G/R, a significant increase in the amplitude of both spontaneous and evoked flashes was observed. 17β-Oestradiol was found to increase the recovery of detrusor strips subjected to A-G/R. The ability of E₂ to suppress contraction in control conditions may explain its ability to aid recovery following A-G/R.     

Role of macrophage inflammatory protein-2 in aspiration-induced lung injury

OBJECTIVE: To determine the role of the chemokine, macrophage inflammatory protein (MIP)-2, in the pathogenesis of aspiration-induced lung injury in the rat. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratories. SUBJECTS: Adult, male Long-Evans rats. INTERVENTIONS: Anesthetized rats underwent induction of lung injury by well-described models of aspiration triggered by intra-tracheal delivery of acid alone, gastric particles alone, or the combination. After injury, induction of MIP-2 messenger RNA in whole lungs and immunoreactive MIP-2 in bronchoalveolar lavage (BAL) fluids was determined. The contribution of MIP-2 to BAL fluid chemotactic activity was defined by using an in vitro chemotaxis assay. The in vivo effect of blocking MIP-2 on pulmonary vascular leak, BAL fluid neutrophils, PaO2/FIO2 ratio, and alveolar-arterial oxygen tension gradient in acid-induced lung injury was determined. MEASUREMENTS AND MAIN RESULTS: Induction of MIP-2 messenger RNA and protein over time was observed in response to all three stimuli. A significant portion (25% to 41%) of the chemotactic activity in BAL fluids from injured rats was inhibited by anti-MIP-2 antibody. After acid injury, blocking of MIP-2 was associated with a 53% decrease in BAL fluid neutrophils and a 33% decrease in pulmonary vascular leak. Although acid injury both impaired oxygenation and increased venous admixture, in vivo blocking of MIP-2 was associated with improved oxygenation as well as decreased venous admixture. CONCLUSIONS: MIP-2 was up-regulated during the development of aspiration-induced lung injury in rats. MIP-2 contributed to lung accumulation of neutrophils via a chemotactic mechanism. Although oxygenation and venous admixture are worsened by acid-induced lung injury in vivo, blocking of MIP-2 at the onset of injury improved these physiologic alterations. Because the aspiration event often is witnessed, chemokines may be valid therapeutic targets for inhibiting the subsequent inflammatory response.