PubMed · 16171044
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
2005. [A challenge].. https://pubmed.ncbi.nlm.nih.gov/16171044/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
The objective of our study was to investigate how Mg2+ enters mammalian cardiac cells. During this work, we found evidence for a previously undescribed route for Mg2+ entry, and now provide a preliminary account of its properties. Changes in Mg2+ influx into rat ventricular myocytes were deduced from changes in intracellular ionized Mg2+ concentration ([fMg2+]i) measured from the fluorescence of mag-fura-2 loaded into isolated cells. Superfusion of myocytes at 37 degrees C with Ca2+-free solutions with both reduced [Na+] and raised [Mg2+] caused myocytes to load with Mg2+. Uptake was seen with solutions containing 5 mm Mg2+ and 95 mm Na+, and increased linearly with increasing extracellular [Mg2+] or decreasing extracellular [Na+]. It was very sensitive to temperature (Q(10) > 9, 25--37 degrees C), was observed even in myocytes with very low Na+ contents, and stopped abruptly when external [Na+] was returned to normal. Uptake was greatly reduced by imipramine or KB-R7943 if these were added when [fMg2+]i was close to the physiological level, but was unaffected if they were applied when [fMg2+]i was above 2 mm. Uptake was also reduced by depolarizing the membrane potential by increasing extracellular [K+] or voltage clamp to 0 mV. We suggest that initial Mg2+ uptake may involve several transporters, including reversed Na+-Mg2+ antiport and, depending on the exact conditions, reversed Na+-Ca2+ antiport. The ensuing rise of [fMg2+]i, in conjunction with reduced [Na+], may then activate a new Mg2+ transporter that is highly sensitive to temperature, is insensitive to imipramine or KB-R7943, but is inactivated by depolarization.
RATIONALE: When paired with training, substances that increase monoaminergic transmission in the brain support motor and language learning in healthy subjects and in rehabilitation after brain lesions. OBJECTIVES: To test the hypotheses that enhancement of central norepinephrine by the selective norepinephrine reuptake inhibitor reboxetine (1) improves skilled motor performance, (2) promotes skilled motor learning, and (3) does not exert these effects by modulation of attention. METHODS: In a double blind, placebo-controlled, crossover study in healthy, adult subjects (n=16), finger-sequence performance and learning was measured after the stimulation of the central noradrenergic system with a single dose (8 mg) of reboxetine and placebo. Effects on attention were assessed by the standardized continuous performance test "CPT-M". RESULTS: No differential effects of reboxetine or placebo on finger-sequence performance, learning and parameters of attention were found. CONCLUSION: Selective stimulation of the central noradrenergic system did not promote skilled motor learning or performance as assessed by finger-sequences. The plasticity-enhancing effect of reboxetine, documented in other studies, appears to be dependent on specific neurophysiological and neuropsychological characteristics of the task, and cannot be generalized to other behavioral paradigms.
Desvenlafaxine succinate (DVS) is a novel serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) that is currently in clinical development for the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Previous studies have documented the pharmacokinetic and pharmacodynamic profiles of DVS in male rats. Similar studies, however, have not been performed in ovariectomized (OVX) rats, a model that mimics the loss of ovarian hormones that occurs at menopause. The goal of the present study, therefore, was to characterize the pharmacokinetic and pharmacodynamic properties of DVS in OVX rats. Desvenlafaxine levels peaked in plasma, brain (total brain minus hypothalamus) and hypothalamus at concentrations of 7.0, 10.8 and 9.5 microM (assuming 1 g = 1 ml), respectively, 30 min post-dosing DVS (30 mg/kg, oral). The apparent terminal half-lives of desvenlafaxine in plasma, brain and hypothalamus were 3.0, 2.1 and 2.5 h, respectively. Based on AUC(0-last), brain to plasma and hypothalamus to plasma ratios were 1.7 and 1.3, respectively. Microdialysis experiments in the medial preoptic area of the hypothalamus showed that DVS (30 mg/kg, s.c.), in the presence of WAY-100635 (5-HT(1A) antagonist), increased 5-HT levels 225% at 1 h post-dosing. Norepinephrine levels increased 44% at 3 h post-dosing while dopamine levels were unchanged. Thus, in OVX rats, DVS has good pharmacokinetic properties, rapid brain penetration, excellent brain penetrability and selectively increases 5-HT and NE levels in the hypothalamus. This work supports the notion that DVS could have utility for treating disorders in menopausal women in which changes in 5-HT and/or NE have been implicated.