No abstract

Objective-We investigated the effects of statin compared with the American Heart Association (AHA) Step I Diet on lipoproteins, vasomotor function, tumor necrosis factor (TNF)-␣, and serological markers of plaque stability. Furthermore, we investigated the mechanism of regulation suggested by experimental studies. Methods and Results-For 14 weeks, we administered AHA dietϩplacebo and AHA dietϩsimvastatin (20 mg daily) to 31 and 32 randomly selected patients with coronary artery disease, respectively. Compared with diet alone, simvastatin significantly improved the percent flow-mediated dilator response to hyperemia from 3.37Ϯ2.28% to 5.89Ϯ2.35% (PϽ0.001) and lowered plasma levels of C-reactive protein from 0.48 to 0.10 mg/dL (PϽ0.001), TNF-␣ from 3.38 to 2.79 pg/mL (PϽ0.001), total matrix metalloproteinase (MMP)-9 from 36 to 28 ng/mL (Pϭ0.006), and tissue inhibitor of matrix metalloproteinase-1 from 80Ϯ30 to 74Ϯ23 ng/mL (Pϭ0.041), and simvastatin lowered to a greater extent MMP-9 activity (from 71 to 52 ng/mL, Pϭ0.006) and MMP-9 activity/tissue inhibitor of matrix metalloproteinase-1 ratios (Pϭ0.018), although this difference did not reach statistical significance. There were significant correlations between the degree of changes in TNF-␣ and the degree of changes in MMP-9 activity (rϭ0.424, Pϭ0.016). However, no significant correlations between lipoprotein levels or flow-mediated dilation percentages and levels of plaque stability markers were determined (Ϫ0.208ՅrՅ0.243). Conclusions-Simvastatin

The mechanism by which glutamate regulates the cytosolic free Ca2+ concentration ([Ca2+]c) in spontaneously firing dopamine neurons is not clear. Thus we have investigated the glutamate-mediated [Ca2+]c dynamics in the acutely isolated dopamine neurons from the rat substantia nigra pars compacta by measuring [Ca2+]c and spontaneously occurring action potentials (SAPs). The freshly isolated dopamine neurons showed tetrodotoxin(TTX)-sensitive spontaneous firing of 2-3 Hz and the resting[Ca2+]c decreased with abolition of the SAPs. The level of [Ca2+]c was affected by the spontaneous firing rate. In the presence of the Na+ channel antagonist, TTX (0.5 μM),glutamate increased [Ca2+]c by activating different glutamate receptors depending on the glutamate concentration used. Addition of glutamate at low concentrations (<3 μM) raised[Ca2+]c mainly by activating metabotropic glutamate receptors (mGluR), whereas at high concentrations (>10 μM) it raised[Ca2+]c mainly by activating AMPA/kainate receptors. The contribution of NMDA receptors to the glutamate-mediated[Ca2+]c rises was largest at intermediate concentrations of glutamate. Activation of mGluR elicited a Ca2+ release from intracellular Ca2+ stores and continuous Ca2+ influx out of the cell. The spontaneous firing activities were highly enhanced by submicromolar levels of glutamate and abolished at levels above 10 μM. From these results, we conclude that at low glutamate concentrations the[Ca2+]c in the dopamine neurons is mainly governed by mGluR and the firing activities, whose rate is regulated at submicromolar glutamate concentrations, but at higher glutamate concentrations[Ca2+]c is dominantly affected by AMPA/kainate receptors.

The endoplasmic reticulum (ER) Ca 2ϩ store plays a key role in integration and conveyance of Ca 2ϩ signals in highly polarized neurons. The interconnected ER network in neurons generates Ca 2ϩ signals in local domains, but the regional interaction is unclear. Here, we show that continuous or repetitive applications of caffeine produced robust Ca 2ϩ release from the ER Ca 2ϩ store in dendritic areas without severe store depletion, but that similar stimuli applied to soma caused rapid store depletion in acutely isolated midbrain dopamine neurons. Partial emptying of the ER Ca 2ϩ store within a dendrite caused a similar level of store depletion in unstimulated dendrites, as well as in soma. Photobleaching and local stimulation experiments revealed that Ca 2ϩ and the dye trapped within the ER diffused rapidly from the soma to dendrites up to 90 m, which we could resolve, suggesting that the ER network acts as a functional tunnel for rapid Ca 2ϩ transport. These data imply that the ER in soma acts as a Ca 2ϩ reservoir supplying Ca 2ϩ to the dendritic store, and that the dendritic store, hence, is able to respond to Ca 2ϩ -mobilizing input signals endurably.