Browsing by keyword "Nimodipine"
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Activation of the sodium pump blocks the growth hormone-induced increase in cytosolic free calcium in rat adipocytesGH promptly increases cytosolic free calcium ([Ca2+]i) in freshly isolated rat adipocytes. Adipocytes deprived of GH for 3 h or longer are incapable of increasing [Ca2+]i in response to GH, but instead respond in an insulin-like manner. Insulin blocks the GH-induced increase in [Ca2+]i in GH-replete cells and stimulates the sodium pump (i.e. Na+/K+-ATPase), thereby hyperpolarizing the cell membrane. Blockade of the Na+/K+-ATPase with 100 microM ouabain reversed these effects of insulin and enabled GH to increase [Ca2+]i in GH-deprived adipocytes. Both insulin and GH activated the sodium pump in GH-deprived adipocytes, as indicated by increased uptake of 86Rb+. Decreasing availability of intracellular Na+ by blockade of Na+/K+/ 2Cl- symporters or Na+/H+ antiporters abolished the effects of both hormones on 86Rb+ uptake and enabled both GH and insulin to increase [Ca2+]i in GH-deprived adipocytes. The data suggest that hormonal stimulation of Na+/K+-ATPase activity interferes with activation of voltage-sensitive calcium channels by either membrane hyperpolarization or some unknown interaction between the sodium pump and calcium channels.
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Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neuronsN-type Ca(2+) channels participate in acute activity-dependent processes such as regulation of Ca(2+)-activated K(+) channels and in more prolonged events such as gene transcription and long-term depression. A slow postsynaptic M(1) muscarinic receptor-mediated modulation of N-type current in superior cervical ganglion neurons may be important in regulating these processes. This slow pathway inhibits N-type current by using a diffusible second messenger that has remained unidentified for more than a decade. Using whole-cell patch-clamp techniques, which isolate the slow pathway, we found that the muscarinic agonist oxotremorine methiodide not only inhibits currents at positive potentials but enhances N-type current at negative potentials. Enhancement was also observed in cell-attached patches. These findings provide evidence for N-type Ca(2+)-current enhancement by a classical neurotransmitter. Moreover, enhancement and inhibition of current by oxotremorine methiodide mimics modulation observed with direct application of a low concentration of arachidonic acid (AA). Although no transmitter has been reported to use AA as a second messenger to modulate any Ca(2+) current in either neuronal or nonneuronal cells, we nevertheless tested whether a fatty acid signaling cascade was involved. Blocking phospholipase C, phospholipase A(2), or AA but not AA metabolism minimized muscarinic modulation of N-type current, supporting the participation of these molecules in the slow pathway. A role for the G protein G(q) was also confirmed by blocking muscarinic modulation of Ca(2+) currents with anti-G(qalpha) antibody. Our finding that AA participates in the slow pathway strongly suggests that it may be the previously unknown diffusible second messenger.
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Prophylactic neuroprotection for cerebral ischemiaBACKGROUND: Treatments for acute ischemic stroke have evolved as knowledge about the pathophysiology of ischemic brain injury has advanced. Treatment strategies under development are aimed at offering neuroprotection acutely after focal cerebral ischemic injury, but delayed initiation of therapy may reduce efficacy. Pretreatment before ischemia begins could offer distinct advantages in patient groups at high risk for ischemic stroke. SUMMARY OF REVIEW: If a neuroprotective drug were available orally, safe, and relatively inexpensive, it could be considered for prophylactic use in high-risk populations. Prophylactic neuroprotection would include (1) short-term neuroprotection before and after high-stroke risk procedures, (2) long-term neuroprotection for primary and secondary intervention in populations at high risk for stroke, and (3) concomitant neuroprotection with agents that have multiple treatment effects. Patients undergoing procedures such as cardiac surgery, endarterectomy, or endovascular therapy, which have a risk of cerebral ischemic events during a defined period, might be considered for short-term, periprocedure prophylactic neuroprotection. Several populations at high long-term risk for initial ischemic stroke have been identified and include those with combinations of vascular risk factors, transient ischemic attacks, atrial fibrillation, and asymptomatic carotid stenosis. Such people, as well as those at risk for stroke recurrence after minor strokes, are readily identifiable and perhaps appropriate for long-term prophylactic neuroprotection. Patients with hypertension and cerebrovascular atherosclerosis have a high stroke risk, and therapies directed at these underlying disorders are available that also have concomitant neuroprotective effects. An ideal drug for trials in these patient groups has not yet been developed, and establishing its efficacy may prove to be an arduous and lengthy task. CONCLUSIONS: The possibility of ameliorating the consequences of an acute ischemic stroke by pretreating high-risk patients with appropriate neuroprotective agents needs to be explored. Several types of high-risk population for prophylactic neuroprotection can be envisioned and then studied in clinical trials.