Nimodipine attenuates both increase in cytosolic free calcium and histologic damage following focal cerebral ischemia and reperfusion in cats.

Abstract

To clarify the mechanism of its effect on ischemic stroke, we investigated the effect of nimodipine, a dihydropyridine calcium antagonist, on changes in cytosolic free calcium, cortical blood flow, and histologic changes following focal cerebral ischemia and reperfusion in 14 cats. Using indo-1, a fluorescent intracellular Ca 2+ indicator, we simultaneously measured changes in the Ca 2+ signal ratio (400 506 nm), reduced nicotinamide adenine dinucleotide fluorescence (464 nm), and reflectance (340 nm) during an ultraviolet excitation (340 nm) directly from the cat cortex in vivo. In six cats treated with vehicle only, the calcium signal ratio increased from 5 minutes after middle cerebral artery occlusion to 30 minutes into reperfusion. The elevation of cytosolic free calcium was significantly attenuated by nimodipine, which was administered by intravenous infusion in eight cats starting 5 minutes after occlusion. Nimodipine had no effect on cortical blood flow during ischemia but induced a hyperperfused state following reperfusion. Nimodipine did not modify changes in the mitochondrial oxidation-reduction state. Nimodipine proved to have beneficial effects on recovery of the electroencephalogram following reperfusion as well as on the extent of focal histologic damage. Our results suggest that nimodipine, when administered during the early stage of focal ischemia, can favorably modify the outcome of stroke by reducing the Ca 2+ entry during both the ischemic and reperfusion periods. (Stroke 1989;20:1531-1537 I n contrast to a relatively good understanding of the hemodynamic and metabolic aspects of stroke, a great deal remains to be clarified concerning the biochemical mechanisms underlying ischemia-induced cellular injury. In the past decade several mechanisms have been postulated to be involved in the production of ischemic and reperfusion injury: acidosis, ], can be assessed in vivo along with changes in nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD/NADH) oxidation-reduction (redox) state and hemodynamics.

Sodium Influx Plays a Major Role in the Membrane Depolarization Induced by Oxygen and Glucose Deprivation in Rat Striatal Spiny Neurons

“…These concentrations of glutamate antagonists fully blocked excitatory postsynaptic potentials (EPSPs) evoked by the activation of glutamatergic corticostriatal fibers in brain slice preparations ( Figure 3C). 11,20 Blockers of high voltage-activated Ca 2ϩ channels have been reported to reduce the neuronal vulnerability to ischemia 27 and the ischemic depolarization in cortical neurons. 2 Thus, we also studied the effect of preincubation of the slices in 10 mol/L nifedipine on the ischemic depolarization.…”

Calcium Channel Density and Hippocampal Cell Death with Age in Long-Term Culture

“…Most studies on the role of excessive Ca 2ϩ influx in cell death have focused on Ca 2ϩ entry via ligand-gated channels (Rothman and Olney, 1987;Choi, 1988); however, it is becoming increasingly recognized that VGCCs, particularly of the L-type, can be a route for toxic levels of Ca 2ϩ influx after a number of insults (Scriabine et al, 1989;Uematsu et al, 1989;Lobner and Lipton, 1993;Lipton, 1994;Stuiver et al, 1996). Furthermore, VGCCs represent a major Ca 2ϩ entry pathway even during the physiological activation of ligand-gated Ca 2ϩ channels (Miyakawa et al, 1992;Jaffe et al, 1994;Regehr and Tank, 1994;Stuart and Sakmann, 1994;Magee and Johnston, 1995;Yuste and Denk, 1995).…”

Biphasic striatal dopamine release during transient ischemia and reperfusion in gerbils.

“…For instance, one could test the hypoth-esis that a calcium channel blocker, such as nimodipine, changes the slope or magnitude of the early dopamine release and perhaps even attenuates the reperfusion response. In fact, Uematsu et al 32 have already shown that nimodipine attenuates both increase in cytosolic free calcium and histological damage following focal cerebral ischemia and reperfusion in cats. Further studies to understand and modify this reperfusion phenomenon are warranted.…”