Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats |
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Authors: | Fiorenzo Dagani Rosaria Ferrari and Laura Canevari |
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Institution: | aIstituto di Farmacologia, Universita`di Pavia, Pavia, Italy |
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Abstract: | Lactate production (Jlac), oxygen consumption rate (QO2), plasma membrane potentials (Em) and cytosolic free calcium levels Ca2+]i were studied on symaptosomes isolated from rat brains, incubated in presence of high doses of nicardipine (90 μM), diltiazem (0.5 mM) and verapamil (0.25 mM), and submitted to depolarizing stimulation or inhibition of mitochondrial respiration. Nicardipine was able to completely prevent the veratridine-induced stimulation ofJlac, QO2andEm depolarization, whereas diltiazem and verapamil were less effective, although the concentrations used were 5 and 3 times higher, respectively, than nicardipine. Diltiazem, verapamil and nicardipine (9 μM) also prevented the veratridine-induced increase in Ca2+]i, this effect being much less pronounced if the drugs were added after veratridine. Monensin (20 μM) was also able to increase Ca2+]i but this effect was not affected by verapamil. Synaptosomes were also submitted to an inhibition of respiration of intrasynaptic mitochondria by incubation with rotenone (5 μM); in this condition of mimicked hypoxiaEm was more positive of about 11 mV; none of the drugs utilized modified this situation. The rotenone-induced 3-fold increase inJlac was barely modified by diltiazem and verapamil but it was completely abolished by nicardipine. The possible mechanism of the counteracting action of the drugs towards veratridine stimulation and rotenone inhibition and the involvement of Na+/Ca2+ exchanger in affecting Ca2+]i are discussed. |
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Keywords: | Synaptosome Bioenergetic [Ca2+]i Na+/Ca2+ exchanger Calcium blockers |
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