title: Effects of diltiazem on bioenergetics, K+ gradients, and free cytosolic Ca2+ levels in rat brain synaptosomes submitted to energy metabolism inhibition and depolarization.
abstract: Diltiazem was able to decrease the oxygen consumption rate and lactate production in synaptosomes isolated from rat forebrains, both under control and depolarized (40 microM veratridine) conditions, starting from a concentration of 250 microM. This effect was particularly evident when synaptosomes were depolarized by veratridine. This depolarization-counteracting action was evident also when transplasma membrane K+ diffusion potentials were measured after depolarization induced by veratridine and by rotenone with a glucose shortage. The concentrations of ATP, phosphocreatine, and creatine were less sensitive to diltiazem action. The concentration/response relationships were the same as those found for the oxygen consumption were the same as those found for the oxygen consumption rate, lactate production, and K+ diffusion potentials. The effects of 0.5 mM diltiazem in counteracting inhibition of energy metabolism induced by rotenone without glucose were no longer detectable when either Ca2+ or Na+ was absent from the incubation medium of synaptosomes. Diltiazem at the same concentrations (starting from 250 microM) was able to inhibit both the veratridine-induced and the rotenone-without-glucose-induced increase in intrasynaptosomal free Ca2+ levels evaluated with the fluorescent probe quin2. The results are discussed in view of a possible effect of diltiazem on voltage-dependent Na+ channels and the possibility of utilizing this approach for counteracting neuronal failure due to derangement of energy metabolism or hyperexcitation.
authors: Institute of Pharmacology, Faculty of Science, University of Pavia, Italy.
authors: F
authors: F
authors: Dagani
authors: F
authors: F
authors: Feletti
authors: L
authors: L
authors: Canevari
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D002118:Calcium / Q000172:deficiency / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004734:Energy Metabolism / Q000187:drug effects*; D009994:Osmolar Concentration; D011188:Potassium / Q000502:physiology*; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D012964:Sodium / Q000172:deficiency; D013574:Synaptosomes / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D014701:Veratridine / Q000494:pharmacology
chemical_list: D012402:Rotenone; D014701:Veratridine; D012964:Sodium; D004110:Diltiazem; D011188:Potassium; D002118:Calcium