Effects of diltiazem on bioenergetics, K+ gradients, and free cytosolic Ca2+ levels in rat brain synaptosomes submitted to energy metabolism inhibition and depolarization.
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.
Dagani
F
F
Institute of Pharmacology, Faculty of Science, University of Pavia, Italy.
Feletti
F
F
Canevari
L
L
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
D012402:Rotenone; D014701:Veratridine; D012964:Sodium; D004110:Diltiazem; D011188:Potassium; D002118:Calcium