Kodavanti P R, Pentyala S N, Yallapragada P R, Desaiah D
Department of Neurology, University of Mississippi Medical Center, Jackson 39216.
Naunyn Schmiedebergs Arch Pharmacol. 1992 Feb;345(2):213-21. doi: 10.1007/BF00165739.
Long term amiodarone (AM) therapy has been associated with several side effects including neurotoxicity. Since AM alters Ca2+ regulated events, we have studied its effects on the compartmentation of free Ca2+ in the synaptosomes as an attempt to understand the mechanism of AM and its metabolite, desethylamiodarone (DEA)-induced neurotoxicity. Intact brain synaptosomes were prepared from male Sprague-Dawley rats. Both AM and DEA produced a concentration dependent increase in intrasynaptosomal free Ca2+ concentration ([Ca2]i) to micromolar levels. The increase in [Ca2]i was not transient and a steady rise was observed with time. Omission of Ca2+ from the external medium prevented the AM- and DEA-induced rise in [Ca2+]i suggesting that AM and DEA increased the intracellular [Ca2+]i due to increased influx of Ca2+ from external medium. AM- and DEA-induced increase in intrasynaptosomal [Ca2+]i was neither inhibited by a calcium channel blocker, verapamil, nor with a Na+ channel blocker, tetrodotoxin. However, the blockade of [Ca2+]i rise by AM and DEA was observed with MK-801, a receptor antagonist indicating that AM and DEA induced rise in [Ca2+]i is through receptor mediated channel. Both AM and DEA also inhibited N-methyl-D-aspartic acid (NMDA)-receptor binding in synaptic membranes in a concentration dependent manner, DEA being more effective, indicating that AM and DEA compete for the same site as that of NMDA and confirm the observation that these drugs increase intrasynaptosomal [Ca2+]i through receptor mediated channel. 45Ca accumulation into brain microsomes and mitochondria was significantly inhibited by AM and DEA, but without any effect on the Ca2+ release from these intracellular organelles.(ABSTRACT TRUNCATED AT 250 WORDS)
