caa a22 4500 469079770 CHVBK 20180323132946.0 cr unu---uuuuu 170328e19920201xx s 000 0 eng 10.1007/BF00165739 doi (NATIONALLICENCE)springer-10.1007/BF00165739 Amiodarone and desethylamiodarone increase intrasynaptosomal free calcium through receptor mediated channel [Elektronische Daten] [Prasada Kodavanti, Srinivas Pentyala, Prabhakara Yallapragada, Durisala Desaiah] Summary: 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. Also, both these drugs did not interfere with inositol 1,4,5-trisphosphate induced Ca2+ release from microsomes even at 10 μM concentration. These results clearly indicate that both AM and DEA increase intrasynaptosomal [Ca2+]i by an action on receptor mediated channel in plasma membrane, but not due to the release of Ca2+ from intracellular storage sites. This initial rise in [Ca2+]i, together with other changes in Ca2+ homeostasis, might be responsible for AM and DEA-induced neurotoxicity. Springer-Verlag, 1992 Amiodarone nationallicence Desethylamiodarone nationallicence Free Ca2+ nationallicence Fura-2 nationallicence Synaptosomes nationallicence 45Ca-uptake nationallicence Inositol phosphates nationallicence Kodavanti Prasada Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut Pentyala Srinivas Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut Yallapragada Prabhakara Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut Desaiah Durisala Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/2(1992-02-01), 213-221 0028-1298 345:2<213 1992 345 210 https://doi.org/10.1007/BF00165739 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00165739 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kodavanti Prasada Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut NATIONALLICENCE 700 1- Pentyala Srinivas Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut NATIONALLICENCE 700 1- Yallapragada Prabhakara Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut NATIONALLICENCE 700 1- Desaiah Durisala Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, 39216, Jackson, MS, USA aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/2(1992-02-01), 213-221 0028-1298 345:2<213 1992 345 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer