PT - JOURNAL ARTICLE AU - I. Tong Mak AU - Joanna J. Chmielinska AU - Lucie Nedelec AU - Armida Torres AU - William B. Weglicki TI - <span class="sc">d</span>-Propranolol Attenuates Lysosomal Iron Accumulation and Oxidative Injury in Endothelial Cells AID - 10.1124/jpet.105.097709 DP - 2006 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 522--528 VI - 317 IP - 2 4099 - http://jpet.aspetjournals.org/content/317/2/522.short 4100 - http://jpet.aspetjournals.org/content/317/2/522.full SO - J Pharmacol Exp Ther2006 May 01; 317 AB - The influence of selected β-receptor blockers on iron overload and oxidative stress in endothelial cells (ECs) was assessed. Confluent bovine ECs were loaded with iron dextran (15 μM) for 24 h and then exposed to dihydroxyfumarate (DHF), a source of reactive oxygen species, for up to 2 h. Intracellular oxidant formation, monitored by fluorescence of 2′,7′-dichlorofluorescin (DCF; 30 μM), increased and peaked at 30 min; total glutathione decreased by 52 ± 5% (p &lt; 0.01) at 60 min. When the ECs were pretreated 30 min before iron loading with 1.25 to 10 μM d-propranolol, glutathione losses were attenuated 15 to 80%, with EC50 = 3.1 μM. d-Propranolol partially inhibited the DCF intensity increase, but atenolol up to 10 μM was ineffective. At 2 h, caspase 3 activity was elevated 3.2 ± 0.3-fold (p &lt; 0.01) in the iron-loaded and DHF-treated ECs, and cell survival, determined 24 h later, decreased 47 ± 6% (p &lt; 0.01). Ten micromoles of d-propranolol suppressed the caspase 3 activation by 63% (p &lt; 0.05) and preserved cell survival back to 88% of control (p &lt; 0.01). In separate experiments, 24-h iron loading resulted in a 3.6 ± 0.8-fold increase in total EC iron determined by atomic absorption spectroscopy; d-propranolol at 5 μM reduced this increase to 1.5 ± 0.4-fold (p &lt; 0.01) of controls. Microscopic observation by Perls' staining revealed that the excessive iron accumulated in vesicular endosomal/lysosomal structures, which were substantially diminished by d-propranolol. We previously showed that propranolol could readily concentrate into the lysosomes and raise the intralysosomal pH; it is suggested that the lysosomotropic properties of d-propranolol retarded the EC iron accumulation and thereby conferred the protective effects against iron load-mediated cytotoxicity. The American Society for Pharmacology and Experimental Therapeutics