title: Infection-mediated vasoactive peptides modulate cochlear uptake of fluorescent gentamicin.
abstract: Inflammatory mediators released during bacterial infection include vasoactive peptides such as histamine and serotonin, and their serum levels are frequently elevated. These peptides also modulate the vascular permeability of endothelial cells lining the blood-brain and blood-labyrinth barriers (BLB). These peptides may also modulate the permeability of the BLB to ototoxic aminoglycoside antibiotics prescribed to resolve bacterial sepsis. To test this hypothesis, we compared the effect of histamine and serotonin on the cochlear distribution of fluorescently conjugated gentamicin (GTTR) in control animals at 0.5, 1 and 3 h after injection of GTTR. The intensity of GTTR fluorescence was attenuated at 1 h in the histamine group compared to control mice, and more intense 3 h after injection (p < 0.05). In the serotonin group, the intensity of GTTR fluorescence was attenuated at 0.5 and 1 h (p < 0.05) and was increased at 3 h compared to control animals, where GTTR intensities peaked at 1 h and then plateaued or was slightly decreased at 3 h. This biphasic pattern of modulation was statistically significant in the apical turn of the cochlea. No difference in the intensity of GTTR fluorescence was observed in kidney proximal tubules. Systemic increases in serum levels of vasoactive peptides can modulate cochlear uptake of gentamicin, likely via permeability changes in the BLB. Conditions that influence serum levels of vasoactive peptides may potentiate aminoglycoside ototoxicity.
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oreg 97239, USA.
authors.forename: Ja-Won
authors.initials: JW
authors.lastname: Koo
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Steyger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002460:Cell Line; D002478:Cells, Cultured; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005839:Gentamicins / Q000493:pharmacokinetics*; D006632:Histamine / Q000494:pharmacology*; D051379:Mice; D012701:Serotonin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D005456:Fluorescent Dyes; D005839:Gentamicins; D012701:Serotonin; D006632:Histamine