Differential response of mast cells separated from various organs and basophils of dogs to the fluoroquinolone antimicrobial levofloxacin.
Histamine releases induced by the fluoroquinolone antimicrobial levofloxacin (LVFX) were investigated using mast cells separated from various organs and peripheral basophils of dogs, being the most susceptible species to quinolone derivatives, in both in vivo and in vitro systems. An intravenous infusion of LVFX at 30 mg/kg over a 30-min period produced endogenous histamine release from 5 min, and a maximum at 30 min, in which the plasma LVFX concentration was approximately 50 microM. A close correlation (r = 0.87, n = 20) between histamine and LVFX concentrations in plasma during the infusion was observed. In the in vitro study, LVFX at 30 microM or more caused histamine release from mast cells separated from the liver and skin, but not from the gastric mucosa, lung, and peripheral basophils. More exactly, the liver mast cells were most susceptible to LVFX among the organs tested. On the other hand, compound 48/80, a prototype histamine liberator, elicited the histamine release from the liver or skin mast cells at 10 microg/ml, and the calcium ionophore A23187 at 1 microM exhibited the histamine release from the mast cells derived from all organs examined. Histochemical analysis revealed that the liver and skin mast cells had positive reaction for both alcian blue and safranin staining, but the gastric mucosa and lung mast cells were only positive for alcian blue staining, indicating that LVFX preferably activated the connective tissue-type mast cells rather than the mucosal-type mast cells. The degranulation of the liver and skin mast cells brought about by either LVFX or compound 48/80, unlike the calcium ionophore A23187, was blocked by pretreatment with pertussis toxin, suggesting the involvement of pertussis toxin-sensitive G proteins. The results obtained from the canine experiments strongly suggest that LVFX induces histamine release from the connective tissue-type mast cells distributed mainly in the liver, somewhat in the cutaneous tissue, through the activation of pertussis toxin-sensitive G proteins.
Mori
K
K
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan. morikslf@daiichipharm.co.jp
Shibano
M
M
Satoh
H
H
Takasuna
K
K
Furuhama
K
K
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001491:Basophils / Q000187:drug effects* / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D003238:Connective Tissue / Q000187:drug effects; D004285:Dogs; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006636:Histamine Release / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D064704:Levofloxacin; D008099:Liver / Q000187:drug effects; D008297:Male; D008407:Mast Cells / Q000187:drug effects*; D009092:Mucous Membrane / Q000187:drug effects; D015242:Ofloxacin / Q000494:pharmacology*; D037342:Pertussis Toxin; D012867:Skin / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000890:Anti-Infective Agents; D007476:Ionophores; D010566:Virulence Factors, Bordetella; D000001:Calcimycin; D064704:Levofloxacin; D015242:Ofloxacin; D007770:L-Lactate Dehydrogenase; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins