title: Ultrastructural changes associated with reversal of chloroquine resistance by verapamil in Plasmodium chabaudi.
abstract: Reversal of chloroquine (CQ) resistance by verapamil, a Ca2+ antagonist, has been shown in CQ-resistant human and rodent malaria parasites. Here, we report ultrastructural changes associated with this phenomenon in CQ-resistant Plasmodium chabaudi (AS strain) after infected mice were administered CQ and verapamil. At parasitaemias of 5-7%, CQ at 6 mg/kg caused little morphological effect on CQ-resistant parasites. In contrast, co-administration of CQ and verapamil at 50 mg/kg induced swelling of food vacuoles with clumped pigment at 2.5 h. Morphological changes other than food vacuole enlargement occurred at 21 and 45 h: disappearance of endoplasmic reticulum, formation of myelin structures, focal cytoplasmic vacuolization and coarse clumping of electron-dense material in nuclei. These structural changes appeared to be very similar to those observed in CQ-sensitive P. chabaudi in mice injected with CQ alone or CQ plus verapamil. On the other hand, verapamil at 50 mg/kg alone did not induce any effect on both CQ-sensitive and CQ-resistant P. chabaudi. These results suggest that swelling of the food vacuoles is an initial event associated with reversal of CQ-resistance by verapamil.
authors.affiliation: Department of Medical Zoology, Osaka City University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohsawa
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: I
authors.initials: I
authors.lastname: Kimata
authors.forename: A
authors.initials: A
authors.lastname: Miki
mesh_terms: D000818:Animals; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D003593:Cytoplasm / Q000187:drug effects / Q000648:ultrastructure; D004347:Drug Interactions; D004351:Drug Resistance; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008854:Microscopy, Electron; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000648:ultrastructure; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002738:Chloroquine; D014700:Verapamil