Study on reversal of chloroquine resistance in malaria parasites by Ca^<2+> antagonists

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1. Preliminary study revealed that several Ca^<2+> antagonists reversed chloroquine (CQ) resistance in mice infected with CQ-resistant Plasmodium chabaudi. In addition to Ca^<2+> antagonists, calmodulin inhibitors, trifluoperazine and chlorpromazine, and tricyclic antidepressants, desipramine and imipramine, reversed CQ-resistance in a dose-dependent manner. These drugs also increased the susceptibility to CQ in CQsensitive P. chabaudi.2. Ca^<2+> antagonists, calmodulin inhibitors and tricyclic antidepressants used in this study did not reverse pyrimethamine resistance in miceinfected with pyrimethamine-resistant P-. chabaudi.3. Measurements of CQ levels in P. chabaudi by high performance liquid" chromatography demonstrated that CQ accumulated in CQ-sensitive parasites much greater than in CQ-resistant parasites. Time-dependent increase in the accumulation of CQ was less pronounced in CQ-resistant parasites.4. Transmission electron microscopy elucidated that CQ induced a variety of morphological changes in CQsensitive P. chabaudi : swelling of the food vacuoles and clustering of malaria pigment in the food vacuole at 2.5hr after injection of CQ and at 24 and 481ir disappearance of endoplasmic reticulum, aggregation of ribosomes and appearance of electron-dense granules in the nucleus. These changes were not observed in CQ-resistant P. chabaudi. However, verapamil induced ultrastructural changes very similar to those observed in CQ-sensitive parasites.These results indicate that Ca^<2+> antagonists reverse CQ resistance by inducing the accumulation of CQ in resistant P. chabaudi.