Lmb. Ursos et al., The effects of chloroquine and verapamil on digestive vacuolar pH of P-falciparum either sensitive or resistant to chloroquine, MOL BIOCH P, 110(1), 2000, pp. 125-134
In the preceding paper, we present a novel method for measuring the digesti
ve vacuolar pH (pH(vac)) of the malarial parasite Plasmodium falciparum, an
d show that, surprisingly, pH(vac) is lower for chloroquine resistant (CQR)
Dd2 parasites relative to chloroquine sensitive (CQS) HB3. These data. may
have important consequences for elucidating mechanisms of antimalarial dru
g resistance and for developing new antimalarial therapy. Additional issues
central to a better understanding of antimalarial pharmacology and antimal
arial drug resistance require detailed comparative data on the effects of k
ey drugs and other compounds on parasite biophysical parameters such as pH(
vac), measured under close-to-physiologic conditions. Since the methods we
develop in the previous paper allow us to record fluorescence signals from
spatially well-defined regions of the living parasite while they are under
continuous perfusion, it is relatively straightforward for us to test how a
ntimalarial drugs (e.g. chloroquine, CQ) and other compounds (e.g. the chem
oreversal agent verapamil [VPL]) affect pH(vac). In this paper, we measure
both short term (i.e. initial perfusion conditions) and longer-term effects
of CQ and VPL for living, intraerythrocytic CQS (HB3) and CQR (Dd2) malari
al parasites under constant perfusion with physiologically relevant buffers
. We find that VPL normalizes pH(vac) for Dd2 to a value near that measured
for HB3, but has no effect on pH(vac) for HB3. Longer term CQ exposure is
found to alter pH(vac) for HB3 but not Dd2, and short-term exposure to the
drug has no significant effect in either strain. The results may help resol
ve longstanding debate regarding the effects of CQ and VPL on parasite phys
iology, and further support our evolving hypothesis for the mechanism of CQ
resistance. (C) 2000 Elsevier Science B.V. All rights reserved.