Leishmania sp.: growth and survival are impaired by ion channel blockers.
In the present work we examined the effect of ion transport blockers on the growth and viability of Leishmania sp. and on the infection of macrophages by the parasite. 4-aminopyridine and glibenclamide block voltage-dependent and K+ ATP channels, respectively; amiloride is used to detect Na+ channels and Na+/H+ antiporters; and anthracene-9-carboxylic acid affects chloride channels. The EC50 for promastigote cultures of three strains of the Leishmania subgenus, namely, Leishmania (Leishmania) NR, Leishmania (Leishmania) amazonensis LTB0016, and Leishmania (Leishmania) major, at their stationary phase of growth, were, respectively, 39, 46, and 464 microM for 4-aminopyridine; 7, 0.8, and 10 microM for glibenclamide and 66, 170, and 10 microM for anthracene-9-carboxylic acid. The amiloride EC50 for NR was 264 microM and 10 microM for L. (L.) major, but was never reached for LTB0016. Higher concentrations of the drugs impaired the exponential growth of Leishmania promastigotes. These results suggest the susceptibility of Leishmania sp. to blockers associated with K+ and Cl- and to Na+ or Na+/H+ transport systems. Blockade of such systems might have impaired the survival of the parasites as promastigotes. In addition, it affected the persistence of parasites in host cells. Although the infection of the macrophage cell line J774 and peritoneal-exudate macrophages was not significantly decreased by concentrations of the drugs around the promastigotes' EC50, the survival of intracellular parasites decreased significantly in the presence of these drugs without affecting the viability of the macrophages. Some blockers consistently gave small EC50 and significantly decreased the infection process as well as the survival of intracellular parasites. Thus, elucidation of their mechanism of action in Leishmania is relevant, since they could represent a potential subject for the development of leishmanicidal drugs.
Ponte-Sucre
A
A
Laboratory of Molecular Physiology, I.M.E., Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.
Campos
Y
Y
Fernandez
M
M
Moll
H
H
Mendoza-León
A
A
D015761:4-Aminopyridine / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology*; D051379:Mice
D000873:Anthracenes; D007473:Ion Channels; C010030:9-anthroic acid; D000584:Amiloride; D015761:4-Aminopyridine; D005905:Glyburide