Anthelmintic Actions of the Cyclic Depsipeptide PF1022A and its Electrophysiological Effects on Muscle Cells ofAscaris suum

Abstract

The cyclic depsipeptide PF1022A, given orally to mice, showed very good anthelmintic activity against Heligmosomoides polygyrus and Heterakis spumosa at 50 mg kg -1 . In vitro, PF1022A was very active against Trichinella spiralis and had good activity against Nippostrongylus brasiliensis at 1 μg ml -1 . An 18-membered enniatin analogue, JES 1798, showed good activity only against N. brasiliensis at 10 μg ml -1 . The optical antipode of PF1022A had poor activity even at 100 μg ml -1 . The effects of PF1022A on the membrane potential and input conductance of somatic muscle of Ascaris suum were examined using a two-microelectrode current-clamp technique. PF1022A did not antagonize the effects of the selective nicotinic agonist levamisole. PF1022A and an analogue, JES 1798, but not the PF1022A antipode, produced a small time-dependent increase in input conductance associated with no potential change. The increase in input conductance did not occur in the Cl - -free bathing solution, suggesting that the increase in input conductance was mediated by Cl - ions. The addition of high concentrations of Ca 2+ to the preparation after the addition of PF1022A did not lead to production of Ca 2+ -activated Cl - channels, suggesting that its mode of action was not that of a Ca 2+ ionophore. The mechanism by which the cyclic depsipeptide might increase the Cl - conductance is discussed.