Effects of dihydroavermectin B 1a and analogs on stretcher muscle of the lined shore crab, Pachygrapsus crassipes

Abstract

1. Dihydroavermectin B 1a (DHAVM, Ivermectin ®) at 1 μM reduces excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively) in stretcher muscle fibres of the lined shore crab, Pachygrapsus crassipes. IPSPs decline faster and more extensively than EPSPs and, unlike EPSPs, do not recover upon replacement of DHAVM with plcrotoxinin-containing medium. 2. Intracellular recordings show DHAVM reduces membrane resistance ( R in) and hyperpolarizes muscle fibres in a concentration-dependent manner, beginning at 10 nM. The rate and magnitude of DHAVM effects on R in mirror its effects on EPSPs. 3. The decline in R in due to DHAVM is sustained over time (i.e. there is no tendency for desensitization); it is also irreversible and not affected by coadministration of 1 mM γ-aminobutyric acid (GABA), 0.1 mM bicuculline methiodide or addition of 20 mM Co 2+ to the recording medium. 4. Replacement of DHAVM-containing medium with medium containing Cl − channel blockers (picrotoxinin or lindane) results in partial recovery of R in, while channel blockers specific for other ions (TTX, TEA, 4-AP or verapamil) are without effect. The decline of R in following application of DHAVM is attenuated in Cl −-free medium. 5. Results of tests using compounds structurally related to DHAVM reveal that relatively minor changes in the molecule often reduce biological activity significantly. Removal of one sugar, for instance, results in a ten-fold reduction in potency. 6. In general, avermectins that stimulate conductance in shore crab muscle also possess anthelmintic activity at similar concentrations, based on studies using the free-living nematode, Caenorhabditis elegans. When exceptions occur, within the range of therapeutic concentrations, weaker activity in the anthelmintic assay may be predicted on the basis of plcrotoxinin irreversibility in the shore crab preparation.