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Glutamate binding studies on membrane preparations from unselected and ivermectin-selected strains of the parasitic nematode of ruminants, Haemonchus contortus, indicated a single class of saturable, high affinity binding sites which are sensitive to ivermectin and exhibit different pharmacological characteristics from any known mammalian glutamate receptor. These studies showed that H. contortus larvae possess substantially more glutamate binding sites with lower affinity than adults. Moreover, selection with ivermectin was associated with an increase in the number of glutamate binding sites in adults and an increase in the affinity for glutamate binding in larvae. When investigating the effects of ivermectin on glutamate binding kinetics, it was discovered that ivermectin decreased Bmax values in unselected, but not in ivermectin-selected, parasites. Inulin intake studies were performed in unselected and ivermectin-selected H. contortus worms to relate the glutamate binding results to the biological activity, pharyngeal pumping. These studies showed that glutamate, ivermectin and the structurally similar anthelmintic, moxidectin, inhibit pharyngeal pumping, and that glutamate influences the effects of ivermectin and of moxidectin, on pharyngeal pumping. Lastly, selection with ivermectin was associated with an alteration of the effects of ivermectin, but not moxidectin, on pharyngeal pumping. The results of this work suggest that a novel ivermectin-sensitive, glutamate receptor, which influences pharyngeal function, is involved in the development of ivermectin resistance in H. contortus.

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The mechanism of benzimidazole (BZ) anthelmintic resistance in Haemonchus contortus was investigated. The total binding (TB), low-affinity binding (LAB) and high-affinity (specific) binding (HAB) of ($ sp3$H) BZs (mebendazole (MBZ), oxibendazole (OBZ), albendazole (ABZ) and oxfendazole (OFZ)) in supernatants derived from BZ-susceptible (S) and BZ-resistant (R) strains were examined and compared. The TB of all ($ sp3$H) BZs was reduced for the R strain. The TB of OBZ, MBZ and ABZ was separated into LAB and HAB. However, OFZ bound with low-affinity. The binding affinity, K$ sb{ rm a},$ and maximum binding, B$ sb{ rm max},$ for the HAB of OBZ and MBZ were calculated using computer programs. Compared with the S strain, the B$ sb{ rm max}$ of the R strain was reduced but the K$ sb{ rm a}$ was not affected. LAB to parasite preparations devoid of tubulin was observed but HAB occurred to preparations containing tubulin only. The HAB per mg protein decreased from egg through larva to adult stage. It was shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot and enzyme-linked immunosorbent assay (ELISA) analysis that the tubulin content per mg protein decreased from egg, through larva to adult worm. The ability of various BZs--OBZ, MBZ, ABZ, OFZ, fenbendazole (FBZ), albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO$ sb2),$ and thiabendazole (TBZ)--to bind tubulin was compared by displacement analysis and their IC$ sb{50}$ ( (BZ) required to inhibit 50% of the ($ sp3$H) BZ binding) and K$ sb{ rm a}$ values were determined. The IC$ sb{50}$ and K$ sb{ rm a}$ values approximately correlated with the known anthelmintic potency (recommended therapeutic doses) of the BZs except for OFZ and ABZSO. Tubulin bound BZs at 4$ sp circ$C with lower K$ sb{ rm a}$ than at 37$ sp circ$C. Western blot of tubulin separated by 2-dimensional electrophoresis showed that the $ beta$-tubulin isoform pattern of the S and R strains were dissimilar whil

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No description available.