Pyrantel resistance alters nematode nicotinic acetylcholine receptor single-channel properties

Resistance to the anthelmintics pyrantel ((E)-1,4,5,6-tetrahydro-1-methyl-2-[2-(2thienyl)ethenyl]pyrimidine) and levamisole ((S)-2,3,5,6-tetrahydro-6-phenylimidazo[2.1 is an increasingly widespread problem in gastro-intestinal nematode infestations. Both compounds act on the nicotinic acetylcholine receptors on the surface of nematode somatic muscle. The patch-clamp technique was used to measure nematode nicotinic acetylcholine receptor properties at 75, 50, -50 and -75 mV in a pyrantel-resistant isolate of Oesophagostomum dentatum. Patch pipettes contained 30 mu M levamisole as agonist. We found that 28.1% of membrane patches contained active receptors, At - 50 mV, the single-channel conductance was 36.2 +/- 1.4 pS, the mean open-time (tau) was 1.45 +/- 0.14 ms and the mean probability of opening (P-o) was 0.004 +/- 0.002. We compared these results with previous work on an anthelmintic sensitive isolate and a levamisole-resistant isolate [Robertson, A.P., Bjorn, H.E,, Martin, R.J., 1999. Levamisole resistance resolved at the single-channel level. FASEB J. 13, 749-760.]. We found that pyrantel-resistant parasites had a reduced percentage of active patches and a reduced P-o value when compared to anthelmintic sensitive worms. We concluded that pyrantel resistance is associated with a modification of the target nicotinic receptor properties. (C) 2000 Elsevier Science B.V. All rights reserved.