Interaction of the neurotoxic pesticides ivermectin and lindane with the enteric GABAA receptor-ionophore complex in the guinea-pig.
In isolated segments of guinea-pig small intestine, gamma-aminobutyric acid (GABA) (3-300 microM), the GABAA receptor agonist 3-aminopropane sulphonic acid (3-APS) (3-300 microM) and ivermectin (1-300 microM) caused concentration-dependent nerve-mediated cholinergic contractions sensitive to tetrodotoxin (1 microM) and hyoscine (1 microM). The EC50 values were 30.2 +/- 4.3, 24.6 +/- 3.1 and 4.8 +/- 0.6 microM, respectively. Picrotoxinin (10 microM), an allosteric blocker of the Cl- channel associated with GABAA receptors, non-competitively antagonized the contractile response caused by each agonist. Like picrotoxinin, lindane (10, 30 microM) caused a dose-related shift to the right of the concentration-response curve to GABA, 3-APS and ivermectin with depression of the maximum response. SR 95531 (3 microM), a competitive antagonist of GABAA receptors, caused a parallel dextral shift of the concentration-response curve to ivermectin with an apparent single point pA2 value of 6.5. Our results suggest that ivermectin and lindane, two neurotoxic pesticides interfering with central GABAErgic transmission, exert agonist and non-competitive antagonist properties at the enteric GABAA receptor-ionophore complex. This peripheral complex can thus be considered as an additional target for the action of both these compounds.
Coccini
T
T
Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
Candura
S M
SM
Manzo
L
L
Costa
L G
LG
Tonini
M
M
D000818:Animals; D018118:Chloride Channels; D005260:Female; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects; D007537:Isometric Contraction / Q000187:drug effects; D007559:Ivermectin / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology; D054830:Sesterterpenes; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D018118:Chloride Channels; D058787:GABA-A Receptor Antagonists; D001556:Hexachlorocyclohexane; D007559:Ivermectin; D008565:Membrane Proteins; D010852:Picrotoxin; D011724:Pyridazines; D011963:Receptors, GABA-A; D012601:Scopolamine; D054830:Sesterterpenes; D013654:Taurine; D013779:Tetrodotoxin; C001355:tramiprosate; C049853:gabazine; C022961:picrotoxinin