Rank-order inhibition by ω-conotoxins in human and animal autonomic nerve preparations

The inhibitory effects of the ω-conotoxins GVIA, MVIIA and MVIIC on electrically-evoked, tetrodotoxin (10−7 M)-sensitive, autonomic nerve activity were studied using human, rat or guinea-pig vas deferens and intestinal tissues. In each preparation from each species, nM concentrations of ω-conotoxins GVIA and MVIIA prevented the neuronally-mediated contractions, whereas ω-conotoxin MVIIC was either markedly less potent (IC50's 1.4 or 2.9 log units more than for ω-conotoxin GVIA in guinea-pig ileum and rat vas deferens, respectively) or was without significant activity (human vas deferens, human Taenia coli) when tested at similar concentrations. In contrast the differences in potency between ω-conotoxins GVIA and MVIIC were considerably less when assayed directly on Ca2+ channel currents evoked from rat superior cervical ganglion neurons in culture (approximately 0.1 log unit difference) and from a stable cell line expressing rat α1B, α2δ, β1b Ca2+ channel subunits (approximately 0.9 log unit). These different rank-orders of inhibitory activity of the conotoxins support the suggestion that there are pharmacologically distinct N-type Ca2+ channels in the peripheral nervous system, and that this tissue-dependent difference is seen in man.