Neomycin and omega-conotoxin GVIA interact at a common neuronal site in peripheral tissues.
1. The present study examined the interaction of omega-conotoxin GVIA (omega-CT) and aminoglycoside antibiotics on electrically evoked, nerve-mediated contractile responses in the rat vas deferens, guinea-pig ileum and guinea-pig left atria. 2. omega-CT caused a time- and concentration-dependent inhibition of the electrically evoked twitch responses of the rat vas deferens and guinea-pig ileum. Aminoglycoside antibiotics inhibited the twitch responses of these preparations with a rank order of potency: neomycin greater than gentamycin greater than kanamycin. omega-CT had no effect on the postjunctional contractile responses of either noradrenaline (vas deferens) or carbachol (ileum). However, at high concentrations neomycin and gentamycin caused significant postjunctional inhibition. The results suggest that omega-CT and aminoglycosides cause prejunctional inhibition in these preparations, with the aminoglycoside antibiotics exhibiting postjunctional inhibitory effects as well at high concentrations. 3. omega-CT caused a concentration- and frequency-dependent inhibition of the neuronally mediated field stimulation enhancement of electrically paced guinea-pig left atria. omega-CT had no effect on either the electrically paced contractile response that was elicited by direct muscle stimulation or the enhancement of the paced response caused by beta-adrenoceptor agonist stimulation. Neomycin caused a concentration-dependent inhibition of the electrically paced contractile response and inhibited the field stimulation response only at concentrations which caused pronounced inhibition of the paced response. Neomycin also caused insurmountable inhibition of responses elicited by beta-adrenoceptor agonist stimulation. Thus, omega-CT caused an exclusive prejunctional inhibition in guinea-pig left atria, whereas the substantial postjunctional effects of neomycin made it difficult to discern any prejunctional activity of neomycin in these experiments. 4. In the vas deferens, ileum and atria the inhibitory effects of omega-CT were long-lasting, whereas the effects of neomycin could be reversed upon wash-out. The disparate kinetics of omega-CT and neomycin allowed for the design of receptor protection studies to determine whether neomycin acts at a prejunctional site in common with omega-CT. The pre-equilibration of a competitive antagonist (neomycin) should prevent the irreversible antagonist (omega-CT) from gaining access to receptors. Pre-exposure of tissues with neomycin prevented the irreversible inhibition of omega-CT. These receptor protection studies suggest that omega-CT and neomycin interact at common neuronal sites in the rat vas deferens, guinea-pig ileum and guinea-pig atria. Neomycin, however, exhibits activity at postjunctional sites as well.
Keith
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RA
ICI Pharmaceuticals, ICI America Inc., Wilmington, Delaware 19897.
LaMonte
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Salama
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D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008978:Mollusk Venoms / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009355:Neomycin / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D020866:omega-Conotoxin GVIA
D008978:Mollusk Venoms; D010456:Peptides, Cyclic; D011943:Receptors, Adrenergic, beta; D020866:omega-Conotoxin GVIA; D009355:Neomycin