Studies on curare-like action of the tripeptide carbobenzoxy-Gly-Gly-Arg-beta-naphthylamide in mouse diaphragm.
The effects of several protease substrates or protease inhibitors on neuromuscular transmission in the isolated mouse phrenic nerve-diaphragm were studied. N-Carbobenzoxy-Gly-Gly-Arg-beta-naphthylamide (Z-GGR-N) but none of the other agents inhibited the nerve-evoked muscle contractions. By means of electrophysiological studies, Z-GGR-N was found to inhibit the amplitudes of both end-plate potentials (epps) (IC50 approximately 50 microM) and miniature end-plate potentials (mepps) but to increase the frequencies of mepps. This tripeptide could protect the nicotinic acetylcholine receptor from the irreversible inhibitory action of alpha-bungarotoxin on the mouse diaphragm. Similar to D-tubocurarine, Z-GGR-N induced tetanic fading both of nerve-evoked muscle contractions and of the amplitude of epps. Furthermore, Z-GGR-N exhibited a greater depression of the amplitudes of train-epps than those of mepps, similar to that of hexamethonium and D-tubocurarine, indicating an effect on presynaptic autoreceptors. Suramin, which could competitively reverse the inhibitory effects of non-depolarizing relaxants, acted in this study as an antagonist of all the effects of Z-GGR-N, especially those at the presynaptic site. All of these findings suggest that Z-GGR-N is a novel tripeptide possessing curare-like actions at both presynaptic and postsynaptic sites and that these actions are independent of its protease substrate property.
Lin-Shiau
S Y
SY
Institutes of Pharmacology and Toxicology, College of Medicine, National Taiwan University, Taipei.
Lin
M J
MJ
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001587:Benzoylarginine-2-Naphthylamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects* / Q000294:innervation; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010791:Phrenic Nerve / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*
D009842:Oligopeptides; D011480:Protease Inhibitors; C030280:benzyloxycarbonyl-glycyl-glycyl-arginine beta-naphthylamide; D001587:Benzoylarginine-2-Naphthylamide; D007611:Aprotinin