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 n euromuscular transmission in the isolated mouse phrenic nerve-diaphrag m were studied. N-Carbobenzoxy-Gly-Gly-Arg-beta-naphthylamide (Z-GGR-N ) but none of the other agents inhibited the nerve-evoked muscle contr actions. By means of electrophysiological studies, Z-GGR-N was found t o inhibit the amplitudes of both end-plate potentials (epps) (IC50 sim ilar to 50 mu M) and miniature end-plate potentials (mepps) but to inc rease the frequencies of mepps. This tripeptide could protect the nico tinic acetylcholine receptor from the irreversible inhibitory action o f alpha-bungarotoxin on the mouse diaphragm. Similar to D-tubocurarine , Z-GGR-N induced tetanic fading both of nerve-evoked muscle contracti ons and of the amplitude of epps. Furthermore, Z-GGR-N exhibited a gre ater depression of the amplitudes of train-epps than those of mepps, s imilar to that of hexamethonium and D-tubocurarine, indicating an effe ct on presynaptic autoreceptors. Suramin, which could competitively re verse the inhibitory effects of non-depolarizing relaxants, acted in t his study as an antagonist of all the effects of Z-GGR-N, especially t hose at the presynaptic site. All of these findings suggest that Z-GGR -N is a novel tripeptide possessing curare-like actions at both presyn aptic and postsynaptic sites and that these actions are independent of its protease substrate property. (C) 1998 Elsevier Science B.V.