EFFECTS OF GABEXATE, A PROTEASE INHIBITOR, ON SMOOTH-MUSCLE OF GUINEA-PIG STOMACH FUNDUS

A protease inhibitor, gabexate (ethyl-p-6-guanidinohexanoyloxy benzoat e), was found to have an antimuscarinic action in muscle strips of the guinea-pig gastric fundus. Gabexate reversibly inhibited carbachol-in duced contractions in the presence of prostaglandin synthesis inhibito rs (indomethacin or meclofenamate) with a pA(2) of 5.66 for the circul ar and 5.25 for the longitudinal muscle. The effect was not affected b y tetrodotoxin. Gabexate also inhibited contractions produced by prost aglandin E(2) (PGE2) (21.7+/-7.3% with 30 mu M, n=12). The inhibition was markedly potentiated by anticholinesterase, diisopropyl fluorophos phate, but converted to contraction by atropine. In the absence of PGE 2, gabexate produced no mechanical response on its own even after atro pine application. Treatment with hemicholinium, an acetylcholine synth esis inhibitor, also converted the relaxant effect of gabexate, applie d during PGE(2)-induced contraction, to contraction. Gabexate also inh ibited contracture induced by 30 mM K+ weakly (13+/-2% with 30 mu M, n =5). This relaxation was abolished by atropine, without converting to contraction. PGE(2) and excess K+ are likely to release acetylcholine from nerve fibres. These results suggest that the inhibitory effect of gabexate is mainly due to the muscarinic receptor blocking action. In addition, gabexate has a potentiating action on the prostaglandin-ind uced contraction.