Effects of gabexate, a protease inhibitor, on smooth muscle of guinea-pig stomach fundus.

A protease inhibitor, gabexate (ethyl-p-6-guanidinohexanoyloxy benzoate), was found to have an antimuscarinic action in muscle strips of the guinea-pig gastric fundus. Gabexate reversibly inhibited carbachol-induced contractions in the presence of prostaglandin synthesis inhibitors (indomethacin or meclofenamate) with a pA2 of 5.66 for the circular and 5.25 for the longitudinal muscle. The effect was not affected by tetrodotoxin. Gabexate also inhibited contractions produced by prostaglandin E2 (PGE2) (21.7 +/- 7.3% with 30 microM, n = 12). The inhibition was markedly potentiated by anticholinesterase, diisopropyl fluorophosphate, but converted to contraction by atropine. In the absence of PGE2, gabexate produced no mechanical response on its own even after atropine application. Treatment with hemicholinium, an acetylcholine synthesis inhibitor, also converted the relaxant effect of gabexate, applied during PGE2-induced contraction, to contraction. Gabexate also inhibited contracture induced by 30 mM K+ weakly (13 +/- 2% with 30 microM, n = 5). This relaxation was abolished by atropine, without converting to contraction. PGE2 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-induced contraction.