IN-VIVO INHIBITION OF NITRIC-OXIDE SYNTHASE BY BISISOTHIOURONIUM AND BISGUANIDINIUM SALTS

The ability of two S, S'-(alkane-1, omega-diyl) bisisothiouronium dibr omides, three N, N'-(alkane-1, omega-diyl) bis guanidinium dinitrates and N, N'-bis(3-guanidinopropyl)piperazine dinitrate to inhibit consti tutive (i.e. endothelial and neuronal forms) and inducible forms of ni tric oxide synthases has been evaluated in vivo. These compounds, synt hesized by two of us (J. C. L. and C. S.), have been tested in vivo; t hey were administered simultaneously with an irritant (carrageenan lam bda) into the pleural cavity. The amount of nitrites collected 0.5 and 7 hours after this injection can be considered as an indicator of nit ric oxide (NO) production. According to previous data, the first harve sting time can be related to activation of constitutive NO synthases a nd the second to activation of inducible NO synthases. These substance s significantly inhibited nitrile production as did 2-methyl-2-thiopse udourea ea sulphate, previously described as a potent inhibitor of NO synthases and considered as the reference compound. The inhibiting eff ect varied according to the chemical structure of the compounds. Resul ts were significantly different from controls at 0.5 h only with the S , S'-(octane-1, 8-diyl) bisisothiouronium dibromide and the S, S'(nona ne-1, 9-diyl) bisisothiouronium dibromide at the highest concentration , N, N'-(heptane-1, 7-diyl) bisguanidinium dinitrate and N, N'-bis(3-g uanidinopropyl)piperazine dinitrate. At 7 h, all the results were sign ificantly different from controls, with a major effect observed with N , N'-(heptane-1, 7-diyl) bisguanidinium dinitrate. The most active sub stances exerted similar effects to the reference substance.