VASOPRESSOR PROPERTIES OF NITRIC OXIDE SYNTHASE INHIBITOR T1059. PART I: SYNTHESIS, TOXICITY, NOS-INHIBITION ACTIVITY, AND HEMODYNAMIC EFFECTS UNDER NORMOTENSIVE CONDITIONS

摘要

Compound T1059 (1-cyclohexanecarbonyl-2-ethylisothiourea hydrobromide) was found to be water soluble, moderately toxic (i.p. LD16 and LD50 of 274 and 380 mg/kg), and capable of competitively inhibiting nitric-oxide synthase (NOS) activity with significant selectivity toward inducible and endothelial isoforms (IC50 for nNOS, iNOS, and eNOS of 60.3, 1.8, and 3.2 mu M, respectively). T1059 was rapidly absorbed after a single i.p. injection (dose range 10 - 30 mg/kg) and distributed in tissues, causing pronounced suppression of endogenous NO production. T1059 at a dose of 10 mg/kg in normotensive anesthetized Wistar rats produced long-term vasoconstriction. The observed changes in vascular tone did not influence inotropic heart function but were accompanied by weak bradycardia.