Vasopressor Properties of Nitric Oxide Synthase Inhibitor T1059. Part I: Synthesis, Toxicity, NOS-Inhibition Activity, and Hemodynamic Effects Under Normotensive Conditions

详细

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 μM, 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.