M.V. Filimonova, L.I. Shevchenko, V.I. Surinova, S.P. Orlenko, V.M. Makarchuk, S.Y. Proskuriakov

The improvement of the shock state treatment remains an urgent medical problem. So, according to U.S. Census, the development of septic shock in this country is registrated in 750 thousand cases a year, and lethality of these states reaches 215 thousand cases per year [1]. Vasopressive drugs, in addition with transfusion therapy, are important especially in the treatment of vasodilatory types of shock. Contemporary vasopressive therapy include α-adrenomimetics (phenylephrine, norepinephrine, dopamine, epinephrine) and polypeptide drugs that affect on V1-receptors in smooth muscle (vasopressin, oktapressin, angiotenzinamid). The main disadvantages of most of the standard vasopressors are a short duration of action and, often, side effects - secondary hypotension, metabolic acidosis, cardiac arrhythmias, central nervous system stimulation. In addition, in the septic and anaphylactic shock, as well as in the later stages of shock of any cause vasodilation often becomes resistant to standard vasopressor action. An alternative to the above vasopressor agents in the treatment of shock may be drugs on the basis of biogenic nitric oxide (NO) synthesis inhibitors. In our previous studies have shown that some isothiourea, tiazoline and thiazine derivatives are fairly potent inhibitors of NO-synthase (NOS) and exhibit vasopressor effects in experimental models of endotoxic and hemorrhagic shock. We have investigated the NOS-inhibitory activity and vasopressor properties of a new isothiourea derivative - N-propionyl-S-isopropyl-ITU hydrobromide (PIITU). Studies indicate that PIITU is an effective inhibitor of endogenous NO. The NOS-inhibitory activity of a single dose of the compound is maintained in vivo for 2-3 hours. Intact animals injected with PIITU showed a mild vasopressor effect. In the endotoxic shock model PIITU, injected at a dose of 1/20 LD50, stabilized the central haemodynamic parameters of animals due to vasoconstriction and increased peripheral vascular resistance. The observed pharmacological properties give the cause to consider PIITU as a promising basis for drugs with a vasopressor, antishock properties.