13 0007-4888/15/1601-00013 © 2015 Springer Science+Business Media New York Methylarginines in Mice with Experimental Atherosclerosis M. A. Gilinsky, R. A. Sukhovershin, and M. S. Cherkanova Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 160, No. 7, pp. 17-20, July, 2015 Original article submitted June 10, 2014 We studied the dynamics of indexes for the system of endogenous regulation of NO bioavail- ability. The content of NO synthase inhibitors (monomethylarginine and asymmetric dimethy- larginine) in the blood of mice was measured after intraperitoneal injections of a nonionic surfactant poloxamer 407 for 2 and 14 weeks. The concentrations of both methylarginines in animals with atherosclerosis due to 14-week administration of poloxamer were much higher than in control specimens. The amount of arginine and symmetric dimethylarginine practically did not differ from the control. Poloxamer-induced model of atherosclerosis is characterized by increased content of NO synthase inhibitors. These changes contribute to the development of endothelial dysfunction and atherosclerosis. Key Words: monomethylarginine; asymmetric dimethylarginine; poloxamer 407; athero- sclerosis Research Institute of Physiology and Fundamental Medicine, Sibe- rian Division of the Russian Academy of Medical Sciences, Novosi- birsk, Russia. Address for correspondence: m.a.gilinsky@physiol. ru. M. A. Gilinsky A large body of evidence obtained by the end of the last century indicates that changes in NO metabolism triggers the following chain of events: decrease in NO bioavailability–endothelial dysfunction–atherosclero- sis [5-7]. Increased concentration of endogenous NO synthase inhibitors (monomethylarginine, MMA, and, particularly, asymmetric dimethylarginine, aDMA) is a factor contributing to the development of athero- sclerosis. aDMA levels correlates with the following direct signs of atherosclerosis: thickening of the arte- rial intima, growth of atherosclerotic plaques, and pro- liferation of smooth muscle cells. It was hypothesized that L-arginine administration can compensate for the negative effects of aDMA [4,7]. This work was designed to evaluate the involve- ment of L-arginine and methylarginines in the devel- opment of atherosclerosis on a relatively simple and stable model of this disorder. Our experiments were performed a previously described model [8-10] based on the use of a nonionic surfactant poloxamer 407 (P-407) [8]. Long-lasting studies have demonstrated that many physiological and biochemical processes typical of atherosclerosis occur on the model of P- 407-induced dyslipidemia and atherosclerosis in mice. It concerns inactivation of endothelial lipase, hepatic lipase, and lipoproteins. No activation of PPAR-α and PPAR-γ is accompanied by a decrease in the content of plasma HDL cholesterol (in vitro and in vivo). The concentration of soluble cell adhesion molecules increases, and atherosclerotic injury to the aorta is formed after intraperitoneal injections of P-407 (0.5 g/ kg with 3-day intervals) for 12-16 weeks. These data confirm reliability of this model [9]. However, activ- ity of a NO-regulating system under these conditions remains unknown. We measured the contents of L-arginine and its methylated derivatives in the dynamics of atheroscle- rosis development due to against the background of repeated intraperitoneal injections of P-407. MATERIALS AND METHODS Experiments were performed on 6 groups of male CBA mice obtained from the vivarium of the Re- search Institute of Physiology and Fundamental Med- icine. Our study was conducted in accordance with the principles of humanity (Rules of Studies with Experimental Animals). Long-term experiment was performed on 2 groups of mice. P-407 in a dose of Bulletin of Experimental Biology and Medicine, Vol. 160, No. 1, November, 2015 PHYSIOLOGY DOI 10.1007/s10517-015-3086-3