CARDIOVASCULAR EFFECTS OF AN ARGINASE II SELECTIVE INHIBITOR

For the first time in vitro experiments there were studied the inhibitory activity and safety of potential molecules arginase II selective inhibitors from the group of norleucine derivatives. Also first the substance under the code ZB49-0010C from the group of norleucine derivatives showed the greatest selectivity and inhibitory activity against arginase II in experiments in vitro. However, this substance in vivo exerts dose-dependent hypotensive action and cardioprotective and endothelial protective effects on the L-NAME induced and homocysteine-induced endothelial dysfunction (ED), which are most pronounced at a dose of 10 mg/kg in intragastric administration. Endothelial protective effect consists of in preventing the increase of coefficient of endothelial dysfunction (CED) and the decrease in the concentration of stable metabolites of nitric oxide in the blood plasma. Cardioprotective effect consists of in preventing the increase of the level of left ventricular pressure during the test for adrenoreactivity and reducing of the cardiac reserve during the overload resistance test, and also in preventing the development of the left ventricular hypertrophy. As part of the study there was investigated the dose-dependent anti-ischemic effect of the arginase II selective inhibitor, substance ZB49-0010C on the chronic limb ischemia in rats, which most pronounced at a dose of 10 mg/kg and consists of in preventing the fall in microcirculatory level on the 29th day of the experiment in the ischemic limb and a protective effect based on the morphological examination of the muscle tissue.

Иллюстрации

Table 1.  Chemical structure of the investigated substances.

Figure 1. Concentration dependence of the inhibitory effect of the substance ZB49-0010С and control substance ABH in relation to the arginase II.

Table 2.  Specific activity of ZB49-0010С in relation to the arginase II, obtained in two independent experiments.

Table 3. The results of the binding potential molecules arginase II selective inhibitors hERG channel in the composition of the membrane fractions using a test system Invitrogen® PredictorTM hERG.

Figure 2A. The dynamic of dose-dependent effect of the ZB49-0010C on the systolic blood pressure  in rats without anesthesia in the acute pharmacological experiment.

Figure 2B. The dynamic of dose-dependent effect of the ZB49-0010C on the  diastolic blood pressure in rats without anesthesia in the acute pharmacological experiment.

 

Figure 2C. The dynamic of dose-dependent effect of the ZB49-0010C on the heart rate in rats without anesthesia in the acute pharmacological experiment.

Figure 3A. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline arterial pressure in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

Figure 3B. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline CED  in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

Figure 3C. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline Total NO  in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

Figure 3D. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline adrenoreactivity in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

Figure 3E. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on  baseline cardiac reserve  in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

Figure 3F. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline the diameter of cardiomyocytes in rats with anesthesia on the back of L-NAME-induced ED.

Comment: * - p<0.05 in comparison with group of intact animals; ** - p<0.05 in comparison with the group of animals with L-NAME-induced ED.

 

Figure 4 A. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline CED  in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

 

Figure 4 B. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline  Total NO in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

 

Figure 4 C. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline  adrenoreactivity in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

 

Figure 4 D. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline adrenoreactivity  in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

 

Figure 4 E Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline  cardiac reserve in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

 

Figure 4 F. Dose-dependent effects of the ZB49-0010C compared with L-Norvaline on baseline the diameter of cardiomyocytes in rats with anesthesia on the back of homocysteine-induced ED.

Comment: * - p<0.05 in comparison with group of Tween; ** - p<0.05 in comparison with the group of animals with homocysteine-induced ED.

Table 4. The results of the evaluation of the microcirculation level in the tibiotarsus muscles and the concentration of stable metabolites of NO (Total NO) in the blood plasma of rats on day 29. (M±m), PU (perfusion units)

Figure 5A. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 5B. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 5C. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 5D. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 5E. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 5F. Photomicrography 200 х: Morphological examination of the tibiotarsus muscles of rats, 29 days of the experiment. A – group of intact animals; B - group with simulated limb ischemia; C – group with simulated limb ischemia + L-NAME; D - group with simulated limb ischemia + L-NAME + ZB49-0010C 1 mg/kg; E - group with simulated limb ischemia + L-NAME + ZB49-0010C 5 mg/kg; F - group with simulated limb ischemia + L-NAME + ZB49-0010C 10 mg/kg. Hematoxylin and eosin stain.

Figure 6. The pathogenesis of endothelial dysfunction and the application points of the action potential endothelial protective agents (L. Santhanam, D. W. Christianson, et al., 2008).

DOI: DOI: 10.18413/2500-235X -2016-2-3-28-45
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