RU2721291C1 - Method of correcting thrombosis by nicorandil in an adma-like model of preeclampsia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental pharmacology, and can be used for correction of thrombosis in ADMA-like model of preeclampsia. That is ensured by reproducing a model of experimental ADMA-like preeclampsia in Wistar rats. Thrombosis is corrected by oral administration of Nicorandil at dose of 10 mg/kg twice day from 14th to 20th day of pregnancy.

EFFECT: method provides marked thrombosis correction in a simulated pathology manifested by increased time of thrombosis.

1 cl, 1 tbl, 1 ex

Description

The invention relates to medicine, in particular to experimental pharmacology and can be used to correct hemostasis in pregnant women.

One of the serious complications of preeclampsia is the syndrome of disseminated intravascular coagulation (DIC). It develops as a result of disorders arising in the hemostatic system, or rather its displacement to the prothrombogenic side (Vucić N, Frleta M, Petrović D, Ostojić V. Thrombophilia, preeclampsia and other pregnancy complications. Acta Medica Croatica. 2009; 63: 4: 297— 305). Therefore, the search for new ways to correct thrombus formation during preeclampsia is an urgent task of modern medicine.

One of the correction options is a method for correcting thrombus formation in pregnant animals using GABA derivatives - compounds RGPU-151, RGPU-152 and phenibut (Karamysheva V.I. Influence of GABA derivatives on blood supply to the uteroplacental complex under normal and experimental gestosis: abstract. Candidate of Medical Sciences, Volgograd, 2014).

The disadvantage of this method is that the derivatives of GABA do not have an activating effect on ATP-dependent (K ⁺ _ATP ) channels. Activation of these channels has an anti-ischemic effect and reduces ischemic events in the placenta. According to modern concepts of the pathogenesis of preeclampsia, placental ischemia is one of its main pathogenetic links (Ahmed A, Dunk C, Ahmad S, Khaliq A. Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen – a review. Placenta (2000) 21 ([Suppl A]): S16 – S24).

In view of the foregoing, the object of the invention is to provide a more effective method for correcting thrombosis in an ADMA-like model of preeclampsia, including the use of nicorandil, which is an activator of K ⁺ _AFT channels (Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure / Tanaka K , Kato K, Takano T, Katagiri T, Asanoi H, Nejima J, Nakashima M, Kamijo T, Sakanashi M. // Journal of Cardiology. 2010.56 (3). 291–299. Doi.org/10.1016/j. jjcc.2010.06.009). Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure / Tanaka K, Kato K, Takano T, Katagiri T, Asanoi H, Neji].

The task is achieved by the fact that, against the background of simulating preeclampsia in an experiment, intraperitoneally administering to pregnant female Wistar rats for 7 days (from 14 to 20 days of pregnancy) an ADMA-like blocker of endothelial NO synthase - N-nitro-L-arginine-methyl ester ( L-NAME) at a dose of 25 mg / kg, oral administration of nicorandil is carried out twice a day at a dosage of 10 mg / kg from the 14th to the 20th day of pregnancy. This leads to a pronounced correction of thrombosis in the simulated pathology.

The method is carried out as follows.

The experiment was performed on white Wistar female rats weighing 250-300 g. An ADMA-like agent, a non-selective blocker of NO synthase, N-nitro-L-arginine-methyl ether (L-NAME) was administered intraperitoneally at a dose of 25 mg / kg / day within seven days (14-20th day of pregnancy). The introduction of nicorandil was carried out twice daily orally at a dosage of 10 mg / kg from 14 to 20 days of pregnancy.

Thrombus formation was caused on day 21 by application of a 50% solution of iron (III) chloride, for which a portion of the isolated carotid artery was isolated from surrounding tissues, a cotton pad moistened with 50% solution of iron chloride (0.025 ml) was placed on it. Blood flow was recorded above the place of application using a Doppler scanner (Minimax - Doppler-K, St. Petersburg). The time of thrombus formation from the moment of application of the iron (III) chloride solution to the complete cessation of blood flow in the carotid artery was noted [Kurz, K.D. Rat model of arterial thrombosis induced by ferric chlo-ride / K.D. Kurz, B.W. Main, G.E. Sandusky // Thromb. Res. - 1990. - V.15. - P. 269 - 280].

The results are statistically processed by calculating the arithmetic mean (M) and standard error of the mean (± m). Assessment of the statistical significance of differences in intergroup comparisons is made according to the two-tailed student t-test for independent groups. Differences are considered statistically significant at p values <0.05.

EXAMPLE OF SPECIFIC IMPLEMENTATION.

Modeling of ADMA-like pre-eclampsia led to a statistically significant (p <0.05) shortening of the time until blood flow in the carotid artery stopped after application of FeCl3 from 1189 ± 18 sec to 841 ± 42 sec (Table 1). In the group of animals with experimental preeclampsia, with the introduction of nicorandil, the coagulation time increased to 1034 ± 26 sec, which is statistically different from the L-NAME group (“untreated” animals).

The effect of nicorandil on the formation of a thrombus in the carotid artery with ADMA-like preeclampsia is shown in Table 1.

Table 1

Index
Group Thrombosis time,
sec Intact Pregnant 1189 ± 18 L-NAME ("untreated" animals) 841 ± 42 ^y L-NAME + Nicorandil (2 * 10mg / kg / day) 1034 ± 26 * ^y

Note: * - p <0.05 - in comparison with L-NAME; ^y - p <0.05 - in comparison with intact ones.

Thus, a pronounced correction of thrombosis by oral administration of nicorandil in a dosage of 10 mg / kg twice a day from 14 to 20 days of pregnancy was revealed, which manifests itself in an increase in thrombosis time compared to the control group (L-NAME) in the experiment.

Claims (2)

A method for correcting thrombosis in an ADMA-like model pre-eclampsia, including the reproduction of a model of experimental pre-eclampsia in Wistar rats, characterized in that nicorandil is administered orally through a probe at a dosage of 10 mg / kg twice daily from 14 to 20 days of pregnancy to correct thrombosis.