RU2453000C1 - Method for placental microcirculation disorder correction in adma-like gestosis model - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves simulating gestosis in Wistar rats by the daily intraperitoneal introduction of L-nitro-arginine-methyl ester 25 mg/kg for 14th to 20th day of pregnancy. Gestosis is corrected by using the daily intragastric introductions of L-norvaline 10 mg/kg once a day with underlying simulation for 7 days.

EFFECT: method provides manifested correction of placental microcirculation disorder ensured by increasing L-arginine availability for NO synthesis.

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Description

The invention relates to medicine, in particular to experimental pharmacology.

Closest to the claimed solution is a method for correcting microcirculation disorders in the placenta in pregnant animals using L-arginine, a substrate for the synthesis of nitric oxide, according to the description of experimental studies in the article: “Pharmacological correction of ADMA-eNOS-associated targets with L-arginine in experimental preeclampsia ”, Kuban Scientific Medical Bulletin, No. 1, 2010, pp. 85-92.

The main disadvantage of this method is that L-arginine is a direct competitor to ADMA, and an increase in its concentration only leads to an increase in the substrate for the formation of NO and activation of NO synthase, which increases the synthesis of NO, the main vasodilating factor. However, another way to increase the synthesis of nitric oxide is to increase the bioavailability of L-arginine. This can be achieved using arginase inhibitors. Therefore, the results of the correction of endothelial dysfunction disorders in an ADMA-like model of pathology in pregnant animals using L-arginine are unsatisfactory.

The objective of the invention is a method for correcting microcirculation disorders in an ADMA-like model of gestosis, including the use of L-norvaline, which belongs to the group of arginase inhibitors.

The objective is achieved by the fact that against the background of modeling gestosis in an experiment, an intraperitoneal injection of pregnant female Wistar rats for 7 days with an ADMA-like blocker of endothelial NO synthase - N-nitro-L-arginine-methyl ether (L-NAME) at a dose of 25 mg / kg microcirculatory disorders are corrected by intragastric administration of L-norvaline at a dose of 10 mg / kg once a day. This leads to a pronounced correction of violations, since the introduction of L-norvaline leads to the blocking of the arginase enzyme, and therefore, to a decrease in the conversion of L-arginine to ornithine and urea. Thus, the introduction of L-norvaline increases the bioavailability of L-arginine for the synthesis of NO, increases the concentration of nitric oxide and reduces microcirculation disorders.

The method is carried out as follows.

The experiments were carried out on white pregnant rats of Wistar females weighing 250-300 g with a gestation period of 14 days. N-nitro-L-arginine methyl ether (L-NAME) is administered intraperitoneally at a dose of 25 mg / kg / day for 7 days (from 14 to 20 days of pregnancy). L-norvaline is administered intragastrically at a dose of 10 mg / kg / day for 7 days. On the 8th day from the start of the experiment (21-22 days of pregnancy), microcirculation in the placenta was measured under anesthesia. The placenta microcirculation was studied using Biopac systems equipment: MP100 polygraph with laser Doppler flowmetry (LDF) LDf100C module and TSD144 sensor. The LDF results were recorded using the Acqknowledge version 3.8.1 program; microcirculation values were expressed in perfusion units (PE).

When statistical data processing is calculated, the average value, the standard deviation. Differences are considered significant at p <0.05.

EXAMPLE OF SPECIFIC IMPLEMENTATION.

Blockade of NO synthase caused by a 7-day administration of L-NAME to pregnant rats led to impaired microcirculation in the placenta, as evidenced by a decrease in its value from 425.90 ± 39.55 PE in intact pregnant animals to 237.50 ± 38.18 PE (p <0.05).

Long-term daily intragastric administration of L-norvaline (10 mg / kg) for 7 days against the background of an ADMA-like model of gestosis in pregnant rats led to a significant increase in the level of microcirculation in the placenta to 455.7 ± 41.5 PE, which is higher than in animals in the group with the introduction of L-NAME (p <0.05).

Thus, the obtained results convincingly indicate a pronounced correction of microcirculation disorders in the placenta under conditions of reproducible ADMA-like gestosis in pregnant rats with L-norvaline.

Claims (1)

A method for correcting microcirculation disorders in the placenta with an ADMA-like model of gestosis, including reproducing gestosis in Wistar rats daily from 14 to 20 days of pregnancy by intraperitoneal administration of L-nitro-arginine-methyl ether at a dose of 25 mg / kg, characterized in that against the background this daily for 7 days is administered intragastrically L-norvaline at a dose of 10 mg / kg once a day.