RU2449381C1 - Method of correcting endothelial dysfunction by l-norvalin in case of adma-like model of gestosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: modeling of ADMA-like model of gestosis in laboratory pregnant rats of Wistar line is carried out by daily introduction of inhibitor of NO-synthase L-NAME in dose 25 mg/kg from 14 to 20 day of pregnancy. Correction of endothelial dysfunction is performed by L-norvalin, which at the background of modeling is introduced intragastrically daily for 7 days in dose 10 mg/kg once per day.

EFFECT: method leads to expressed dysfunction correction under conditions of specific mechanisms of pathological process course in pregnant women.

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Description

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

Closest to the claimed solution is a method of correcting endothelial dysfunction 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 L-arginine" ADMA-eNOS-associated targets "in experimental pre-eclampsia", Kuban Scientific Medical Journal, 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. 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 technical result of the invention is a method for the correction of endothelial dysfunction in an ADMA-like model of gestosis, including the use of L-norvaline, which belongs to the group of arginase inhibitors.

The technical result is achieved by the fact that against the background of gestosis simulation 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 endothelial dysfunction is 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 N0, increases the concentration of nitric oxide and reduces endothelial dysfunction.

The method is as follows.

The experiments were carried out on white pregnant female Wistar rats weighing 250-300 g with a gestational age 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, under anesthesia (chloral hydrate 300 mg / kg), a catheter is inserted into the right carotid artery to record blood pressure (BP), bolus administration of pharmacological agents is carried out in the right femoral vein. Vascular tests for endothelium-dependent vasodilation (ESV) are performed - intravenous administration of acetylcholine (AH) at a dose of 40 μg / kg, and endothelium-independent vasodilation (ENZV) - intravenous administration of sodium nitroprusside (NP) at a dose of 30 μg / kg with a calculated ) - Patent No. 2301015 of June 20, 2007 (Bull. No. 17).

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

Concrete example

The blockade of NO synthase caused by the 7-day administration of L-NAME to pregnant rats disrupted the relationship between vasodilating and vasoconstrictor mechanisms for regulating vascular tone, as evidenced by the results of vascular tests for endothelium-dependent relaxation (acetylcholine) and endothelium-independent (increase) sodium nitrossruss 1.28 ± 0.23 in intact pregnant animals up to 3.06 ± 0.32 * (p <0.05). Prolonged, for 7 days, daily intragastric administration of L-norvaline (10 mg / kg) against the background of an ADMA-like model of gestosis in pregnant rats led to a significant decrease in QED to 1.50 ± 0.1, which is two times less than in the group of animals with the introduction of L-NAME (p <0.05).

Thus, the obtained results convincingly indicate a pronounced correction of endothelial dysfunction in the conditions of the reproduced ADMA-like model of gestosis in pregnant rats with L-norvaline.

Claims (1)

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