RU2433486C1 - Method of correcting endothelial dysfunction by medication "etoxydol" in case of l-name induced nitrogen oxide deficiency - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in order to correct endothelial dysfunction white male rats of Wistar line have endothelial dysfunctions modelled by intro-peritoneum introduction of N-nitro-L-arginine methyl ether in dose 25 mg/kg daily, for seven days. Degree of dysfunction development is estimated by ratio of indices of endothelium-independent and endothelium-dependent vasodilation. Correction of endothelial dysfunction is carried out by intra-peritoneum introduction of medicine "Etoxydol" in dose 25 mg/kg one time per day, for 7 days in the morning.

EFFECT: correction of endothelial dysfunction by novel derivative of 3-oxypyridine in specially developed for this purpose dose and mode of medication introduction.

2 tbl, 1 ex

Description

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

Closest to the claimed solution is a method for the correction of endothelial dysfunction using the drug "Mexidol" described by Pokrovsky M.V. and co-authors in the article “Study of the endothelial protective and coronary action of 3-hydroxypyridine derivatives” published in the journal Kuban Scientific Medical Bulletin No. 4 (109), pp. 104-109. This article describes the endothelioprotective effects of a derivative of 3-hydroxypyridine - mexidol with L-NAME-induced nitric oxide deficiency.

However, this method does not cover the assessment of the endothelioprotective effects of a new derivative of 3-hydroxypyridine - the drug "Ethoxidol" (VSC BAS, Moscow Region, Staraya Kupavna).

The objective of the invention is a method for the correction of endothelial dysfunction with L-NAME-induced deficiency of nitric oxide, including intraperitoneal administration of a substance of a new derivative of oxypyridine ethoxidol at a dose of 25 mg / kg

This object is achieved by the fact that against the background of modeling endothelial dysfunction by intraperitoneal administration to a laboratory animal of a blocker of NO synthase N-nitro-L-arginine methyl ester (L-NAME) at a dose of 25 mg / kg daily, for 7 days, it is corrected by intraperitoneal administration of the drug "Ethoxidol" at a dose of 25 mg / kg for 7 days.

The method is as follows.

The experiments were carried out on white rats male Wistar line weighing 180-200 g. N-nitro-L-arginine methyl ether (L-NAME) was administered intraperitoneally daily at a dose of 25 mg / kg / day for 7 days. Ethoxidol (VNC BAV Moscow Region, Staraya Kupavna, Russia) was administered intraperitoneally at a dose of 25 mg / kg for 7 days in the morning. On the 7th day from the start of the experiment, under anesthesia (chloral hydrate 300 mg / kg), a catheter is inserted into the left carotid artery to record blood pressure (BP), bolus administration of pharmacological agents is carried out in the right femoral vein. Hemodynamic parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) are measured continuously using the sensor and the Biopac computer program. Functional tests: endothelium dependent vasodilation (ESV) - intravenous administration of acetylcholine (AH) at a dose of 40 μg / kg, endothelium independent vasodilation (ENZV) - intravenous administration of sodium nitroprusside (NP) at a dose of 30 μg / kg.

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

Concrete example

A bolus intravenous administration of AH for 3-5 seconds led to a sharp drop in blood pressure, reaching a peak in intact animals for systolic pressure (SBP) of 84.3 ± 4.4, for diastolic pressure (DBP) - 38.7 ± 2.8 and for average arterial pressure (SRAD) 53.9 ± 2.7 mm Hg, while during the first 2-3 seconds a sharp bradycardia developed up to 130-150 beats per minute. Recovery of blood pressure occurred on average for 42.2 ± 0.8 seconds after normalization of the heart rhythm. ENZV was also characterized by a decrease in SBP to 83.0 ± 3.7, DBP to 42.1 ± 4.4 and SRAD to 55.7 ± 3.5 mm Hg. followed by complete recovery on average within 45.1 ± 1.0 sec. Blockade of NO synthase with the help of a long, daily, intraperitoneal injection of L-NAME (N-nitro-L-arginine methyl ester at a dose of 25 mg / kg) for 7 days caused arterial hypertension (SBP - 190.3 ± 6.7, DBP - 145.0 ± 3.9, SAD - 160.1 ± 4.6 mm Hg) and led to a smaller decrease in blood pressure after administration of AH (SBP to 110.6 ± 5.2, DBP to 82, 8 ± 6.6, CAP up to 92.1 ± 6.1 mm Hg) and NP (CAP up to 88.7 ± 4.7, DBP up to 50.8 ± 4.2 and CAP up to 63.4 ± 4.1 mmHg) compared with intact animals.

The simultaneous administration of L-NAME and ethoxidol led to an optimal decrease in the initial BP values, since the initial BP numbers were lower: SBP - 156.5 ± 8.6, DBP - 114.7 ± 12.2 mm Hg. Potentiation of a decrease in blood pressure indicators in response to the administration of AX was also noted (table 1).

Table 1 Dynamics of blood pressure and heart rate in modeling nitric oxide deficiency and correction of endothelial dysfunction with ethoxide. Groups of animals Functional Tests GARDEN, mmHg DBP, mmHg Heart rate, beats in min Intact Source 137.7 ± 3.7 101.9 ± 4.3 420.0 ± 9.0 EZV with AH 84.3 ± 4.5 38.7 ± 2.8 416.0 ± 14.0 ENZV with NP 83.0 ± 3.7 42.1 ± 4.4 415.0 ± 10.0 Receiving L-NAME (25 mg / kg) Source 190.3 ± 6.7 * 145.0 ± 3.9 * 428.0 ± 11 EZV with AH 110.6 ± 5.2 * 82.8 ± 6.6 * 426.0 ± 14.0 ENZV with NP 88.7 ± 4.7 50.8 ± 4.2 426.0 ± 13.0 L-NAME (25 mg / kg) + ethoxidol (25 mg / kg) Source 156.5 ± 8.6 ** 114.7 ± 12.2 ** 350.0 ± 16.2 EZV with AH 94.0 ± 6.4 * * 55.0 ± 4.9 ** 322.0 ± 12.8 ENZV with NP 103.8 ± 6.7 51.8 ± 4.8 355.9 ± 14.9 * - p <0.05 compared with the group of intact animals ** - p <0.05 compared with the group of animals treated with L-NAME

The fundamental difference in ESV and ENZV in intact animals and animals with the introduction of an inhibitor of NO synthase L-NAME naturally led us to the necessity of deriving a special indicator characterizing the degree of endothelial dysfunction, which is the ratio of the area of the triangle over the trend in the reaction of restoration of blood pressure in response to the introduction of NP to the area triangle above the trend of the reaction of restoration of blood pressure in response to the introduction of AH.

We calculated this ratio for each animal in the intact group and rats after modeling the blockade of NO synthase and obtained a difference of this indicator by a factor of 5 — 1.1 in intact animals and 5.4 in animals treated with L-NAME, respectively.

Thus, for a further assessment of the effect of AH and NP in ESV and ENZV, we used this ratio as an indicator of the correction of endothelial dysfunction. So, in the group where ethoxidol was introduced against the background of the administration of the NO synthase inhibitor L-NAME, this ratio corresponded to a value of 2.3 ± 0.2 (table 2).

table 2 Indicators reflecting the correction of endothelial dysfunction with the introduction of L-NAME ethoxidol. Groups of animals Functional Tests The increase in the fall of the vascular reaction by SRAD (mm Hg) Vascular reaction time (sec) The area of the vascular reaction (conventional units) The ratio of the areas of the vascular reaction of AH to NP Intact OH 59.9 ± 2.9 42.2 ± 0.8 1268.0 ± 74.8 NP 61.0 ± 3.0 45.1 ± 1.0 1375.3 ± 93.7 1.1 ± 0.1 L-NAME OH 68.0 ± 4.1 20.0 ± 1.4 695.3 ± 87.6 * NP 98.0 ± 2.0 67.4 ± 1.4 3322.7 ± 116.7 * 5.4 ± 0.6 * L-NAME + Ethoxidol 25 mg / kg OH 68.0 ± 4.9 49.2 ± 4.3 ** 1560.8 ± 330.1 ** 2.3 ± 0.2 ** NP 69.2 ± 4.1 93.5 ± 8.1 ** 3363.9 ± 454.1 ** * - p <0.05 compared with the group of intact animals ** - p <0.05 compared with the group of animals treated with L-NAME

Thus, the results obtained allow us to ascertain the correction of endothelial dysfunction with the drug "Ethoxidol" against the background of the introduction of L-NAME.

Claims (1)

A method for the correction of endothelial dysfunction, characterized in that in an experiment for white rats, males of the Wistar strain with endothelial dysfunction modeled by intraperitoneal administration of an inhibitor of endothelial NO synthase N-nitro-L-arginine methyl ester at a dose of 25 mg / kg daily for 7 days, evaluating the degree of development of dysfunction in relation to the indices of endothelium-independent and endothelium-dependent vasodilation, ethoxidol is administered intraperitoneally at a dose of 25 mg / kg once a day, for 7 days, in the morning.