RU2353369C1 - Josamycin therapy for endothelium dysfunction correction associated with l-name-induced nitrogen oxide deficiency - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine, particularly to experimental cardiopharmacology and can be used for endothelium dysfunction correction. For this purpose dysfunction is modelled by intraperitoneal introduction of L-nitro-arginine-methyl ester dosed 25 mg/kg daily during 7 days to rats. This therapy is combined with endogastric introduction of macrolide agent Josamycin dosed 10 and 30 mg/kg singly a day.

EFFECT: method provides correction in any antioxidant profile.

1 ex, 1 tbl

Description

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

The prototype of the claimed solution is P No. 2226101 "Method for limiting the necrosis zone when modeling coronary occlusion myocardial infarction in animals with a reduced antioxidant background."

The main disadvantage of this method is that azithromycin only works with a low antioxidant background of the body. To eliminate this drawback, the macrolide antibiotic josamycin was used at a concentration of 30 mg / kg, which acts with any antioxidant background of the body,

In the correction of endothelial dysfunction, drugs with antioxidant activity are considered promising, since the main mechanism underlying endothelial dysfunction is a decrease in the production and bioavailability of nitric oxide (NO) while increasing the level of superoxide anion due to an increase in the oxidative activity of NADP (Markov H.M. Oxidative stress and endothelial dysfunction // Patol. Physiology and experimental therapy. 2005. No. 4. P.5-9).

The technical result of the invention is a method for correcting endothelial dysfunction, including the use of a macrolide antibiotic josamycin in a small dose of 10 mg / kg and in a larger dose of 30 mg / kg.

The technical result is achieved by the fact that, against the background of modeling endothelial dysfunction in an experiment, an intraperitoneal injection of a blocker of NO synthesis of L-nitro-arginine methyl ether (L-NAME) at a dose of 25 mg / kg is carried out intraperitoneally for 7 days, and it is corrected by intragastric administration with antioxidant the action of josamycin macrolide in doses of 10 and 30 mg / kg once a day, which leads to activation of the correction of endothelial dysfunction.

The method is carried out as follows.

The experiments were carried out on white rats male Wistar line weighing 180-220 g. N-nitro-L-arginine methyl ether (L-NAME) was administered intraperitoneally at a dose of 25 mg / kg / day. Josamycin in one study group is administered daily intragastrically once a day in a small dose of 10 mg / kg, and in the other group in a larger dose - 30 mg / kg. On the 8th day from the start of the experiment, under anesthesia (ethinal sodium 50 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 Bioshell 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.

EXAMPLE OF SPECIFIC PERFORMANCE

Assessment of the state of vascular wall reactivity was carried out after functional vascular tests were performed using the calculated indicator - endothelial dysfunction coefficient (QED) according to the technique developed in our laboratory P No. 2301015.

We calculated a special indicator characterizing the degree of endothelial dysfunction, which is the ratio of the area of the triangle over the trend of the reaction of blood pressure recovery in response to the introduction of NP to the area of the triangle over the trend of the reaction of blood pressure recovery in response to the introduction of AH in each animal in the intact group and rats after modeling the blockade of NO synthase and received a 5-fold difference in this indicator — 1.1 in intact and 5.4 in animals treated with L-NAME, respectively.

Thus, to assess the effect of AH and NP in ESV and ENZV, we used this ratio as an indicator of the correction of endothelial dysfunction. In the group where, against the background of the administration of the NO synthase inhibitor L-NAME, josamycin was administered, this ratio corresponded to a value of 1.4 ± 0.3 at a dose of 10 mg / kg and 0.9 ± 0.2 at a dose of 30 mg / kg (table one).

Table 1.
Indicators reflecting the correction of endothelial dysfunction on the background of the introduction of L-NAME with josamycin at a dose of 10 and 30 mg / kg 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 ± 2.4 1268.0 ± 74.8 1.1 ± 0.1 NP 61.0 ± 3.0 45.1 ± 3.0 1375.3 ± 93.7 L-NAME 25 mg / kg OH 68.0 ± 4.1 20.0 ± 4.5 * 695.3 ± 87.6 * 5.4 ± 0.6 * NP 98.0 ± 2.0 * 67.4 ± 4.6 * 3322.7 ± 116.7 * L-NAME + Josamycin 10 mg / kg OH 89.5 ± 6.3 ** 47.8 ± 3.7 ** 2143.2 ± 227.3 ** 1.4 ± 0.3 ** NP 83.0 ± 8.0 * 67.0 ± 3.9 * 2862.9 ± 384.3 * L-NAME + Josamycin 30 mg / kg OH 96.3 ± 7.4 * 69.5 ± 7.5 ** 3473.5 ± 584.8 ** 0.9 ± 0.2 ** NP 58.0 ± 3.0 ** 85.1 ± 7.1 * 2461.5 ± 237.4 * Note: * - p <0.05 - in comparison with intact, ** - p <0.05 - in comparison with L-NAME

Thus, the results obtained allow us to ascertain the activation of correction of endothelial dysfunction with josamycin in small and large doses.

Claims (1)

A method for correcting endothelial dysfunction, characterized in that the experiment simulates dysfunction daily for 7 days. intraperitoneal administration of L-nitro-arginine methyl ester to rats at a dose of 25 mg / kg, and against this background, the macrolide preparation josamycin was administered intragastrically at doses of 10 and 30 mg / kg once a day.