RU2500425C2 - Method for endothelial dysfunction correction by solution of homoeopathic dilutions of human endothelial nitrogen oxide synthase antibodies in complex with solution of homoeopathic dilutions of angiotensin ii receptor c-terminal fragment antibodies - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental cardiology, and concerns the L-NAME-induced endothelial dysfunction correction. That is ensured by introducing the mixture of solutions of homoeopathic dilutions of rabbit monoclonal antibodies to human endothelial nitrogen oxide synthase C12, C30, C200 (9 ml/kg/day) in complex with the mixture of solutions of homoeopathic dilutions of angiotensin II receptor C-terminal fragment antibodies C12, C30, C200 in a dose of 9 ml/kg/day.

EFFECT: method provides the effective endothelial dysfunction correction in the specific experimental environment.

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Description

The invention relates to medicine, in particular to experimental cardiopharmacology, and can be used to correct L-Name-induced endothelial dysfunction.

The prior art method for the correction of endothelial dysfunction with a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase of human nitric oxide - C12, C30, C200, described in RF patent No. 2306953 C1 (A61K 39/395, 09/27/2007).

The disadvantage of this method is that the main mechanism of action of a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase of nitric oxide - C12, C30, C200 is an increase in the number of eNOS, which limits its effectiveness.

The objective of the invention is to increase the efficiency of correction of endothelial dysfunction with a mixture both by increasing the number of eNOS, and by eliminating the effects of angiotensin II.

The solution of this problem is ensured by the fact that against the background of modeling L-name-induced endothelial dysfunction in the experiment, intraperitoneal administration to the laboratory animal for 28 days of NO synthesis blocker of L-nitro-arginine methyl ether (L-NAME) at a dose of 12.5 mg / kg / day., its correction is carried out by introducing a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase of human nitric oxide - C12, C30, C200 (intragastrically, 2 times a day at 4.5 ml / kg (9 ml / kg / day. )) in combination with a mixture of solutions of g homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor -C12, C30, C200, intragastrically, 2 times a day at 4.5 ml / kg (9 ml / kg / day).

The use in the claimed method of a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase of nitric oxide - C12, C30, C200 in combination with a mixture of solutions of homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor - C12, C30, C200 leads not only to an increase in the number eNOS but also to the blockade of angiotensin receptors-1 type and eliminate such effects of angiotensin II as: the conversion of nitric oxide into peroxynitrate, stimulation of endothelin synthesis, stimulation of cytokine production and thereby initiating inflammation in the vascular wall, hyperactivation of the renin-angiotensin aldosterone system (RAAS), leading to the formation of endothelial dysfunction.

The claimed method can be carried out as follows.

The experiments were carried out on white rats male Wistar line weighing 250-300 g. N-nitro-L-arginine methyl ether (L-NAME) was administered intraperitoneally at a dose of 12.5 mg / kg / day. On the 29th day from the start of the experiment, under anesthesia (thiopental 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 TSD104A sensor and MP100 hardware and software complex, manufactured by Biopac System, Inc., USA. 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.

The degree of development of endothelial dysfunction is estimated using the coefficient of endothelial dysfunction (QED), which is the ratio of the area of the triangle over the trend of the reaction of restoration of blood pressure (BP) in response to the introduction of nitroprusside (NP), while the points of the lower leg are the maximum drop in blood pressure and the exit point of the level AD on a plateau with the introduction of a functional test with the introduction of NP, to the area of the triangle above the trend of the reaction of restoration of blood pressure in response to the introduction of acetylcholine (AX), moreover, for the smaller of the cathetus s take the difference between the end point of the cardiac component and the point of restoration of blood pressure during the introduction of a functional test with the introduction of AX, and the large legs in these triangles are indicators of the recovery time of the vascular reaction to the introduction of AX and NP, expressed in seconds; the area of the calculated triangles is expressed in arbitrary units (see, for example, the well-known methodology described in patent RU 2301015).

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

Processing of the obtained experimental data during functional tests for endothelium-dependent (acetylcholine 40 μg / kg iv) and endothelium-independent (nitroprusside 30 mg / kg iv) vascular relaxation in experimental animals made it possible to establish that intraperitoneal administration of L-Name at a dose of 12 , 5 mg / kg for 28 days causes an increase in the coefficient of endothelial dysfunction to 3.5 ± 0.5 srvc. units (Table 1), whereas in the control group of animals (intragastric administration of distilled water, at a dose of 9 ml / kg / day), it amounted to 1.2 ± 0.1 srvc. units

In the group of animals, where, against the background of the administration of L-NAME at a dose of 12.5 mg / kg, a mixture of solutions of homeopathic dilution of polyclonal rabbit antibodies to human nitric oxide endothelial synthase was administered intragastrically for 28 days, at a dose of 9 ml / kg - C12, C30 , C200 QED amounted to - 1.8 ± 0.1 srvc. units

Table 1 Dynamics of blood pressure and endothelial dysfunction coefficient in modeling L-Name-induced endothelial dysfunction and its correction with a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to human endothelial synthase nitric oxide, at a dose of 9 ml / kg - C12, C30, C200 in combination with a mixture of solutions homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor - C12, C30, C200 at a dose of 9 ml / kg / day Groups of animals Functional
naya test GARDEN, mmHg DBP, mmHg S of the vascular reaction during ESVD with AH and ENVD with NP, conventional units QED, conv. units Control (daily, intragastric administration of distilled water 9 ml / kg / day) Source 159.2 ± 5.4 124.2 ± 4.7 1.2 ± 0.1 OH 96.9 ± 6.7 52.0 ± 3.0 3071.2 ± 501.1 NP 113.8 ± 6.1 55 ± 2.4 3617.2 ± 560.1 Receiving L-NAME (12.5 mg / kg) Source 204.8 ± 10 * 164.2 ± 5.9 * 3.5 ± 0.5 * OH 111.3 ± 7.4 64.7 ± 4.3 * 3700.2 ± 536.9 NP 118.2 ± 9.9 61.4 + 4.4 11922.8 ± 1838.9 * L-NAME (12.5 mg / kg) + a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to human endothelial NOS - C12, C30, C200 (9 ml / kg / day) Source 230.1 ± 8.8 * 175.1 ± 6.4 * 1.8 ± 0.2 ** OH 116.4 ± 4.0 * 73.5 ± 3.5 * 5826.0 ± 801.2 ** NP 108.1 ± 4.6 60 ± 3.6 9628.5 ± 970.1 * L-NAME (12.5 mg / kg) + a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to human endothelial NOS - C12, C30, C200 (9 ml / kg / day) + a mixture of solutions of homeopathic dilutions of antibodies to the c-terminal fragment of the angiotensin receptor II-C12, C30, C200 (9 ml / kg / day) Source 213.6 ± 4.6 * 166.8 ± 2.7 * 1.4 ± 0.1 ** OH 116.9 ± 5.5 * 73.3 ± 3.4 * 3295.3 ± 201.4 NP 122.3 ± 4.6 70.5 ± 4.5 * 4546.2 ± 299.4 ** Note: * - p <0.05 in comparison with the control group; ** - p <0.05 compared with the L-NAME group. GARDEN - systolic blood pressure, DBP - diastolic blood pressure, S - area above the curve for restoration of blood pressure during pharmacological tests, QED - coefficient of endothelial dysfunction.

In the group of animals, where against the background of the introduction of L-Name at a dose of 12.5 mg / kg, a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase of human nitric oxide, at a dose of 9 ml / kg, C12, C30 was intragastrically administered for 28 days , C200 in combination with a mixture of solutions of homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor - C12, C30, C200 QED - 1.4 ± 0.1, which is significantly lower than in the group with pathology modeling and in the group with mono correction with a mixture of solutions of homeopathic dilutions polyclone rabbit antibodies to endothelial synthase of human nitric oxide, at a dose of 9 ml / kg - C12, C30, C200.

Thus, the obtained results allow us to state the correction of L-Name-induced endothelial with the introduction of L-Name at a dose of 12.5 mg / kg for 28 days with a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to human endothelial synthase nitric oxide, at a dose of 9 ml / kg - C12, C30, C200 in combination with a mixture of solutions of homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor - C12, C30, C200, with intragastric administration at a dose of 9 ml / kg of each of them, reducing QED to that level in control group of animals - 1.2 ± 0.1 srvc.

Claims (1)

A method for correcting endothelial dysfunction with a solution of homeopathic dilutions of antibodies to human nitric oxide endothelial synthase in combination with a solution of homeopathic dilutions of antibodies to the C-terminal fragment of angiotensin II receptor, characterized in that in the experiment the male rats of the Wistar strain for 28 days, against the background of intraperitoneal administration L-Name at a dose of 12.5 mg / kg, daily, 2 times a day, 4.5 ml / kg (9 ml / kg / day), a mixture of homeopathic dilutions of polyclonal rabbit anti-endothelial antibodies is administered intragastrically lial synthase of human nitric oxide - C12, C30, C200, at a dose of 9 ml / kg in combination with a mixture of solutions of homeopathic dilutions of antibodies to the C-terminal fragment of the angiotensin II receptor - C12, C30, C200 (2 times a day for 4.5 ml / kg (9 ml / kg / day), intragastrically.