RU2707060C1 - Method of endothelial dysfunction correction with asialised erythropoietin in an adma-like model of preeclampsia - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to experimental pharmacology, can be used for correction of endothelial dysfunction in ADMA-like model of preeclampsia. That is ensured by reproducing the pre-eclampsia model in Wistar rats by daily intraperitoneal introduction of L-nitro-arginine-methyl ester 25 mg/kg on 14–20th day of pregnancy. Correction of simulated pathology is carried out by subcutaneous administration of asialised erythropoietin from 10 to 20 days of pregnancy in dose of 2.4 mcg/kg once a day.EFFECT: method provides pronounced correction of endothelial dysfunction in the simulated pathology due to pronounced anti-ischemic and antioxidant action of the administered preparation.1 cl, 1 tbl, 1 ex

Description

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

Closest to the claimed solution is a Method for the correction of endothelial dysfunction with recombinant erythropoietin in an ADMA-like model of gestosis (RU No. 2462766, publ. 09/27/2012), which includes reproducing a gestosis model in Wistar rats by intraperitoneal administration of L-nitro every day from 14 to 20 days of gestation arginine methyl ester at a dose of 25 mg / kg. To correct a simulated pathology, recombinant erythropoietin is administered subcutaneously at a dose of 50 IU / kg on the 7th, 10th, 13th, 16th, 19th day of pregnancy.

The disadvantage of this method is that by binding to the homodimeric receptor, erythropoietin can activate erythropoiesis, which leads to a violation of the rheological properties of the blood and is an undesirable phenomenon in ischemia (Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives / N. Kanek , E. Kako, K. Sawamoto // Front Cell Neurosci. - 2013 .; Erythropoietin: recent developments in the treatment of spinal cord injury / S. Carelli, G. Marfia, A. Maria Di Giulio).

This fact makes it impossible to increase the dose of erythropoietin with its low efficiency. Therefore, the results of the correction of endothelial dysfunction with an ADMA-like model of pathology in pregnant animals using recombinant erythropoietin are unsatisfactory.

One of the ways to eliminate this drawback is the creation of erythropoietin derivatives with a short period of life. To activate the cytoprotective effects of erythropoietin, it is sufficient to contact the heterodimeric receptor for a short time (5 minutes). To activate erythropoiesis, a long-term constant presence of erythropoietin at the homodimeric receptor is necessary. (Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives [Text] / N. Kaneko, E. Kako, K. Sawamoto // Front Cell Neurosci. - 2013; Erythropoietin: recent developments in the treatment of spinal cord injury [Text] / S. Carelli, G. Marfia, A. Maria Di Giulio [et al.] // Neurol Res Int. - 2011; The use of erythropoietin and its derivatives to treat spinal cord injury [Text] / A Mofidi, A. Bader, S. Pavlica [et al.] // Mini Rev Med Chem. - 2011).

However, despite the obvious prerequisites, the question of the effectiveness of the derivative under study in connection with the change in its lifetime remains ambiguous. This is due to the fact that in various tissues and organs metabolic, regulatory and other processes have their own not only temporary, but also other features. The placenta is a dynamically developing organ with a complex combination of processes of organogenesis and appoptosis. In addition, changes in the spatial structure, mass and charge also leave the question of its permeability through tissue barriers and, in particular, the placental barrier open.

In connection with the foregoing, an object of the invention is a method for correcting endothelial dysfunction in an ADMA-like model of preeclampsia, including the use of asialized erythropoietin having a short half-life.

The task is achieved by the fact that, against the background of simulating preeclampsia in an experiment, intraperitoneal administration to pregnant female Wistar rats for 7 days of 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 subcutaneous administration of asialized erythropoietin at a dose of 2.4 μg / kg once a day from 10 to 20 days of pregnancy.

The technical result is a more pronounced correction of endothelial dysfunction with a simulated pathology. This effect is associated with a pronounced anti-ischemic and antioxidant effect of asialized erythropoietin.

THE METHOD IS CARRIED OUT AS FOLLOWS.

The experiments were performed on white pregnant rats of Wistar female females weighing 250-300 g. N-nitro-L-arginine methyl ether (L-NAME) was administered intraperitoneally at a dose of 25 mg / kg / day for 7 days (from 14 to 20 days of pregnancy ) Asialized erythropoietin is administered subcutaneously from 10 to 20 days of pregnancy at a dose of 2.4 μg / kg 1 r / day.

On the 21st day of pregnancy 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 ) (RU No. 2301015, publ. 06/20/2007).

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

EXAMPLE OF SPECIFIC IMPLEMENTATION.

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 1.21 ± 0.08 in the intact group of pregnant animals up to 3.10 ± 0.35 in the control group (p <0.05). In addition, there was a significant increase in systolic and diastolic blood pressure from 123.2 ± 3.46 and 87.3 ± 5.71 to 194.9 ± 7.88 and 149.8 ± 4.73 mm Hg. respectively. Subcutaneous administration of asialized erythropoietin 1 r / day (2.4 μg / kg) from 10 to 20 days of pregnancy led to a significant decrease in QED to 1.67 ± 0.12, which is more than two times less than in the group of animals with the introduction L-NAME (p <0.05), as well as the correction of systolic and diastolic blood pressure - 167.3 ± 3.43 and 129.4 ± 4.17 mmHg respectively. The effect of asialized erythropoietin on blood pressure and QED are shown in table 1.

Table 1

Thus, the obtained results convincingly indicate a pronounced correction of endothelial dysfunction under the conditions of the similar model of pre-eclampsia in pregnant rats reproduced by ADMA with asialized erythropoietin.

Claims (1)

A method for correcting endothelial dysfunction with asialized erythropoietin in an ADMA-like model of preeclampsia, comprising reproducing a model of preeclampsia 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 for correction of the simulated pathology is administered subcutaneously asialized erythropoietin at a dose of 2.4 μg / kg 1 time per day from 10 to 20 days of pregnancy.