Anti-arrhythmic agent

FIELD: medicine, chemistry of peptides.

SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.

EFFECT: valuable medicinal properties of agent.

1 tbl, 1 ex

 

The invention relates to the section of experimental medicine and can be used to create a new effective anti-arrhythmic drug.

Today it is known that ligands of opioid receptors possess analgesic [3] and immunomodulatory [2] actions.

Used the tool deltorphin D was synthesized in the Department of Pathology, University of Kentucky (Lexington, Kentucky, USA).

In its structure this connection peptide of the following composition:

Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2

For the first time revealed its antiarrhythmic effect.

Previously it was shown that injection of peptide agonists μ-opioid receptor is accompanied by increased tolerance of the heart to the arrhythmogenic effects of epinephrine, aconitine and CaCl2[1]. Considering the obtained results, let us assume that the drug deltorphin D which are able to bind with opioid receptors, can also have antiarrhythmic action. Therefore the research on the impact of deltorphin D on the stability of the heart to the arrhythmogenic action of transient ischemia and reperfusion.

The invention will be clear from the following description.

Experiments conducted on rats male Wistar rats weighing 200-250 g, anesthetized with ketamine (50 mg/kg intraperitoneally). Arrhythmia was modeled PR is using the occlusion of the left coronary artery (10 min) and subsequent restoration of coronary blood flow (reperfusion 10 min) [4]. During the whole experiment the animals were housed in artificial ventilation of room air, which was performed using the modernized machine RO-2 (St. Petersburg, Russia). During ischemia and reperfusion were recorded ECG in the second chest leads to determining the frequency of occurrence of ventricular heart rhythm disturbance (arrhythmia, tachycardia and fibrillation) in the group. Recording and processing of ECG data was carried out with the help of the biopotential amplifier (UBF-03, Russia) and computer Pentium using the original software package. Deltorphin D was dissolved in dimethyl sulfoxide (DMSO) followed by dilution of a 45%aqueous solution of 2-hydroxypropyl-β-cyclodextrin (Sigma-RBI, Natick, MA, USA). The study drug was administered intravenously 15 minutes before coronariography at a dose of 0.3 mg/kg served as Control animals in which simulated transient ischemia and reperfusion without the introduction of drugs. The results were processed statistically using the method χ2and t-student test.

Example. Study the antiarrhythmic activity of deltorphin D was carried out according to the following scheme.

The control group was taken 15 animals, which for 15 min to simulate arrhythmias was intravenously injected with isotonic NaCl solution. B group of experimental animals was taken 14 rats over 15 MINDO of coronarography was intravenously injected a solution of the drug. Then, within each series of experiments conducted ECG recording in the second chest leads and counted the frequency of occurrence of multiple ventricular extrasystoles (MIA), episodes of ventricular tachycardia (VT) and ventricular fibrillyatsy (state), and the number of animals without cardiac arrhythmias (BIA). The results were summed up for each group and statistically were analyzed by nonparametric criterion χ2.

During ischemia, as shown in table 1, the introduction of deltorphin D (0.3 mg/kg) decreases the incidence MIA in 1.5, VT - 2.5 times. In addition, a 3 times increase in the number of rats without ventricular arrhythmias. At reperfusion reduced the likelihood of adipose tissue and MGE 3.8 and 2.4 times, respectively. In addition, 3 times increases the number of animals without cardiac rhythm.

The results indicate that models of ischemic and reperfusion arrhythmias deltorphin D has a pronounced antiarrhythmic effect during 10-minute coronariography and subsequent reperfusion.

Thus, this drug can be used as a new anti-arrhythmic drug.

Table1
Ischemia Reperfusion
BIA(%)MGA(%)Adipose tissue(%)BIA(%)MGA(%)Adipose tissue(%)
Control(n=15)2(13)13(87)11(73)2(13)12(86)8(53)
Deltorphin D*******
(0.3 mg/kg) (n=14)6(43)8(57)4(29)6(43)5(36)2(14)
Notes: * P<0.01; ** P<0.025; *** P<0.05 (trustworthiness in relation to control)

LITERATURE

1. Lishmanov SHE, Maslov LN, Krylatov AV Peripheral μ-opiate receptors and regulation of the stability of the heart to the arrhythmogenic effects. BBM. 1998. 125(6): S-653.

2. Plotnikoff, N., Miller G. Enkephalins as immunomodulators. Int. J. Immunopharm. 1983. 5(5): P.437-441

3. Roemer D., H. Buescher, R. Hill et al A synthetic enkephalin with prolonged par-enteral and oral analgesic activity. Nature. 1977. No. 268. R-549.

4. Schultz J.E.J., Hsu AK, Nagase h., Gross G.J. TAN-67, δ1-opioid receptor agonist, reduces infarct dementia size via activation of Gi/oproteins and KATPchannels. Am. J. Physiol. 1998. 274: H909-H914.

The use of a ligand of the opioid receptor deltorphin D as a new antiarrhythmic agent.


 

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