It was shown that arginine vasopressin positively affects the course of cardiac arrhythmias caused by aconitine, atropine, glypine, amphetamine, and ketamine, but not by calcium chloride. Key Words: arginine vasopressin; cardiac arrhythmiasAlong with regulation of renal function and vascular tone, learning and memory processes, sleep, wakefulness, pain reception, and immunity, the peptide hormone arginine vasopressin (AVP) exerts strong effect on cardiac rhythm [7]. Administration of AVP causes bradycardia which can originate from direct interaction of AVP with its V1 receptors or from imbalance between adrenergic and cholinergic processes [10]. The ability to affect cardiac rhythm is a specific characteristic of antiarrhythmic drugs [4]. The aim of the present study was to investigate the AVP potential tot the correction of experimental arrhythmias caused by different chemical compounds. MATERIALS AND METHODSExperiments were carried out on adult male albino mice (18-22 g) and rats (150-180 g). In mice, arrhythmia was induced by intravenous injection of KCI in a dose of 300 mg/kg. In rats, arrhythmias were induced by subcutaneous injection of aconitine (200 ktg/kg), atropine (10 mg/kg), glypine (5 mg/kg), amphetamine (10 mg/kg), or ketamine (25 mg/kg). AVP was administered 10 min prior to arrhythmia-inducing drugs. During the experiment, rats were placed into special penal-like cages. ECG was recorded in standard lead II by subcutaneous stainless-steel electrodes connected with a RM-6000 polygraph. The data were analyzed statistically using Student's t test.Institute o1~ Toxicoloc.pj-, Russian Ministry" of Health, St. Petersburg RESULTSIn mice, KCI injection induced ventricular fibrillations with lethal outcome within 1 min. AVP administered in doses of 0.1, 0.01, or 0.001 mg/kg neither prevented KCl-induced death, nor prolonged the survival period.Ten minutes after aconitine injection, all rats exhibited various types of extrasystole which lasted over 60 min. In 50% of the rats, 0.1 mg/kg AVP prevented extrasystoles and maintained the sinus rhythm. In the remaining rats AVP significantly delayed the development of extrasystole that appeared 60 min after aconitine injection.Ten minutes after administration of atropine, amphetamine, or ketamine, sinus tachycardia of varying degree was observed for over 60 rain. AVP in a dose of 0.01 mg/kg postponed and in a dose of 0.1 mg/kg prevented atropine-induced tachycardia. It also slowed down heart rate, and as a result, 10 min after atropine injection bradycardia developed instead of tachycardia. AVP significantly shortened the effects of glypine, a muscarinic cholinergic receptor blocker. With the preceding AVP administration glypine-induced sinus tachycardia lasted only 10 min.AVP in a dose of 0.1 mg/kg completely prevented amphetamine-induced tachycardia and slowed down heart rate.In AVP-treated rats, ketamine tailed to produce tachycardia; sinus bradycardia was observed during the entire observation period (Table 1).
Mathematical analysis of the data obtained in experiments on the whole organism revealed that blockade of M(2)-cholinergic receptors increased both heart and respiratory rates. Blockade of M(1)-cholinergic receptors alleviated tachycardia induced by M(2)-receptor blockade.
Among numerous preparations possessing M-cholinoblocking properties, a special group is formed by poly(methylene tetraamines):ArCHzNR.I_A_N R2_B_NR2_A_N RI_.CH2Ar, Iwhere A = (CH2)n, n = 4-8; B = (CH2),~, m = 4-12; Ar = Ph, o-MeOC6H4, hetaryl, etc.; R l, R 2 = H or Me (in various combinations) [1].These compounds significantly differ by their structures from conventional cbolinolytics representing modified (e.g., "loaded" by introducing additional bulky substituents) acetylcholine or its agonists. Nevertheless, tetraamines I are capable of effectively blocking the M-cholinoreacfive systems. In most cases, their affinity toward the M2 receptor subtype is higher compared to that with respect to the MI and M3 sub-In recent years, certain relationships have been established between the pharmacological properties and chemical structures of tetraamines I [1]. However, all the compounds studied in this respect had very similar structures, whereby the fragments separating nitrogen atoms are represented by polymethylene chains with only the chain lengths or terminal aromatic groups varying from one to another compound. It was therefore of interest to extend the scope of our search, in particular, by partly replacing methylene units with aromatic groups capable of significantly modifying the properties of fihal products. Because of an increase in both the rigidity of molecules and their ability to bind to the rt-electron acceptors, the conformational properties of the new compounds were expected to differ significantly from those of their precursors. This must obviously affect the biological activity of these compounds, including the specificity of interaction with Mcholinoreceptors of various subtypes.
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