[The ability of NMDA glutamate receptor blockers to prevent a pentylenetetrazole kindling in mice and morphological changes in the hippocampus].

We investigated in mice the relationship between convulsions and morphological changes of hippocampal neurons that arise in the development of pentylentetrazol (PTZ)-induced kindling. The kindling was caused by of 35 mg/kg PTZ i.p. 3 times a week for a month. By the end of this period, 70% of the mice responded to the injections of PTZ with pronounced clonic or tonic-clonic seizures. The hippocampal slices (layer stratum pyramidale, CA1, Nissl's stain) obtained from mice exhibiting seizures revealed a large number of modified cells (24.7 +/- 2.1%). These hyperchromic neurons have been characterized by a decrease of the size cell body, there was a loss of turgor, the body cells shrink, and dendritic spines curl. Part of the cells took the shape of elongated neck. Such modified the dark type of neurons contained only 2.3 +/- 2.3% in the hippocampus of intact mice, and 30% of the mice resistant to the convulsive action ofPTZ during the period of observation. The expression of protein NeuN (Fox3) in hippocamal neuron including the hyperchromic once suggests that neurons on the whole did not die and were relatively viable. Preventive administration of NMDA receptor blockers (0.5 mg/kg, memantine 0.1 mg/kg or IEM-1958 1 mg/kg, s.c.) 30 minutes prior to PTZ reduced the proportion of mice which exhibited PTZ kindling from 70% to 40%. The modified neurons were observed in which the PTZ kindling due to the blocker presence did not develop, i.e., the same as in intact mice. Contrary, 24.0 +/- 5.6% of hyperchromic neurons were found in the hippocampal slices from mice manifested seizures, despite the co-administration of NMDA blockers. The data obtained indicate that modified neurons are the result of seizures suffered by the animals in the course of PTZ kindling, and that the blockade of NMDA glutamate receptors can suppress manifestations of seizures and the accompanying morphological changes of hippocampal neurons.

[Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats].

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.

[The effect of ionotropic glutamate receptor antagonist on pentylenetetrazole-indused seizures in Krushinsky-Molodkina rats].

Krushinsky-Molodkina (KM) rats exhibit inherited susceptibility to audiogenic seizures and auditory stimuli induce generalized tonic-clonic seizures that resemble human epilepsy. The aim of this study was to compare the neurological manifestations of pentylenetetrazole (PTZ)-induced seizures in Wistar and KM rats to clarify the contribution of inherited susceptibility to audiogenic seizures, and to assess the anticonvulsant activity of NMDA receptor blockers memantine and IEM-1921 (1-phenylcyclohexylamine) in the PTZ-induced seizure model in KM rats. KM rats exhibited increased seizure severity relative to Wistar rats, and the death of KM rats was observed in 2.1 times more likely. Both NMDA receptor blockers showed anticonvulsant activity in the PTZ-induced seizure model, however IEM-1921 was more potent than memantine. IEM-1921 reduced the average intensity of the seizures by 2 points on a 5-point scale, and the total duration of generalized seizures was decreased by 41 times. IEM-1921 completely prevented the death of animals, while memantine only slightly decreased the mortality (68% in control conditions vs. 50% with administration of memantine). The results of the present study suggest that NMDA receptors are involved in the molecular mechanisms of seizures of different etiologies.

[Influence of tenotomy on posttetanic responses of the rat fast and slow muscle].

The effect of two weeks of tenotomy on posttetanic isometric contractile responses of the rat fast: Extensor digitorum longus and slow: soleus muscles was studied in experiments on isolated muscle preparations. Direct tetanic stimulation (100 impulses, 50 Hz) increased the force of contractions by 20-25% (p < 0.05) of both, control and tenotomized fast muscles. Identical to above tetanic stimulation of control, slow muscle resulted in posttetanic depression, a decrease in the amplitude of contractile responses. Tenotomized slow muscles did not develop posttetanic depression. Caffeine (4 mM) increased and dandrolene (10 microM) decreased the force of unitary and tetanic contractions of control and tenotomized muscles. Neither drug, however, affected development of posttetanic phenomena in ether fast or slow muscles. The fact that in extensor digitorum longus, posttetanic potentiation is preserved for at least forty days of tenotomy but disappears after only 2 weeks of denervation suggests important role of neurotrophic influences in regulation of posttetanic responses of fast muscles.

Effects of memantine on convulsive reactions and the organization of sleep in krushinskii-molodkina rats with an inherited predisposition to audiogenic convulsions.

Krushinskii-Molodkina rats, which have a genetic predisposition to audiogenic convulsions, are used as a natural animal model for studies of the actions of anticonvulsants. It is important to understand the extent to which changes in glutamatergic synaptic transmission is involved in the mechanisms producing convulsive states and in the functional organization of the sleep-waking cycle in rats of this strain. The present report describes experiments addressing this, in which i.m. doses of 5 and 10 mg/kg of a noncompetitive NMDA glutamate receptor antagonist of the memantine type were given at different times (30 min, 1, 2, and 3 h) before presentation of sound stimuli (sine-wave tones at 8 kHz, 90 dB). Effects on the latent periods of the initial motor excitation, the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. The greatest attenuation of convulsive seizures, to a level consisting only of motor excitation, was obtained in 60% of the rats between 1 and 2 h after administration. There were no differences between the effects of doses of 5 and 10 mg/kg. When doses were given 3 h before sound provocation, convulsive reactions became more marked than at 2 h, though they were nevertheless more marked than in controls. Krushinskii-Molodkina rats with chronically implanted electrodes for recording brain electrical activity were used to study the effects of memantine on the organization of sleep. These experiments showed that the rats' sleep during the first hour after dosage consisted only of short episodes of superficial slow-wave sleep, and that even this sleep disappeared completely 54.4 +/- 4.9 and 39.9 +/- 5.2 min after administration of the agent at doses of 5 and 7 mg/kg, respectively. Rats showed a complete absence of sleep for 2 and 2.5 h, respectively, after which episodes of slow-wave sleep reappeared. The first episodes of REM sleep was seen in rats only after 3.3 +/- 0.2 and 3.7 +/- 0.2 h after memantine injections. The appearance of these episodes provided evidence that the effects of memantine on the activity of the somnogenic system of the animals' brains were complete and that recovery of the normal organization of the sleep-waking cycle had started. The synchronicity and codirectionality of the blocking action of memantine on sleep organization and measures of audiogenic convulsions in Krushinskii-Molodkina rats is evidence for the involvement of glutamatergic synapses with NMDA receptors in both the regulation of the somnogenic systems and the pathogenesis of epileptiform manifestations in rats.

[Effects of memantine on convulsive reactions and sleep-waking cycle in Krushinskii-Molodkina strain rats with the inherited predisposition to audiogenic convulsions].

Krushinskii-Molodkina strain rats have an inherited predisposition to audiogenic convulsions and are used as a natural animal model in the anticonvulsive drugs studies. We have investigated whether changes in the glutamatergic synaptic transmission are involved in the mechanism of audiogenic convulsions and functional organization of sleep-waking cycle observed in rats of this line. For this purpose Memantine, a selective uncompetitive blocker of NMDA receptors was used. Memantine was injected i.m. at the dose 5 or 10 mg/kg injected 30 min, 1, 2 or 3 hours before the sound stimulus (the sine-wave tone 8 kHz, 90 db). We evaluated the latent period of initial enhanced motor activity, the appearance and intensity of clonic seizures, and thereafter the tonic seizures accompanied by extension of limbs and tail. The maximal attenuation of convulsive attack to the level of initial motor excitement only was occurred in 60% of rats between 1 and 2 hours after memantine pretreatment. No difference between the doses 5 and 10 mg/kg was observed. The effect of memantine began to decrease when memantine was injected 3 h before convulsion provocation. The recording of EEG by chronically implanted electrodes was performed from the rats of Krushinsky-Molodkina line for the study of memantine effects on the sleep organization. The sleep of these rats during the first hour after 5 or 7 mg/kg memantine injection exhibited as the short periods of slow-wave sleep only which disappeared completely thereafter 54.4 +/- 4.9 and 39.9 +/- 5.2 min correspondingly. The complete sleep loss was observed approximately 2-2.5 hours later and followed by appearance of episodes of slow-wave sleep. The first episodes of fast-wave sleep occurred 3-4 hours later. Their reappearance evidenced of the completion of memantine action on the somnogenic brain systems and the beginning of recovery of normal sleep-waking organization. Thus the manifestations of unidirectional and synchronous memantine action on audiogenic seizures and disturbances of sleep-waking mechanisms may speak about involvement of NMDA receptors in both of epileptogenesis and somnogenic system of Krushinsky-Molodkina rats line.

Involvement of ionotropic glutamate receptors in the appearance of arecoline tremor in mice.

Administration of the muscarinic cholinoreceptor agonist arecoline (6 mg/kg, s.c.) to mice induced long-lasting tremor. The ability of non-competitive antagonists of ionotropic glutamate receptors to suppress the onset of tremor was studied. These antagonists, i.e., adamantane and phenylcyclohexyl derivatives, selectively blocked NMDA-type receptor channels (monocations) or both NMDA-and AMPA-type channels (dications). Both types of blocker weakened arecoline tremor, though the dose-response relationships were different for mono-and dications. The effects of dications appeared only at low blocker doses (0.0001-0.01 micromol/kg) but gradually disappeared on dose elevation. These data lead to the conclusion that the mechanism of pathogenesis of arecoline tremor predominantly involves NMDA-type receptors. Moderate blockade of AMPA-type receptors could potentiate the preventive effect of mixed-action antagonists (anti-NMDA+anti-AMPA), though predominance of blocking action against AMPA-type receptors prevented this effect.

[Involvement of ionotropic glutamate receptors in the genesis of arecoline-induced tremor].

The muscarinic agonist arecoline (6 mg/kg, subcutaneously in mice) induced a long-lasting tremor. The inhibitory potency of non-competitive antagonists of ionotropic glutamate receptors has been studied. These antagonists are the derivatives of adamantane and phenylcyclohexyl. A part of them: monocationic compounds, selectively block the NMDA-receptor channels, their dicationic analogues affecting both channels of the NMDA- and the AMPA-glutamate receptors. Monocationic blockers effectively reduced the arecoline-evoked tremor and their potency correlated with ability to block the NMDA-receptor channels. Dicationic blockers revealed protective effect only in low range doses (0.0001-0.01 microM/kg). Further increase of the dose reduced or completely abolished this effect. This suggests that the NMDA-receptors are involved in the genesis of arecoline-evoked tremor. The only moderate blockade of the AMPA-receptors potentiates the drug blocking action but the prevalent blockade of these receptors impedes the effect on arecoline-evoked tremor.

Effects of ionotropic glutamate receptor channel blockers on the development of pentylenetetrazol kindling in mice.

Experiments on mice were performed to study the ability of monocationic and dicationic adamantane and phenylcyclohexyl derivatives to prevent the development of kindling induced by i.p. administration of pentylenetetrazol (Corasol, 35 mg/kg). The monocationic phenylcyclohexyl derivative IEM-1921 effectively slowed the development of kindling, this being seen over a wide range of doses (0.0001-0.1 micromol/kg). A monocationic adamantane derivative (memantine), also a selective non-competitive blocker of NMDA receptors, produced a similar effect at doses 100 times higher. The anticonvulsive activity of the dicationic phenylcyclohexyl derivative IEM-1925, which could block both types of glutamate receptors, differed from the activity of the monocationic derivative by having a more complex dose-response relationship. Thus, the development of kindling was suppressed by essentially the same doses as needed for the monocation IEM-1921 (0.001 micromol/kg). However, on reducing the dose by a factor of 10 (0.0001 micromol/kg), IEM-1925 facilitated the development of kindling. This difference in the prophylactic activities of selective NMDA receptor blockers and substances able to block both NMDA and AMPA receptors provides evidence that the mechanism of kindling involves both types of ionotropic glutamate receptor and the effects of compounds depend not only on the ratio of the contributions of these receptors, but also on the kinetic characteristics of the blocking action.

[Effects of blockade of ionotropic glutamate receptors on the development of pentylenetetrazole kindling in mice].

Effects of mono- and dicationic derivatives of adamantane and phenylcyclohexyl on the petyleneterazole-induced (35 mg/kg i. p.) kindling were studied in the experiments on mice. Monocationic derivative of phenylcyclohexyl IEM-1921, effectively retarded the development of kindling beginning the dose 0.0001 microM/kg. Memantine: derivative of adamantane (derivative of adamatane) produced the same effect with 100-fold increased dose. Dicationic derivative ofphenylcyclohexyl: IEM-1925, is able to block equally the open channels of both NMDA and subtype of Ca-permeable AMPA receptors. Its effect on kindling differed markedly from selective NMDA antagonists (IEM-1921 and memantine) in more complicated dose-dependence. The retardation of kindling IEM-1925 was induced at 0.001 microM/kg. On the contrary, a 10-time lower dose: 0.0001 microM/kg, facilitated the development of kindling. The observed difference in the activity of selective NMDA antagonists and the drugs combining anti-NMDA and anti-AMPA potency indicates that both types of ionotropic glutamate receptors are involved in the mechanism of petyleneterazole-induced kindling. The integral effect of channel blockade evoked by drugs seems to be dependent not only upon the ratio of the receptor types but on the kinetics of drug action, too.

The involvement of glutamatergic transmission in the mechanism of movement disorders induced by reversive rotation of white mice.

The ability of the selective non-competitive NMDA receptor blocker MK-801 and a series of new glutamate antagonists --the adamantane derivatives IEM-1754 and IEM-1857 and phencyclidine (IEM-1925)--to prevent movement disorders induced by reversive rotation in mice was studied. l.p. MK-801 at a dose of 0.15 ml and IEM-1754 at a dose of 5.0 mg/kg prevented the development of akinesia in response to reversive rotation as effectively as scopolamine, a known agent which provides effective prophylaxis for movement diseases. IEM-1857, the quaternary analog of IEM-1754, was not effective. IEM-1925 significantly increased the responses of mice to reversive rotation, possibly because of its high activity in relation to other subtypes of glutamate receptors. These data provide evidence for the involvement of glutamatergic transmission in the mechanism of movement disorders of vestibular origin.

[The participation of glutaminergic transmission in the mechanism of movement disorders induced by reverse rotation in white mice]. / Uchastie glutamatergicheskoi peredachi v mekhanizme dvigatel'nykh narushenii, vyzvannykh reversivnym vrashcheniem belykh myshei.

Administration of MK-801 or IEM-1754 prevented akinesia in mice induced by reversing rotation, not less effectively than scopolamine. Quaternary adamantane derivative IEM-1857 was ineffective. IEM-1925 enhanced the locomotor disturbance induced by reversing rotation due, probably, to different spectrum of its antiglutamate action. The data obtained suggest involvement of glutamate synaptic transmission in development of locomotor disturbances of a vestibular origin.

[A nondepolarizing muscle relaxant with rapidly developing and short-term action]. / Nedepoliarizuiushchii miorelaksant s bystro razvivaiushchimsia i kratkovremennym deistviem.

The pharmacological properties of the new nondepolarizing myorelaxant IEM-1213 and of its mixture with tercuronium were studied in experiments on anesthetized cats. Intravenous infusion of a blocking dose of IEM-1213 did not cause a change in the level of arterial pressure and blockade of the sympathetic ganglia but induced blockade of the heart muscarine receptors. The effect of IEM-1213 develops more rapidly and lasts for a shorter time than that of dithylin. Intravenous infusion of a mixture of IEM-1213 and tercuronium constituting 35 and 60% of the blocking dose of the former and, respectively, 35 and 20% of the blocking dose of the latter causes an effect similar in the time of its development to that of intravenous infusion of a total dose of IEM-1213 alone.

[Directions in the development of postsynaptic nondepolarizing muscle relaxants with rapidly developing action]. / O napravleniiakh razrabotki postsinapticheskikh nedepoliarizuiushchikh myshechnykh relaksantov s bystro razvivaiushchimsia deistviem.

The experiments on unconscious cats have shown that the myoparalytic effect of postsynaptic non-depolarizing myorelaxants which have a trimethylammonium cationic group develops more rapidly than that of their triethylammonium analogues. The compound IEM-1213 is given as an example of a trimethylammonium derivative with the rigid structure of the molecule having an unusual rapidly developed effect.

Effect of endogenous digoxin-like factor and digoxin antibody on myocardial Na+, K(+)-pump activity and ventricular arrhythmias in acute myocardial ischaemia in rats.

OBJECTIVE: The aim was to study whether a circulating sodium pump inhibitor (endogenous digoxin-like factor) contributes to the genesis of early ventricular arrhythmias in acute myocardial ischaemia in rats. METHODS: Effects of digoxin antibody (260 micrograms.kg-1) on the incidence of ventricular arrhythmias, plasma digoxin-like immunoreactivity (DELFIA immunoassay), Na+, K+, and Mg2+ ions, and activity of the ouabain sensitive Na+, K(+)-pump in different regions of myocardium have been studied in propranolol naive and propranolol pretreated rats exposed to acute coronary artery ligation. Adult male Wistar rats were divided into six experimental groups: (1) saline pretreated controls; (2) saline pretreated coronary artery ligated rats; (3) coronary artery ligated rats pretreated with 260 micrograms.kg-1 digoxin antibody; (4) propranolol pretreated controls; (5) propranolol pretreated rats with acute myocardial ischaemia; (6) rats with acute myocardial ischaemia pretreated with both propranolol and digoxin antibody. RESULTS: Acute myocardial ischaemia in saline pretreated rats was associated with a twofold increase of plasma digoxin-like immunoreactivity and ventricular arrhythmias, but did not lead to changes in myocardial Na+, K(+)-pump activity. Pretreatment of coronary artery ligated rats with digoxin antibody reduced the total duration of ventricular tachycardia and ventricular fibrillation during a 15 minute postligation period from 201 (SEM 34) to 46(18) seconds (p < 0.002) but did not alter activity of the myocardial Na+, K(+)-pump. In rats pretreated with propranolol, acute myocardial ischaemia was associated with a twofold inhibition of the Na+, K(+)-pump in left atrial and left ventricular myocardium, and with a 69% increase in plasma K+ concentration. Administration of digoxin antibody to propranolol pretreated coronary artery ligated rats in parallel with the antiarrhythmic effect prevented the increase in plasma K+ concentration and inhibition of Na+, K(+)-pump in the left atrial, but not the left ventricular myocardium. CONCLUSIONS: A circulating digoxin-like factor contributes to the pathogenesis of myocardial ischaemia induced ventricular arrhythmias. As propranolol pretreatment of coronary artery ligated rats inhibited the Na, K(+)-pump in myocardium, the inhibitory effect of endogenous digoxin-like factor on Na+, K(+)-ATPase was probably masked in propranolol naive animals by the stimulatory action of catecholamines on Na+, K(+)-ATPase described previously.

[Ganglioside protection of the erythrocyte membranes in myocardial ischemia]. / Zashchita gangliozidami membran éritrotsitov pri ishemii miokarda.

Myocardial ischemia was shown to lead to modification of structural and functional organization of rat erythrocyte membranes. Thus, it was found that the activity of Na+, K+-ATP-ase markedly decreased, while accumulation of LPO products and of lysophosphatidylcholine (lyso--PC) took place in erythrocyte membranes of rats subjected to myocardial ischemia. Using nonpenetrating modifier trinitrobenzosulfonic acid, an increase in the content of modified phosphatidylethanolamine in erythrocyte membranes of ischemic rats was revealed as compared to the membranes of control animals. The intravenous administration of gangliosides (30 mg/kg) resulted in partial normalization of Na+, K+(-)ATPase activity, of LPO product and lysoPC content and of transbilayer distribution of lipids.

Endogenous plasma Na,K-ATPase inhibitory activity and digoxin like immunoreactivity after acute myocardial infarction.

PURPOSE OF INVESTIGATION: The aim was to look for the presence of circulating factor(s) with Na,K-ATPase inhibitory properties and digoxin like immunoreactivity in patients after acute myocardial infarction. DESIGN: Venous blood samples were obtained when the patients were admitted and different methods were used to monitor the plasma concentrations of factor(s) with properties of digitalis. SUBJECTS - These were 26 patients of both sexes (mean age 57.7 years, range 40-72) during the first 24 h of a first transmural acute myocardial infarct, 11 male patients with unstable angina pectoris (52.5 years, 45-67), and 18 healthy male controls (25 to 50 years). MEASUREMENTS AND MAIN RESULTS: There was significant inhibition of ouabain sensitive Na,K-ATPase in intact erythrocytes in patients with myocardial infarction [1.4(SEM 0.15)mumol Pi.mg-1.h-1] compared with patients with unstable angina pectoris [3.1(0.4), p less than 0.01] and healthy controls [3.4(0.25), p less than 0.01]. In myocardial infarction complicated by ventricular fibrillation (n = 5) Na,K-ATPase activity was significantly lower than in the other 21 patients [0.95(0.2) and 1.55(0.11) mumol Pi.mg-1.h-1 respectively, p less than 0.05]. There was no change in erythrocyte Na,K-ATPase activity in myocardial infarction complicated by acute pulmonary oedema, nor was there any difference in activity in erythrocyte ghosts obtained from the patients with myocardial infarction v healthy controls, at 0.47(0.13) v 0.50(0.02) mumol Pi.mg-1.h-1. Boiled plasma supernatants obtained from the patients with myocardial infarction inhibited Na,K-ATPase in erythrocytes from healthy subjects. This inhibitory effect was antagonised by antidigoxin antibody. Plasma inhibitory potency was correlated with erythrocyte Na,K-ATPase activity in the patients with myocardial infarction (r = -0.65, p less than 0.001, n = 23). There was a 2.5-fold increase in plasma digoxin like immunoreactivity in the patients with myocardial infarction [1.65(0.5) ng.ml-1] using DELFIA fluoroimmunoassay as compared with five healthy controls [0.04(0.12), p less than 0.05] and nine patients with unstable angina [0.48(0.11), p less than 0.05]. There was no difference in plasma digoxin like immunoreactivity in myocardial infarction complicated or not by ventricular fibrillation, but there was very low digoxin like immunoreactivity in patients with myocardial infarction complicated by acute pulmonary oedema [0.26(0.08) ng.ml-1, n = 7]. There was no correlation between plasma digoxin like immunoreactivity and either plasma Na,K-ATPase inhibitory potency or erythrocyte Na,K-ATPase activity. CONCLUSIONS: The results show that plasma factor(s) with some of the properties of digitalis are increased in acute myocardial infarction.

[The role of an endogenous digoxin-like factor in regulating blood circulation and in the origin of arrhythmia in myocardial ischemia]. / Rol' éndogennogo digoksinopodobnogo faktora v reguliatsii krovoobrashcheniia i proiskhozhdenii aritmii pri ishemii miokarda.

The history of the discovery of endogenous digoxin-like factor (EDF) is described and the role played by the substance in blood circulation regulation, in the pathogenesis of arterial hypertension is discussed. The authors provide their own data (both experimental and clinical ones) concerned with EDF participation in the pathogenesis of early ventricular fibrillations in acute myocardial ischemia. Experiments on rats demonstrated that myocardial infarction (MI) is marked by a negative linear correlation between the intensity of ventricular fibrillations and the activity of Na,K-ATPase of intact red blood cells (r = -0.84) that mirrors the content of circulating EDF. Administration to the animals of digoxin antibodies binding EDF resulted in the antiarrhythmic effect and in the recovery of the enzyme activity. The patients demonstrated, within the first day of MI, a 76-percent inhibition of the activity of Na,K-ATPase of red blood cells. A correlation was discovered between the enzyme activity and the capacity of protein-free supernatants of blood plasma for inhibiting Na,K-ATPase, which indicates the presence of circulating EDF in blood plasma.