Mechanism of cardioprotective effect of adenocine and non-glycoside cardiotonic drugs during experimental chronic cardiac insufficiency.

The therapeutic action of adenocine during cardiac insufficiency (heart failure) caused by ischemic (stenosis) or reperfusion (removal of ligature) injury to the myocardium prevents depletion of ATP, the major energy source for myocytes in the right and left ventricles, and a drop in NAD/NADH ratio. The development of energy shortage during heart failure cannot be eliminated by ß-acetyldigoxin, levosimendan, or milrinone: the content of ATP in the right and left ventricular myocardium remained below the normal level by 28 and 29%, 37 and 33%, 32 and 28%, respectively; the NAD/NADH ratio of the energy supply system in cardiomyocytes did not return to normal. Adenocine increased the content of NAD to the normal level in both the right and left ventricles, while it remained below the normal level after administration of ß-acetyldigoxin (by 24 and 19.5%, respectively), levosimendan (by 27 and 29%), and milrinone (by 26 and 24%). In contrast to ß-acetyldigoxin, levosimendan, and milrinone, adenocine inhibited activity of poly(ADP-ribose) polymerase in both ventricles. It is concluded that adenocine directly inhibits the key enzyme triggering apoptosis; we also hypothesized that this drug activates the regulatory and signal mechanisms arresting apoptotic alterations in the myocardium during heart failure.

Submolecular mechanisms underlying in vitro and in vivo effect of cardiac glycosides on contractile activity of myocardial myofibrils during heart failure.

The development of severe heart failure associated with toxicoallergic myocarditis is accompanied by profound structural and conformational changes in the outer domain of actin (major protein in a thin filament of cardiomyocyte sarcomere). These changes were revealed in subdomains 1 (Cys374 and Cys10) and 2 (Lys61 and Tyr69). Structural and conformational changes in the monomer and protomer of the actin thread during heart failure were energetically forbidden. Variations in the distance between amino acid residues exceeded 0.26 nm. They were partly or completely reversible in vivo under the influence of cardiotropic drug refracterin with high antihypoxic activity, as well as in vitro after treatment with digitalis preparations optimizing the concentration of ATP.

[The subcellular pathophysiology of heart failure due to toxic-allergic myocarditis and the action of refracterin on intracardiac hemodynamics and the functional state of the 3 subcellular cardiomyocyte systems responsible for the act of contraction-relaxation]. / Subkletochnaia patofiziologiia nedostatochnosti serdtsa, obuslovennoi toksiko-allergicheskim miokarditom, i deistvie refrakterina na vnutriserdechnuiu gemodinamiku i funktsional'noe sostoianie trekh subkletochnykh sistem kardiomiotsita otvetstvennykh za akt sokrashchenie--rasslablenie.

It is shown that cardiotropic drug refracterin promotes recovery of cardiac contraction and relaxation, their coordination destroyed in cardiac failure (CF) caused by 10-day toxico-allergic myocarditis (TAM). Pumping capacity of the heart returns to normal after normalization of functional activity of three systems of cardiomyocyte responsible for contraction-relaxation: contractile proteins, energy supply and calcium transport. The key process is refracterin-related reestablishment of normal content and proportion of adenyl nucleotides and creatininephosphate and regulation role of phosphorylation and energy of metabolic processes in the cells and their interaction. Thus, refracterin effectiveness lies in its ability to interfere in intracellular metabolic processes in the myocardium, to reestablish normal homeostasis of the systems responsible for contraction-relaxation function and eventually to remove left ventricular cardiac dysfunction.

[Differences in mechanisms of action of beta-acetyldigoxin, strophanthin K and ouabain]. / O razlichii mekhanizmov deistviia beta-atsetildigoksina, strofantina K i uabaina.

In vitro on skinned myocardial fibers (SMF) with extracted or functionally inactivated enzymes and membranes of mitochondria, longitudinal sarcoplasmic reticulum, triads and sarcolemma, new evidence of beta-acetyldigoxin and strophanthin K direct stimulating effects on contractile protein system of myocardium has been obtained. It has been revealed in energy release stimulation and force generation, in quantitative (beta-acetyldigoxin) or quantitative and qualitative (strophanthin K) stimulation of energy transduction, in the increase of contractile process cooperativity and Ca-sensitivity of SMF as well as in the SMF relaxation time extension (in the case of strophanthin K). It is suggested that different effects of beta-acetyldigoxin and strophanthin K are due to the differences in the conformations of actomyosin ensembles formed by strong bound (AMESB), which are induced by the influence of these cardiac glycosides. It has been demonstrated that ouabain (strophanthin K) has no direct effect on functioning of AMESB.

[Effects of strophanthin K and beta-acetyldigoxin in vitro on energy transformation of myocardial contractile protein system in toxic-allergic lesions of the cardiac muscle]. / Deistvie strofantina K i beta-atsetildigoksina in vitro na preobrazovanie énergii sistemoi sokratitel'nykh belkov miokarda pri toksiko-allergicheskom porazhenii myshtsy serdtsa.

Strophanthin K and beta-acetyldigoxin in vitro in concentration of 10(-6) M in TAM sharply increased the force generated by isolated myocardial contractile protein system (MCPS), and normalized the work performed by the system. This was accompanied by increase of ATP internal energy release (enthalpy) intensity, while a portion of energy, dissipating into heat did not increase proportionally. The mechanical efficiency of contractile process was normalized due to beta-acetyldigoxin, and exceeded the normal level due to strophanthin K effect. Strophanthin K proved a positive effect on quantitative and qualitative economy of MCPS energy utilization, while beta-acetyldigoxin effected, on the whole, extensively.

[The action of strophanthin K and beta-acetyldigoxin in vitro on the energy transformation by the contractile protein system of the normal cardiomyocyte]. / Deistvie strofantina K i beta-atsetildigoksina in vitro na preobrazovanie énergii sistemoi kontraktil'nykh belkov normal'nogo kardiomiotsita.

It was shown in experiments on myocardial fiber bundles (MGFB) from normal heart that strophantin K and beta-acetildigoxin in vitro in concentration of 10(-6) M sharply increased the value of force generated by contractile protein system and its ability to perform work. In this case strophantin K significantly increased energy transformation efficiency. It was concluded that in myocardial contractile protein system a regulator of qualitative and quantitative energy transformation is functioning (a kind of economizer).

Dose-dependent shortening of systolic time intervals after intake of pengitoxin.

The systolic time intervals (STI) corrected for changes in the heart rate, electromechanical systole (QS2c) and left ventricular ejection time (LVETc), and the ECG-derived PQ-time and QT-interval were measured in five female and four male healthy subjects. Each volunteer took 0.15, 0.30, 0.45, 0.60, 0.75 or 0.90 mg pengitoxin over six days, with a glycoside-free interval of two or three weeks between two doses. The glycoside plasma level was measured radioimmunologically. Linear correlations were found between the shortening of QS2, LVET, and QT (delta QS2c, delta LVETc, delta QTc) and the plasma level of 16-acetyl-gitoxin. The PQ-time showed a flat dose-dependent increase. The shortening of STI observed after therapeutic and subtoxic doses of pengitoxin was in accordance with that after intake of digitoxin and digoxin in corresponding doses. The efficacy of pengitoxin estimated by shortening of STI justifies the administration of daily maintenance doses between 0.30 and 0.45 mg.

Uptake and liberation of [3H]16-acetyl-gitoxin in the isolated guinea pig atrium.

In isolated, spontaneously beating guinea-pig atria the uptake, liberation and inotropic effect of [3H]16-acetyl-gitoxin were studied. At a concentration of 53.5 nmol/l 16-acetyl-gitoxin caused an increase in contractile force of 21% within 45 min. Within 60 min, 190.7 pmol per g tissue were taken up. The tissue-to-medium radioactivity ratio (T/M ratio) was 4.7. In the wash-out experiments, 40% of the accumulated radioactivity was liberated into the medium within 30 min, while the glycoside-dependent increment of inotropy ceased to continue. The kinetic properties of 16-acetyl-gitoxin were found to resemble more closely those of digitoxin than those of ouabain.

Studies on cardioactive steroids. V. Structure-activity relationships of derivatives of 16 alpha-gitoxin.

The potency of 17 derivatives of 16 alpha-gitoxin was tested in the isolated atrium and heart of the guinea pig and the contractility-increasing activity of the 16 alpha-gitoxin 16 alpha-acetate was compared with that of 16 alpha-gitoxin in the anesthetized dog. The potency of 16 alpha-gitoxin was increased by the substitution of 16 alpha-OH for 16 alpha-methyl ether, 16 alpha-acetate and 16 alpha-nitrate. Substitution of the 16 alpha-acetyl group for substituents with a higher molar volume diminished this enhanced potency. Variation in the digitoxose moiety caused an increase or decrease in potency depending on the position and number of the substituted OH groups. In spite of changes in 16 alpha-OH, the low influence on rhythmicity persisted, as was found in experiments in the dog.

[Influence of digitalis on pindolol activity in exercise-induced cardiac failure in patients with coronary disease (author's transl)]. / Einfluss von Digitalis auf die Pindolol-Wirkung bei Koronarkranken mit Belastungsherzinsuffizienz.

The activity of the beta-receptor blocker pindolol (0.4 mg i.v.) was investigated alone and in combination with digitalis (moderately fast loading) in 12 patients with coronary heart disease and without manifest signs of cardiac insufficiency. These patients showed pathological increase of left ventricular filling pressure during exercise testing. The exercise-induced rise of the mean pulmonary arterial and capillary pressures were increased by pindolol. Concurrently the increase of cardiac frequency was clearly diminished during ergometry (from 107/min without pindolol to 96/min, P less than 0.005). Digoxin given orally for an average of 5 days prevented the pressure increase in the pulmonary circulation induced by pindolol during exercise testing and at rest. The frequency reducing effect of pindolol was potentiated by digitalis. Use of digitalis alone did not influence mean exercise-induced pressure increase of the pulmonary circulation. In fact in some cases deterioration of these parameters was observed.

Cardiac effects of 16-acetyl-gitoxin, the active glycoside after penta-acetyl-gitoxin administration.

The inotropic and arrhythmogenic effects of 16-acetyl-gitoxin and digoxin were studied in isolated cardiac preparations and in anaesthetized dogs. ECG alteration-producing and lethal doses of both glycosides were determined in anaesthetized cats. In the isolated guinea-pig atrium, the properties of 16-acetyl-gitoxin are identical with those of ouabain, and in the isolated guinea-pig heart they are equal to those of digoxin, while gitoxin and penta-acetyl-gitoxin produce equieffective reactions at higher glycoside concentrations. In the cat, 75% of lethal doses of 16-acetyl-gitoxin and digoxin provoke ECG changes (qrs complex prolongation). The ratio of the lethal doses amounts to 1:2.8 and 1:3.5 (digoxin:16-acetyl-gitoxin). In case of equal contractile increment, the ratio of glycoside doses in dogs amounts to 1:1.3, while the percentages of rhythm disturbances following both glycosides are identical. Apart from slight deviations of the doses used, the cardiac properties of 16-acetyl-gitoxin are equal to those of digoxin.