Cardiotonic Drugs Research Articles

Pharmacological postconditioning by sevoflurane during cardiac surgery

Optimization of myocardial protection during cardiac surgery with a long period of anoxia infarction using sevoflurane postconditioning of myocardium. to develop the optimal pharmacological postconditioning protocol with sevoflurane for infarction patients ,undergoing cardiac surgery. Two groups were formedfor this study: CON] 00 (n-32) with aortic cross-clamping time 114±15 min and SEV100 group (n-34), where the myocardium anoxia was 119±22 minutes. According to previously developed in the pilot study Protocol, we added sevofturane in the circuit of extracorporeal circulation in a dose of 2.0 vol. % 20 minutes before removing the clamp from the aorta and the first 20 min of reperfusion in the group SE V100. In the group CON1 00 pharnacological postconditioning wasn't conducted. To assess the adequacy of the cardioprotection against ischemic damage in operated patients, we used the following clinical and laboratory parameters: changing the level of troponin T; the concentration of lactate and glucose as a marker of severity of anaerobic metabolism; concentration of proinflammatory cytokines IL-6, IL-8, TNF-alpha in blood serum as reperfusion injury markers. Also we used the registration of central hemodynamics data: measuring the mean invasive blood pressure; central venous pressure; Cardiac output was measured by the method of transesophageal echocardiography TEEcho-CG, calculated left ventricular ejection fraction by Simpson. We evaluated the clinical course of the perioperative period: incidence ofperioperative myocardial ischemia; the need and the duration ofuse of cardiotonic drugs in the perioperative period; the incidence of reperfusion arrhythmias; the frequency of self-recovery heart rate. According to the results of anaerobic metabolism markers, we can conclude that the period of the myocardium anoxia ofpatients in both groups experienced no significant difference. However; a completely different pattern was observed when comparing the proinflammatory cytokines, such as IL-6, IL-8, TNF-a. This confirms that the group SEV] 00 survived the reperfusion is much better than the group CON100. Instrumental examination also showed that the group ofpatients in which pharmacological postconditioning with sevofturane was held signficantly better suffered ischemia and reperfiision injury compared to control group. Self-recovery heart rate after removing the aorta clamp in the group CON100 was observed in 81%, in group SEV100 same - 93%. Similarly, the frequency of myocardial ischemia episodes on the ECG in reperfusion period was two times lower in the group SEV100 compared with group CON100 - 5.8% and 12.5% respectively. Reperfusion arrhythmia is almost 3 times more frequent in the group CON100 - 21,8%, in the group SEV100, where he conducted pharmacological postconditioning with sevoflurane is 8.8%.. Combined with sevoflurane cardioprotection FPC has a much better resistance to myocardial ischemia-reperfusion injury in patients with myocardial infarction time over 100 minutes than monoprotection with cardioplegic solution "Console ". This method can be recommended as an additional method ofprotection against myocardial ischemia-reperfusion injury.

Efficacy of different cardiotonic drug on severity of endotoxemia under heart failure coupled with systemic inflammatory syndrome in experiments

Efficacy of different cardiotonic drug on severity of endotoxemia under heart failure coupled with systemic inflammatory syndrome in experiments

Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca(2+) removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan.

Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca(2+) sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca(2+) handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca(2+)-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca(2+) sensitivity, in vitro cellular Ca(2+) homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca(2+) recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca(2+) sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca(2+) transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca(2+) extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) to Ca(2+) transient diastole in LPS-evoked sepsis but rather depressed Na(+)/Ca(2+) exchanger and plasmalemmal Ca(2+) ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca(2+) extrusion pathways resulting in intracellular diastolic Ca(2+) overload. Levosimendan, apart from stabilizing Ca(2+)-troponin C complexes, potently improves cellular Ca(2+) extrusion in the septic heart.

Characterization of degradation products of ivabradine by LC-HR-MS/MS: a typical case of exhibition of different degradation behaviour in HCl and H2SO4 acid hydrolysis.

A validated stability-indicating HPLC method was established, and comprehensive stress testing of ivabradine, a cardiotonic drug, was carried out as per ICH guidelines. Ivabradine was subjected to acidic, basic and neutral hydrolysis, oxidation, photolysis and thermal stress conditions, and the resulting degradation products were investigated by LC-PDA and LC-HR-MS/MS. The drug was found to degrade in acid and base hydrolysis. An efficient and selective stability assay method was developed on Phenomenex Luna C18 (250 × 4.6 mm, 5.0 µm) column using ammonium formate (10 mM, pH 3.0) and acetonitrile as mobile phase at 30 °C in gradient elution mode. The flow rate was 0.7 ml/min and detection wavelength was 286 nm. A total of five degradation products (I-1 to I-5) were identified and characterized by LC-HR-MS/MS in combination with accurate mass measurements. The drug exhibited different degradation behaviour in HCl and H2SO4 hydrolysis conditions. It is a unique example where two of the five degradation products in HCl hydrolysis were absent in H2SO4 acid hydrolysis. The present study provides guidance to revise the stress test for the determination of inherent stability of drugs containing lactam moiety under hydrolytic conditions. Most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation pattern of the drug and its degradation products. In silico toxicity revealed that the degradation products (I-2 to I-5) were found to be severe irritants in case of ocular irritancy. The analytical assay method was validated with respect to specificity, linearity, range, precision, accuracy and robustness.

Versatile cardiac troponin chimera for muscle protein structural biology and drug discovery.

Investigation of the molecular interactions within and between subunits of the heterotrimeric troponin complex, and with other proteins in the sarcomere, has revealed salient structural elements involved in regulation of muscle contraction. The discovery of new cardiotonic drugs and structural studies utilizing intact troponin, or regulatory complexes formed between the key regions identified in troponin C and troponin I, face intrinsic and technical difficulties associated with weak protein-protein interactions and with solubility, aggregation, stability of the overall architecture, isotope labeling, and size, respectively. We have designed and characterized a chimeric troponin C-troponin I hybrid protein with a cleavable linker that is useful for producing isotopically labeled troponin peptides, stabilizes their interaction, and has proven to be a faithful representation of the original complex in the systolic state, but lacking its disadvantages, making it particularly suitable for drug screening and structural studies.

INVESTIGATIONS OF THE INFLUENCE OF SUFAN ON MYOCARDIAL METABOLISM IN CASES OF EXPERIMENTAL HEART FAILURE

This article presents the results of an influence by the new non-glycoside structure, metabolic cardiotonic drug “sufan” on the energetic metabolism and oxidative homeostasis indicators—in myocardium, brain, and spleen of intact rats and rats with adriamycin-induced heart failure. It was established that sufan increased the coefficient of oxidative/reduced forms of nicotinamide coenzymes, reduced the adriamycin, causing deterioration of the energetic metabolism and the pro-oxidative-anti-oxidative homeostasis. The use of the non-glycoside structure cardiotonic drug, sufan, is recommended in order to prevent cardiotoxic effects of the anthracycline antibiotics.

Cardioprotective Effects of Indian Gooseberry (Emblica officinalis Gaertn) and its Phytochemicals: A Review

Emblica officinalis Gaertn or Phyllanthus emblica Linn, colloquially known as the Indian gooseberry or amla, is an important medicinal plant in the Indian traditional system of medicine, the Ayurveda and is classified as a Hrudya which when translated means cardiotonic drug. Numerous preclinical studies with laboratory animals have shown that amla does possess cardioprotective and anticoagulant effects and is useful in delaying/preventing/ reducing experimentally induced cardiotoxicity, atherosclerosis, myocardial infarction, hypertension and reducing ischemic-reperfusion injury. The pleiotropic effect of amla is believed to be due to the presence of various phytochemicals and studies have shown that the tannoids (emblicanin-A and –B), gallic acid, ellagic acid and corilagin also possess cardioprotective properties. Additionally, clinical studies have also shown that the regular intake of amla was effective in reducing the cholesterol levels and the effect to be similar to that of the conventionally used HMG CoA reductase inhibitor, simvastatin. Recent studies have also shown that amla improves endothelial function and reduced biomarkers of oxidative stress and systemic inflammation in patients with type 2 diabetes mellitus. This review for the first time summarizes the results related to these properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a cardioprotective/ cardiotonic therapeutic drug in humans.

PP-028 Investigation of the new metabolic cardiotonic drug sufan

BackgroundAdverse drug reactions are a major problem of modern pharmacotherapy. Many drugs’ side effects narrow their field of use; require special medical care and careful checks when they are used....

Cucurbit[7]uril assisted ultraviolet to visible fluorescence switch of a heart medicine

Host-guest interactions between cucurbit[7]uril (CB7) and a cardiotonic drug, milrinone, have been explored using steady state and pico-second time-resolved techniques. A novel fluorescence switch from ultraviolet (UV) to visible (cyan) is observed as a consequence of upward pKa shift of the drug inside the nano-cavity of cucurbit[7]uril.

Human cardiac troponin complex. Structure and functions

Troponin complex is a component of skeletal and cardiac muscle thin filaments. It consists of three subunits - troponin I, T, and C, and it plays a crucial role in muscle activity, connecting changes in intracellular Ca2+ concentration with generation of contraction. In spite of more than 40 years of studies, many aspects of troponin functioning are still not completely understood, and several models describing the mechanism of muscle contraction exist. Being a key factor in the regulation of cardiac muscle contraction, troponin complex is utilized in medicine as a target for some cardiotonic drugs used in the treatment of heart failure. A number of mutations in troponin subunits are associated with development of different types of cardiomyopathy. Moreover, for the last 25 years cardiac isoforms of troponin I and T have been widely used for immunochemical diagnostics of pathologies associated with cardiomyocyte death (myocardial infarction, myocardial trauma, and others). This review summarizes the existing evidence on the structure and function of troponin complex subunits, their role in the regulation of cardiac muscle contraction, and their clinical applications.

The genus Eremophila (Scrophulariaceae): an ethnobotanical, biological and phytochemical review

Eremophila (Scrophulariaceae) is an endemic Australian genus with 214 species, which is commonly known as Fuchsia bush, Emu bush or Poverty bush. Plants of this genus played an important role for the Australian Aborigines who used them widely for medicinal and ceremonial purposes. Many studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. Thorough phytochemical investigations of different Eremophila species have resulted in the isolation of more than 200 secondary metabolites of different classes with diterpenes as major constituents. Biological studies and traditional clinical practice demonstrated that Eremophila and its bioactive compounds possess various pharmacological properties. Plants were employed especially as a cardiotonic drug and also as potent anti-inflammatory, antimicrobial and antiviral agents. Further investigations are required to explore other Eremophila species, to evaluate the different biological activities of either their extracts or the isolated compounds and the possible underlying modes of action.

A review of pharmacognostical, phytochemical and pharmacological properties of Lagenaria siceraria: A miracle herb

Lagenaria siceraria (Bottle gourd) class Magnoliopsida family Cucurbitaceae is an excellent fruit in the nature consisting of all the essential constituents that are necessary for normal and good health of human beings. Lagenaria siceraria is official in Ayurvedic Pharmacopoeia. Traditionally, Lagenaria siceraria fruits had been used as a general tonic, cardiotonic, and cardioprotective drug. In addition, it had also been used as aphrodisiac, diuretic, antidote to certain poisons, scorpion stings, and alternative purgative. Lagenaria siceraria is also used to relieve pain, ulcers and fever. Scientific researches have shown that Lagenaria siceraria possesses anthelmintic, antibacterial, antifungal, immunomodulatory, anti-allergic, analgesic, anti-inflammatory, antioxidant, free radical scavenging, cytotoxic, antihyperlipidemic antidiabetic, hepatoprotective, anxiolytic and memory enhancing properties. In this review article we have tried to provide a detailed survey of the literature on the scientific researches of pharmacognostical, phytochemical and pharmacological properties of this wonderful herbal drug.

Characterization of a Cardiac Troponin C-Troponin I Chimera Protein

Association of the regulatory N-domain of cardiac troponin C (cNTnC) with the switch region of cardiac troponin I (cTnI147-163) is a major step in Ca2+ regulation of myocardial contraction by troponin as it triggers a series of downstream events that leads to contraction. Investigation of this interaction in the presence and absence of ligands, including Ca2+ and cardiotonic drugs, is important to understanding the regulation of cardiac contraction. This is commonly studied in vitro using isolated cNTnC and cTnI147-163; however, this does not accurately reflect the in situ environment since cNTnC and cTnI147-163 are spatially confined in the myofibril by being attached to their respective structural scaffold domains, the C-domain of cTnC (cCTnC) and the troponin T binding region of cTnI (cTnI80-136). We have designed, expressed and characterized a cardiac chimera (cChimera) protein containing cNTnC linked to cTnI144-173 through a linker containing a tobacco etch virus or thrombin protease cleavage site (similar to skeletal chimera of Tiroli et al, 2005). Our results show that Ca2+ binding to cChimera (KD 0.15 ± 0.05 μm) is tighter than to cNTnC (KD 2.6 ± 0.1 μm) and to that observed in skinned muscle fibers (KD 1.2 μm). We assessed binding of the calcium sensitizer dfbp-o, and desensitizer W7, and show that cChimera is particularly useful for studying and searching interactions of cNTnC-cTnI144-173 with potential agonists. Our cChimera also facilitates the production of the switch cTnI peptide using bacterial cultures by enzyme specific proteolysis after expression along with cNTnC. The dynamic properties of cChimera, along with Ca2+ and drug binding properties, make cChimera a convenient system for the investigation of regulation of troponin by small molecules that target the cTnC-cTnI interface.

A comparison of the effects of digoxin, ouabain and milrinone on naloxone-precipitated withdrawal syndrome in mice

Modulation of Na+, K+-ATPase activity by acute and chronic opiates has been established for many years. However, the effects of digoxin, a putative inhibitor of Na+, K+-ATPase, on naloxone-precipitated morphine withdrawal syndrome are unknown. In the present study, a digoxin dose-response curve was conducted to observe the effects on naloxone-precipitated withdrawal and locomotor activity in mice. Higher doses of digoxin (1.0 and 2.5mg/kg) inhibited locomotor activity and naloxone-precipitated withdrawal jumping and weight loss, while lower doses of digoxin (0.1 and 0.25mg/kg) inhibited withdrawal weight loss precipitated by naloxone without affecting locomotor activity and naloxone-precipitated withdrawal jumping. To explore the possible mechanisms underlying this behavior, another Na+, K+-ATPase inhibitor ouabain, which does not cross the blood brain barrier, and another cardiotonic drug milrinone, a non-inhibitor of Na+, K+-ATPase, were also included in the present study. Both milrinone and ouabain inhibited, in a dose-dependent manner, naloxone-precipitated weight loss while neither affected naloxone-precipitated withdrawal jumping nor locomotor activity in mice. These results indicate that both the cardiotonic effects and central inhibition of Na+, K+-ATPase contribute to the inhibitory effects of digoxin on morphine withdrawal syndrome in mice.

Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): A target for heart failure and platelet aggregation

Twenty-six 2-pyridone derivatives (8a–8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis–Hillman acetates (7a–7k) and enamino esters or nitriles (3a–3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.

Cardiovascular Catecholamine Receptors in Children: Their Significance in Cardiac Disease

Adrenoceptors and dopamine receptors are grouped together under the name 'catecholamine receptors.' Catecholamines and catecholaminergic drugs act on catecholamine receptors located on or near the cardiovascular system. The physiological effects of catecholamine receptor stimulation are only partly understood. The catecholaminergic drugs used in critical care medicine today are not selective, or are, at best, in part selective for the various catecholamine receptor subtypes. Many patients, however, depend on them. A variety of animal models has been developed to unravel catecholamine distribution and function. However, the identification of species heterogeneity makes it imperative to determine catecholamine receptor distribution and function in humans. In addition, age-related alterations in catecholamine receptor distribution and function have been identified in human adults. This might have implications for our understanding of the effect of catecholamines in pediatric patients. This article will focus on the pediatric population and will review currently available in vitro data on the distribution and the function of catecholamine receptors in the cardiovascular system of fetuses and children. Also discussed are relevant young animal models and in vivo hemodynamic effects of cardiotonic drugs acting on the catecholamine receptor in children requiring major cardiac surgery. A better understanding of these topics might provide clues for new, receptor subtype-selective, therapeutic approaches in newborns and children with cardiac disease.

Abstract 3461: A chemical screen for the identification of novel therapeutics for pediatric brain tumors

Abstract Treatment of brain tumors in children has greatly improved over the past decades, but current treatment protocols lack specificity, killing not only tumor cells, but also “healthy” normal brain cells. Moreover, current therapy still fails in approximately 20% of medulloblastoma patients, 50% of ependymomas and 80% of children suffering from high grade glioma. Treatment mostly consists of surgery, followed by chemotherapy and radiotherapy, and although this kind of therapy is among the most effective treatment options available, it is not sufficient. Therefore, new therapeutic drugs are required that specifically kill brain tumor cells and/or sensitize to irradiation, sparing normal brain tissue. In order to identify such novel compounds, drug screens were set up in a semi-high throughput format, using Gaussia luciferase (Gluc) activity as cell viability readout. As opposed to other forms of luciferase, Gluc is secreted in the medium, allowing the measurement of luciferase activity without lysing the cells. Since the Gluc signal has been shown to be linearly related to cell number, this assay can be used to determine cell viability at different points after drug treatment. In addition, an Acumen eX3 laser scanning cytometer was used in parallel, to determine cell number and cytometric parameters. We screened two small molecule libraries (2960 compounds) for cell growth inhibitory or radiosensitizing properties on pediatric high-grade glioma, ependymoma and medulloblastoma cell lines and primary patient material. Cells were incubated with a concentration of 1µM of the different compounds, either as single agent or in combination with 3 Gray irradiation, and cell viability was determined over a period of 4 days of incubation. A reduction of >75% of cell growth was considered to be significant. In general, 4 different groups of small molecules could be distinguished: 1) compounds that did not affect cell proliferation compared to controls, 2) compounds that block cell cycle progression, 3) compounds that induce cell death independently of irradiation, and 4) radiosensitizers. A total of 114 compounds was identified that inhibited cell growth and/or sensitized towards irradiation. Among the compounds that induced cell death were microtubule inhibitors, alkylating agents, topoisomerase inhibitors and anthracyclins. Besides these known anti-cancer agents we also identified a large number of cardiotonic drugs, benzimidazoles and limonoids that effectively killed brain tumor cells. We are currently investigating these hits and expanding our drug screens with additional primary pediatric brain tumor cells. In addition, we are repeating the screens on non neoplastic primary human cells, including astrocytes, to assess the therapeutic index of these drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3461. doi:10.1158/1538-7445.AM2011-3461

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 β-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 β-acetyldigoxin (by 24 and 19.5%, respectively), levosimendan (by 27 and 29%), and milrinone (by 26 and 24%). In contrast to β-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.

Beating-heart coronary artery bypass surgery with the help of mini extracorporeal circulation for very high-risk patients

Left ventricle dysfunction and co-morbidities are responsible for a large number of complications after coronary artery bypass graft (CABG) surgery. The best strategy for these patients, including the use or not and type of extracorporeal circulation (ECC), the use of minimized ECC (MECC), or conventional ECC (CECC), remains unclear. The aim of the present study was to investigate the potential effect of on-pump beating-heart (OPBH) surgery with the help of MECC for CABG in patients with a high-risk EuroSCORE and to compare this strategy to three other different procedures, including OPCAB and MECC or CECC with cardiac arrest. Patients were included if their EuroSCORE was strictly >" xbd="1427" xhg="1404" ybd="1477" yhg="1440"/>9. Four groups were retrospectively compared: an OPCAB, an OPBH, a MECC and a CECC group under cardiac arrest. 214 patients, mean age 74.26 ± 8.5 years, 68.7% male, were operated. Mean EuroSCORE was 12.1 ± 2.9, left ventricular (LV) function 37.4 ± 12.3%, recent myocardial infarction (MI) 49.5%, renal failure 48.1%, chronic obstructive pulmonary disease (COPD) 42.2%, and peripheral vascular disease (PVD) 55.6%. Mean number of grafts per patient was 2.4 ± 0.7. Our study showed that it was possible, in very high-risk patients, to carry out revascularisation with OPBH similar to that using MECC or CECC under cardiac arrest (p=NS). This technique reduces troponin release (3.23 vs 6.56, p<0.01), postoperative myocardial complications (2% vs 8%, p<0.01), cardiotonic drug prescription (15.7% vs 31.3%, p<0.01), ventilation time (4.57H vs 6.48H, p<0.01) and length of stay (LOS) in ICU (2.16 vs 2.53, p=0.02). The OPBH method seems to be safe, secure and effective in this population of very high-risk patients, reducing early complications and multi-organ failure. OPBH surgery, combining MECC without aortic cross-clamping, makes it possible to perform complete revascularization and is an interesting alternative for CABG in high-risk patients.

Comparative Therapeutic Effi cacy of Adenocin and Non-Glycoside Cardiotonic Drugs in Chronic Heart Failure at Rest and under Conditions of Heart Overload

Experiments were performed on the model of chronic heart failure. Functional capacity of myocardial structures under conditions of maximum pressure overload was within the upper limit of normal after treatment with Adenocin. The myocardial functional reserve and potential capacity index were shown to increase to normal under these conditions. Dobutamine, levosimendan, and milrinone increased functional capacity under conditions of maximum pressure overload. Treatment with adenocin restored diastolic function of the heart under conditions of maximum pressure overload. The end-diastolic pressure increased, but remained 1.7 times below the level observed in heart failure. After treatment with dobutamine and milrinone, the end-diastolic pressure (8th episode of ligation) did not differ from the level observed in heart failure, while after administration of levosimendan this parameter decreased by 31%. Contraction-relaxation coupling was completely restored under the influence of Adenocin in all episodes of ligation both before and after removal of the ligature. Nearly all animals with heart failure were resistant to 8 episodes of ligation after treatment with Adenocin (89 vs. 96% under normal conditions). Under these conditions, the survival rate of animals after administration of levosimendan, milrinone, and dobutamine was 65, 60, and 61%, respectively, (the mortality rate of animals with heart failure was 75%). Adenocin, a cardiotonic drug with cardioprotective properties, in contrast to other cardiotonic drugs, has a modulatory effect on the system of cell energy supply, restores myocardial reserves, and improves myocardial function under conditions of overload.