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István Edes

Publications and source records attributed to István Edes.

At least 19 recordsLinked to original sources
PubMed2006

Rate of tension redevelopment is not modulated by sarcomere length in permeabilized human, murine, and porcine cardiomyocytes.

The increase in Ca(2+) sensitivity of isometric force development along with sarcomere length (SL) is considered as the basis of the Frank-Starling law of the heart, possibly involving the regulation of cross-bridge turnover kinetics. Therefore, the Ca(2+) dependencies of isometric force production and of the cross-bridge-sensitive rate constant of force redevelopment (k(tr)) were determined at different SLs (1.9 and 2.3 mum) in isolated human, murine, and porcine permeabilized cardiomyocytes. k(tr) was also determined in the presence of 10 mM inorganic phosphate (P(i)), which interfered with the force-generating cross-bridge transitions. The increases in Ca(2+) sensitivities of force with SL were very similar in human, murine, and porcine cardiomyocytes (DeltapCa(50): approximately 0.11). k(tr) was higher (P < 0.05) in mice than in humans or pigs at all Ca(2+) concentrations ([Ca(2+)]) [maximum k(tr) (k(tr,max)) at a SL of 1.9 mum and pCa 4.75: 1.33 +/- 0.11, 7.44 +/- 0.15, and 1.02 +/- 0.05 s(-1), in humans, mice, and pigs, respectively] but k(tr) did not depend on SL in any species. Moreover, when the k(tr) values for each species were expressed relative to their respective maxima, similar Ca(2+) dependencies were obtained. Ten millimolar P(i) decreased force to approximately 60-65% and left DeltapCa(50) unaltered in all three species. P(i) increased k(tr,max) by a factor of approximately 1.6 in humans and pigs and by a factor of approximately 3 in mice, independent of SL. In conclusion, species differences exert a major influence on k(tr), but SL does not appear to modulate the cross-bridge turnover rates in human, murine, and porcine hearts.

Adult↗
PubMed2006

H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice.

Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H(2)O(2)) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles ( approximately 100 microm in diameter) of mice with T2-DM (C57BL/KsJ-db(-)/db(-)) exhibited greater basal tone to increases in intraluminal pressure (20-120 mmHg) than that of control vessels (at 80 mmHg, control: 25 +/- 5%; db/db: 34 +/- 4%, P < 0.05), which was reduced back to control level by catalase (db/db: 24 +/- 4%). Correspondingly, in carotid arteries of db/db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H(2)O(2) was significantly greater. In control arterioles, exogenous H(2)O(2) (0.1-100 micromol/l) elicited dilations (maximum, 58 +/- 10%), whereas in arterioles of db/db mice H(2)O(2) caused constrictions (-28 +/- 8%), which were converted to dilations (maximum, 16 +/- 5%) by the thromboxane A(2)/prostaglandin H(2) (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H(2)O(2)-induced arteriolar responses in either control or db/db mice. Also, in arterioles of db/db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H(2)O(2) is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A(2)/prostaglandin H(2) in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.

Animals↗
PubMed2006

[Increase of homocysteine in cardiovascular diseases in Hungary].

UNLABELLED: There are only very few epidemiological data about homocysteine levels in patients suffering from cardiovascular (CV) disease in Hungary, however, homocysteine is a newly recognized, independent risk factor of CV diseases. AIM OF THE STUDY: Therefore, in the present study, data of 1010 East-Hungarian patients with signs of CV disease were analyzed retrospectively for correlation between the level of homocysteine and CV diseases, laboratory parameters, as well as genetic differences. PATIENTS AND METHODS: From the studied patient population a control ("healthy") group has been selected according to the following criteria: lack of previous stroke or stenosis of the carotid arteries or the lower extremities, lack of coronary artery stenosis more than 50%, no previous coronary intervention or an angiography diagnosed progression of the coronary atherosclerosis. RESULTS: The level of homocysteine showed statistically significant negative linear correlation with HDL-cholesterol and the anti-atherogenic ApoAI, and showed a positive correlation with CRP and FXIII activities in the entire patient population. When compared to the control group, homocysteine level was significantly higher in patients with previous stroke or acute myocardial infarction, coronary stenosis, progressive coronary disease, physical inactivity, MTHFR gene polymorphism, low folate or vitamin B12 level in both men and women. In patients with type II diabetes the level of homocysteine was significantly higher only in women. CONCLUSIONS: It can be concluded that the level of homocysteine in patients suffering from various CV diseases is high in Hungary. This may have a prognostic value, and shows that reduction of homocysteine level in these patients may be beneficial.

Adult↗
PubMed2006

Increased cyclooxygenase-2 expression and prostaglandin-mediated dilation in coronary arterioles of patients with diabetes mellitus.

Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2-dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(-). Isolated arterioles (89+/-15 microm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(-): 32+/-7%; DM(+): 37+/-5%; P=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 micromol/L) were significantly (P<0.05) greater in DM(+) than DM(-) patients (10 nmol/L: 77+/-10% versus 38+/-14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(-), patients' bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20+/-4% and 29+/-7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(-) patients. We conclude that in coronary arterioles of diabetic patients bradykinin induces enhanced COX-2-derived prostaglandin-mediated dilation. These findings are the first to show that in humans diabetes mellitus increases COX-2 expression and dilator prostaglandin synthesis in coronary arterioles, which may serve to increase dilator capacity and maintain adequate perfusion of cardiac tissues.

Aged↗
PubMed2006

[Lowering cholesterol: how low is low enough?].

The mean cholesterol level of the civilized modern humans is above the one considered "physiological", and a biological gradient exists between serum cholesterol level and cardiovascular events. Clinical studies on cholesterol lowering revealed that cardiovascular risk can be lowered in parallel along this gradient, and the "lower is better" rule appears to be supported by the current evidence. LDL cholesterol level should minimally be reduced on average by 50% to approach the "physiological" cholesterol concentration in order to halt the progression of atherosclerosis. Using the initial doses of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the first-line lipid lowering drugs, this goal cannot be reached. On the other hand, high doses of statins increase the frequency of adverse events, which should contribute to the common failure of putting patients to their lipid targets in a real-world setting. Consequently, the combination of low dose statins and another cholesterol lowering agent with a mechanism of action different than synthesis inhibition (such as ezetimibe) may be the optimal clinical approach to avoid the dose-dependent adverse events. The ongoing large head-to-head clinical trials will clarify the efficacy and safety of cholesterol lowering combination therapy relative to statins in the reduction of cardiovascular risk.

Anticholesteremic Agents↗
PubMed2006

High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion.

Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: approximately 160 microm) of HFD, rat dilations to ACh (at 1 microM, maximum: 83 +/- 3%) and histamine (at 10 microM, maximum: 16 +/- 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 +/- 2 and 46 +/- 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N(omega)-nitro-l-arginine methyl ester reduced ACh- and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD rats. The superoxide dismutase mimetic Tiron or xanthine oxidase inhibitor allopurinol enhanced ACh (maximum: 90 +/- 2 and 93 +/- 2%, respectively)- and histamine (maximum: 30 +/- 7 and 37 +/- 8%, respectively)-induced dilations in HFD arterioles, whereas the NAD(P)H oxidase inhibitor apocynin had no significant effect. Correspondingly, in carotid arteries of HFD rats, an enhanced superoxide production was shown by lucigenin-enhanced chemiluminescence, in association with an increased xanthine oxidase, but not NAD(P)H oxidase activity. In addition, a marked xanthine oxidase immunostaining was detected in the endothelial layer of the gracilis arterioles of HFD, but not in control rats. These findings suggest that, in obese rats, NO mediation of endothelium-dependent dilation of skeletal muscle arterioles is reduced because of an enhanced xanthine oxidase-derived superoxide production. These alterations demonstrate substantial dysregulation of arteriolar tone by the endothelium in HFD-induced obesity, which may contribute to disturbed tissue blood flow and development of increased peripheral resistance.

Acetylcholine↗
PubMed2006

The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles.

1. We characterized the vasoactive effects of OR-1896, the long-lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. 2. The effect of OR-1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (approximately 150 microm) diameters was investigated by videomicroscopy. 3. OR-1896 elicited concentration-dependent (1 nM-10 microM) dilations in coronary (maximal dilation: 66+/-6%, relative to that in Ca2+-free solutions; pD2: 7.16+/-0.42) and gracilis muscle arterioles (maximal dilation: 73+/-4%; pD2: 6.71+/-0.42), these dilations proving comparable to those induced by levosimendan (1 nM-10 microM) in coronary (maximal dilation: 83+/-6%; pD2: 7.06+/-0.14) and gracilis muscle arterioles (maximal dilation: 73+/-12%; pD2: 7.05+/-0.1). 4. The maximal dilations in response to OR-1896 were significantly (P<0.05) attenuated by the nonselective K+ channel inhibitor tetraethylammonium (1 mM) in coronary (to 34+/-9%) and gracilis muscle arterioles (to 28+/-6%). 5. Glibenclamide (5 or 10 microM), a selective ATP-sensitive K+ channel (KATP) blocker, elicited a greater reduction of OR-1896-induced dilations in skeletal muscle arterioles than in coronary microvessels. 6. Conversely, the selective inhibition of the large conductance Ca2+-activated K+ channels (BK(Ca)) with iberiotoxin (100 nM) significantly reduced the OR-1896-induced maximal dilation in coronary arterioles (to 21+/-6%), but was ineffective in skeletal muscle arterioles (72+/-8%). 7. Accordingly, OR-1896 elicits a substantial vasodilation in coronary and skeletal muscle arterioles, by activating primarily BK(Ca) and K(ATP) channels, respectively, and it is suggested that OR-1896 contributes to the long-term hemodynamic effects of levosimendan.

Acetamides↗
PubMed2006

Effects of ad hoc clopidogrel loading versus pre-treatment on P-selectin expression after coronary stent implantation.

Stents represent a thrombogenic surface where one of the earliest events is the deposition of platelets. Activated platelets express neoepitopes that enable them to form homo- and heterotypic aggregates and activate the coagulation system. In this study, we investigated the effects of ad hoc clopidogrel treatment compared to a clopidogrel pretreated group on platelet P-selectin expression. We found that after stent implantation in the ad hoc treated group, P-selectin expression decreased after 1 h, while the initial decrease in platelet count normalized after 4 h. Aspirin non-responsiveness did not influence the results. These data point to the beneficial effect of clopidogrel treatment in reducing platelet reactivity during stenting.

Clopidogrel↗
PubMed2006

Mistyping of angiotensinogen M235T alleles.

Conflicting results are to be found in the literature on the relationship between the M235T polymorphism of the angiotensinogen (AGT) gene and hypertension. The controversy may be due to insufficient numbers of subjects, the variability of the inclusion criteria and the different genotype analysis methods used. We have experienced that the most frequently used, original polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method involves significant uncertainties when the TT genotype is determined, independently of the restriction digestion. To make the determination more accurate, we improved the PCR by designing a new antisense primer containing only one mismatch instead of the two in the original protocol and also by adding DMSO to the PCR reaction mixture. The original and our improved methods were compared by using DNA from 123 patients: parallel determinations resulted in values of 33 MM, 90 MT and 0 TT with the original method and of 33 MM, 56 MT and 34 TT with the improved RFLP protocol. In summary, a plausible explanation for some of the conflicting data published on AGT M235T polymorphism may be that inaccuracies arose during the determination of the genotype.

Angiotensinogen↗
PubMed2005

Phosphorylation-dependent desensitization by anandamide of vanilloid receptor-1 (TRPV1) function in rat skeletal muscle arterioles and in Chinese hamster ovary cells expressing TRPV1.

It has been proposed that activation of vanilloid receptor-1 (TRPV1) affects the vasotone of resistance arteries. One of the endogenous activators of TRPV1 is anandamide. The effects of anandamide on TRPV1 responsiveness were tested on isolated, pressurized (80 mm Hg) skeletal muscle (m. gracilis) arterioles (179 +/- 33 microm in diameter). We found that the TRPV1 agonist capsaicin (1 microM) elicited a substantial constriction in isolated arterioles (51 +/- 12%). In contrast, anandamide (0-100 microM) did not affect arteriolar diameter significantly (3 +/- 5%). Isolated vessels were also preincubated with anandamide (30 microM for 20 min). This anandamide pretreatment completely blocked capsaicin-induced arteriolar constriction (response decreased to 1 +/- 0.6%), and this inhibition was reversed by a protein phosphatase-2B inhibitor (cyclosporin-A; 100 nM, 5 min) treatment (constriction, 31 +/- 1%). An exogenous TRPV1-expressing cell line [Chinese hamster ovary (CHO)-TRPV1] was used to specifically evaluate TRPV1-mediated effects of anandamide. The efficacy of anandamide in this system, as determined by 45Ca2+ uptake, was 65 +/- 8% of that of capsaicin. Upon treatment of the cells with cyclosporin-A or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), anandamide was transformed to a full agonist. Anandamide treatment caused an acute desensitization in these cells as measured by intracellular Ca2+ imaging. Application of cyclosporin-A or PMA reversed this desensitization. Our data suggest that anandamide may cause a complete (albeit phosphorylation-dependent) desensitization of TRPV1 in skeletal muscle arterioles and in CHO-TRPV1 cells, which apparently transforms the ligand-gated TRPV1 into a phosphorylation-gated channel. This property of anandamide may provide a new therapeutic strategy to manipulate TRPV1 activity.

Animals↗
PubMed2005

[Current practice and future perspectives of myocardial stem cell therapy].

Myocardial infarction became more frequent mainly in the developed countries in the past decades. Beside the pharmacological (thrombolysis, beta-blockers, ACE-inhibitors, antiplatelet- and lipid-lowering drugs, etc.) and interventional (percutaneous coronary intervention, intraaortic balloon pump, resynchronization therapy, left ventricular assist devices etc.) procedures the quality of life of patients and the morbidity and mortality data were improved. However we experience development of heart failure following myocardial infarction because of significant cell loss and left ventricular remodeling. Until now there was not any therapeutic procedure affecting via cardiomyocyte renewal, but in the last 5 years the myocardial stem cell therapy was introduced to human clinical phase. In this review the authors summarized the general features of stem cells, why these cells are in the focus of the interest and their preclinical and clinical applications in myocardial infarction. Promising issues suggests, that intramyocardial implantation of autologous bone marrow derived stem cells become a new therapeutic modality in treatment of myocardial infarction. The stem cell therapy and regenerative medicine would open new perspectives in cardiology. However it is very important to remark, that this, as every medical procedure can be dangerous and can cause side effects. A lot of molecular and cellular mechanism of cell therapy is not clear at present, that's why we should be careful with this opportunity holding in our hands. We have to plan multicenter clinical trials to evaluate the long term safety and efficacy of the procedure.

Angioplasty, Balloon, Coronary↗
PubMed2005

Peroxynitrite-induced alpha-actinin nitration and contractile alterations in isolated human myocardial cells.

OBJECTIVE: Peroxynitrite-mediated myocardial protein nitration has been associated with a depressed cardiac pump function. In the present study, an attempt was made to elucidate the molecular background of peroxynitrite-evoked alterations in the human myocardium. METHODS: Isometric force generation was measured in permeabilized human ventricular myocytes and biochemical methods were employed to identify the proteins affected by peroxynitrite-induced nitrotyrosine formation. RESULTS: The maximal Ca(2+)-activated isometric force (pCa=4.75) decreased to zero with increasing concentrations of peroxynitrite in a concentration-dependent manner (IC50: 55+/-4 microM; based on a total of 75 myocytes). However, there were no differences before and after the application of 50 microM peroxynitrite in the Ca(2+)-sensitivity of force production (pCa50: 5.89+/-0.02 and 5.86+/-0.04), in the steepness of the Ca(2+)-force relationship (nHill: 2.22+/-0.11 and 2.42+/-0.25), and in the actin-myosin turnover kinetics (k(tr) at saturating [Ca2+]: 1.14+/-0.03 1/s and 1.05+/-0.07 1/s) (P>0.05). Nevertheless, 50 muM peroxynitrite greatly deteriorated the cross-striation pattern and induced a slight, but significant, increase in the passive force component (from 2.1+/-0.1 to 2.5+/-0.2 kN/m2; n=57 cells), reflecting ultrastructural alterations. Western immunoblots revealed that 50 microM peroxynitrite selectively induced the nitration of a protein with an apparent molecular mass of about 100 kDa. Subsequent immunoprecipitation assays identified this nitrated protein as alpha-actinin, a major Z-line protein. CONCLUSIONS: These results suggest alpha-actinin as a novel target for peroxynitrite in the human myocardium; its nitration induces a contractile dysfunction, presumably by decreasing the longitudinal transmission of force between adjacent sarcomeres.

Actinin↗
PubMed2005

Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain.

The vanilloid receptor (TRPV1 or VR1) is a molecular integrator of various painful stimuli, including capsaicin, acid, and high temperature. It can also be activated by endogenous ligands, like the cannabinoid 1 receptor (CB1) agonist anandamide. TRPV1 is well characterized at the terminals of sensory nerves involved in the pain pathway. There is also evidence that TRPV1 is expressed in the brain but little is known about its function. Here, using commercially available specific antibodies to investigate the localization of TRPV1 in the brain of the rat, we report that TRPV1 was expressed in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. Immunohistochemical analyses showed high expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. To address the question of subcellular localization, immunoelectronmicroscopy was used. TRPV1-like staining was detected in the synapses (mostly, but not exclusively in post-synaptic dendritic spines), on the end feet of astrocytes and in pericytes. In summary, TRPV1 expression shows wide distribution in the brain of the rat, being found in astrocytes and pericytes as well as in neurons. Its localization is consistent with multiple functions within the central nervous system, including the regulation of brain vasculature.

Animals↗
PubMed2005

Calpain-1-sensitive myofibrillar proteins of the human myocardium.

Calpain-1 is a ubiquitous intracellular Ca2+-activated protease, which has been implicated in the pathogenesis of reversible myocardial depression (i.e. myocardial stunning) that follows ischemia and reperfusion via myofibrillar protein degradation. However, the target proteins of this degradative process in the human myocardium have not yet been identified. In order to compare the levels of Calpain-1 susceptibility within a set of human myofibrillar proteins (titin, alpha-fodrin, desmin, troponin T (cTnT), troponin I (cTnI) and alpha-actinin), crude left ventricular tissue homogenates were incubated for 0.5, 15, 30, 60 or 120 min in the presence of Calpain-1 (1 U or 5 U). Differences in the kinetics and extents of protein degradation were subsequently evaluated by using silver-stained SDS-polyacrylamide gels and Western immunoblot analyses. These assays revealed myofibrillar proteins with high (titin and alpha-fodrin), moderate (desmin and cTnT), or low (cTnI and alpha-actinin) relative Calpain-1 susceptibilities. The level of phosphorylation of cTnI did not explain its relatively low Calpain-1 susceptibility. Moreover, the molecular mass distributions of the truncated alpha-fodrin, desmin and cTnI fragments resulting from Ca2+-dependent autoproteolysis exhibited marked similarities with those of their Calpain-1-clipped products. These in vitro results shed light on a number of structural (titin, alpha-fodrin, desmin and alpha-actinin) and regulatory (cTnT and cTnI) proteins within the contractile apparatus as potential targets of Calpain-1. Their degradation may contribute to the development of postischemic stunning in the human myocardium.

Actinin↗
PubMed2005

Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone.

We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P<0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P<0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8+/-8% (mean+/-SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 microM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Pharmacological mechanisms contributing to the clinical efficacy of levosimendan.

Acute decompensation of chronic heart failure is a direct life-threatening situation with short-term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+-sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+-sensitization through binding to troponin C in the myocardium, and the opening of ATP-sensitive K+ channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long-term benefits on mortality following short-term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of preclinical and clinical investigations suggest that the combination of levosimendan-induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+-sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP-sensitive K+ channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.

Animals↗