Levosimendan : Studies on its mechanisms of action and beyond

Acute heart failure syndrome represents a prominent and growing health problem all around the world. Ideally, medical treatment for patients admitted to hospital because of this syndrome, in addition to alleviating the acute symptoms, should also prevent myocardial damage, modulate neurohumoral and inflammatory activation, and preserve or even improve renal function. Levosimendan is a cardiac enhancer having both inotropic and vasodilatory effects. It is approved for the short-term treatment of acutely decompensated chronic heart failure, but it has been shown to have beneficial clinical effects also in ischemic heart disease and septic shock as well as in perioperative cardiac support. In the present study, the mechanisms of action of levosimendan were studied in isolated guinea-pig heart preparations: Langendorff-perfused heart, papillary muscle and permeabilized cardiomyocytes as well as in purified phosphodiesterase isoenzyme preparations. Levosimendan was shown to be a potent inotropic agent in isolated Langendorff-perfused heart and right ventricle papillary muscle. In permeabilized cardiomyocytes, it was demonstrated to be a potent calcium sensitizer in contrast to its enantiomer, dextrosimendan. It was additionally shown to be a very selective phosphodiesterase (PDE) type-3 inhibitor, the selectivity factor for PDE3 over PDE4 being 10000 for levosimendan. Irrespective of this very selective PDE3 inhibitory property in purified enzyme preparations, the inotropic effect of levosimendan was demonstrated to be mediated mainly through calcium sensitization in the isolated heart as well as the papillary muscle preparations at clinically relevant concentrations. In the isolated Lagendorff-perfused heart, glibenclamide antagonized the levosimendan-induced increase in coronary flow (CF). Therefore, the main vasodilatory mechanism in coronary veins is believed to be the opening of the ATP-sensitive potassium (KATP) channels. In the paced hearts, CF did not increase in parallel with oxygen consumption (MVO2), thus indicating that levosimendan had a direct vasodilatory effect on coronary veins. The pharmacology of levosimendan was clearly different from that of milrinone, which induced an increase in CF in parallel with MVO2. In conclusion, levosimendan was demonstrated to increase cardiac contractility by binding to cardiac troponin C and sensitizing the myofilament contractile proteins to calcium, and further to induce coronary vasodilatation by opening KATP channels in vascular smooth muscle. In addition, the efficiency of the cardiac contraction was shown to be more advantageous when the heart was perfused with levosimendan in comparison to milrinone perfusion.Sydämen akuutti vajaatoiminta muodostaa maailmanlaajuisesti huomattavan ja yhä laajenevan terveydenhoito-ongelman. Kyseessä on sairaalahoitoa vaativa oireyhtymä, jossa optimaalisen lääkehoidon tulee olla paitsi oireenmukaista, myös ehkäistä sydänlihas- ja munuaisvauriota sekä hillitä neurohumoraalista aktivaatiota ja tulehdusreaktioita. Levosimendaani on sydämen supistusvireyttä lisäävä aine, jolla on myös verisuonia laajentava ominaisuus. Se on hyväksytty akuutisti dekompensoituneen kroonisen vajaatoiminnan lyhytaikaiseen hoitoon. Sillä on kuitenkin edullisia vaikutuksia myös iskeemisessä vajaatoiminnassa ja septisessä sokissa sekä perioperatiivisena kardiologisena tukena. Tässä työssä levosimendaanin vaikutusmekanismeja tutkittiin eristetyissä marsun sydänlihaspreparaateissa: Langendorff-perfusoidussa sydämessä, papillaarilihaksessa ja permeabilisoiduissa sydänlihassoluissa sekä puhdistetuissa fosfodiesteraasi-isoentsyymi (PDE) preparaateissa. Levosimendaani lisäsi supistusvireyttä voimakkaasti sekä eristetyssä sydämessä, että papillaarilihaksessa. Sydänlihassoluissa se osoittautui tehokkaaksi kalsiumherkistäjäksi, toisin kuin sen optinen enantiomeeri, dextrosimendaani. Lisäksi se osoittautui erittäin valikoivaksi PDE tyyppi-3 estäjäksi. Selektiivisyys PDE3:n ja PDE4:n välillä oli 10 000 kertainen. Huolimatta PDE3:a estävästä ominaisuudesta, levosimendaanin supistusvireyttä lisäävän vaikutuksen eristetyssä sydämessä ja papillaarilihaksessa osoitettiin välittyvän kalsiumherkkyyttä lisäävän ominaisuuden kautta. Eristetyssä sydämessä glibenklamidi esti levosimendaanin aiheuttaman sepelvaltimovirtauksen nousun. Näin ollen sepelsuonia laajentava vaikutus näyttäisi välittyvän ATP-herkkien kaliumkanavien (KATP) kautta. Tahdistetussa sydämessä levosimendaanin aiheuttama sepelvaltimovirtauksen nousu ei ollut yhdensuuntainen hapenkulutuksen nousun kanssa. Tämä osoittaa, että levosimendaanilla oli suora sepelsuonia laajentava vaikutus. Levosimendaanin farmakologinen vaikutus oli selvästi erilainen kuin milrinonin, joka lisäsi sepelvaltimovirtausta yhdensuuntaisesti hapenkulutuksen nousun kanssa. Tässä työssä osoitettiin, että levosimendaanin sydämen supistusvireyttä lisäävä ominaisuus liittyy sen sitoutumiseen sydänlihassolun troponiini C molekyyliin ja tätä kautta supistuvien proteiinien lisääntyvään kalsiumherkkyyteen ja että, sepelvaltimovirtausta lisäävä ominaisuus liittyy sen KATP kanavia avaavaan ominaisuuteen. Lisäksi osoitettiin, että levosimendaanilla perfusoidun sydämen supistusvireyden nousu oli hapenkulutukseltaan edullisempaa kuin milrinonilla perfusoidun sydämen supistusvireyden nousu

Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat

Peer reviewe

Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy

Angiotensin II (Ang II) induces mitochondrial dysfunction. We tested whether Ang II alters the "metabolomic" profile. We harvested hearts from 8-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGRs) and controls (Sprague-Dawley), all with or without Ang II type 1 receptor (valsartan) blockade. We used gas chromatography coupled with time-of-flight mass spectrometry to detect 247 intermediary metabolites. We used a partial least-squares discriminate analysis and identified 112 metabolites that differed significantly after corrections (false discovery rate q <0.05). We found great differences in the use of fatty acids as an energy source, namely, decreased levels of octanoic, oleic, and linoleic acids in dTGR (all P<0.01). The increase in cardiac hypoxanthine levels in dTGRs suggested an increase in purine degradation, whereas other changes supported an increased ketogenic amino acid tyrosine level, causing energy production failure. The metabolomic profile of valsartan-treated dTGRs more closely resembled Sprague-Dawley rats than untreated dTGRs. Mitochondrial respiratory chain activity of cytochrome C oxidase was decreased in dTGRs, whereas complex I and complex II were unaltered. Mitochondria from dTGR hearts showed morphological alterations suggesting increased mitochondrial fusion. Cardiac expression of the redox-sensitive and the cardioprotective metabolic sensor sirtuin 1 was increased in dTGRs. Interestingly, valsartan changed the level of 33 metabolites and induced mitochondrial biogenesis in Sprague-Dawley rats. Thus, distinct patterns of cardiac substrate use in Ang II-induced cardiac hypertrophy are associated with mitochondrial dysfunction. The finding underscores the importance of Ang II in the regulation of mitochondrial biogenesis and cardiac metabolomics, even in healthy hearts

Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure

Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage