Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

NEP inhibitors enhance C-type natriuretic peptide-induced relaxation in porcine isolated coronary artery.

C-type natriuretic peptide (CNP), a local regulator of vascular tone and cell proliferation, is eliminated from the circulation via NPR-C receptors and neutral endopeptidase enzyme (NEP, EC. 3.4.24.11). The increased contractility of coronary arteries in different cardiovascular diseases made us study the possible enhancement of vasodilator capacity of exogenously added CNP with concomitant NEP inhibition on porcine coronary arteries in vitro. CNP (0.006-1.4 microM) concentration dependently relaxed the U46619 (0.07-0.4 microM) precontracted preparations in an almost equally effective manner in the presence and absence of functional endothelium with maximum effects of about 40%. The combined NEP/endothelin-converting enzyme inhibitor (NEP/ECE inhibitor), phosphoramidon (10 microM) or the specific inhibitor of the NEP, thiorphan (10 microM) resulted in an enhanced magnitude of CNP-induced relaxation without significant change in the EC50 both on endothelium intact and endothelium deprived preparations. The inhibition of endothelin receptors by PD 142893 (10 microM) enhanced the relaxing effect of CNP in the presence but not in the absence of functional endothelium indicating a functional antagonism between CNP and endothelin. Our results suggest that inhibition of CNP degradation may endue this endogenous peptide with therapeutic potency in cardiovascular diseases.

Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery.

Levosimendan, a new type of inodilator drugs, is known to activate membrane adenosine 3',5'-triphosphate-sensitive potassium (KATP) channels in some vascular smooth muscles and causes vasorelaxation. The involvement of potassium channels in the mechanism of the coronary artery relaxing effect of the drug has not been established. In the present study performed in the porcine epicardial coronary artery, the effect of levosimendan (0.009-3.2 microM) was compared to cromakalim (0.0125-5 microM), the known activator of ATP-sensitive potassium (KATP) channels, in the presence of glibenclamide (GLI), an inhibitor of KATP channels and tetraethylammonium (TEA), the non-selective inhibitor of potassium channels. The interaction of levosimendan with the specific calcium-activated potassium channel (KCa) blocker, iberiotoxin (IBTX), and the voltage-sensitive potassium channel (KV) blocker, 4-aminopyridine (4-AP), was also studied. All the experiments were performed in the isometric tension of endothelium denuded porcine isolated epicardial coronary arteries precontracted with 20 mM potassium chloride. 1 microM GLI decreased the maximum of cromakalim-induced relaxation by 60% but did not affect the action of levosimendan. In contrast, 2 mM TEA decreased only the coronary artery relaxing effect of levosimendan. 100 nM IBTX suppressed the maximum effect of levosimendan by only 15% while 0.5 mM 4-AP significantly shifted the concentration-response curve of the inodilator to the right. 5 mM 4-AP caused a maximum of 33% decrease of levosimendan-induced relaxation. These results indicate that, in porcine isolated epicardial coronary artery, the vasorelaxing mechanism of levosimendan involves the activation of voltage-sensitive and, at large concentrations, calcium-activated potassium channels.