Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of the myocardium.
ABSTRACT Myocardial contractile function after coronary artery bypass graft surgery is often depressed and may require inotropic support, particularly in patients on treatment with beta-adrenergic and Ca2+ blockers. In view of the increase in cytosolic Ca2+ during early reperfusion, use of Ca2+ sensitizing agents may be preferable to adrenergic agonists for enhancement of contractile function after cardioplegic arrest. The aim of this study was to assess the efficacy of the Ca2+ sensitizer, levosimendan, as an inotrope on the mechanical recovery of hearts after normothermic and hypothermic cardioplegic arrest in the absence and presence of Ca2+ and beta-blockers. Isolated perfused working guinea pig hearts were perfused in the absence or presence of propranolol (10(-6) M) and/or nifedipine (10(-8) M), subjected to 45 minutes of normothermic or 180 minutes of hypothermic cardioplegic arrest, reperfused, and exposed to increasing concentrations of levosimendan (10(-9) to 10(-6) M). Levosimendan (10(-7) to 10(-6) M) has positive inotropic, chronotropic, and vasodilatory effects on normoxic perfused control hearts, as well as during reperfusion after 45 minutes of normothermic cardioplegic arrest. Similar effects were elicited in the presence of the blockers. Levosimendan had no stimulatory effect during reperfusion of hearts subjected to prior hypothermic arrest. Except for the increase in heart rate, the effects of levosimendan on functional performance during reperfusion were comparable with those of adrenaline. Levosimendan elicits a positive inotropic and chronotropic response during reperfusion of hearts after normothermic cardioplegic arrest, both in the absence and presence of Ca2+ and beta-adrenergic blockers.
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ABSTRACT: Levosimendan is a novel inodilator agent, which enhances myocardial performance without substantial changes in oxygen consumption. The combination of positive inotropic and vasodilator effects of levosimendan relates to its Ca-sensitizing and K channel opening effects. Levosimendan is one of the best documented pharmacological agents used in the management of acute heart failure syndromes. Interest in levosimendan has recently been renewed owing to its potential in supporting cardiac function in patients with ischemic heart disease and cardiogenic or septic shock. It has been also demonstrated that levosimendan can be used as a bridge therapy for the perioperative phase of cardiac surgery. The ability of levosimendan to improve myocardial function without substantially increasing oxygen consumption may appear paradoxical but is indeed possible via improved efficacy, not only with regard to the effects on the contractile apparatus of the cardiomyocytes but also when its composite hemodynamic effects are considered. The energy balance equation, therefore, should take into account the effect of levosimendan on all energy-consuming and energy-producing paths. Moreover, levosimendan-evoked KATP channel opening may possess favorable effects on mitochondrial adenosine triphosphate synthesis conferring cardioprotection during ischemic insults.Journal of cardiovascular pharmacology 04/2009; 53(4):302-10. · 2.83 Impact Factor
Article: Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone.[show abstract] [hide abstract]
ABSTRACT: 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.Journal of Cardiovascular Pharmacology 10/2005; 46(3):369-76. · 2.29 Impact Factor