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. 2001 Jul;86(1):81–87. doi: 10.1136/heart.86.1.81

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model

E du Toit 1, D Hofmann 1, J McCarthy 1, C Pineda 1
PMCID: PMC1729816  PMID: 11410569

Abstract

OBJECTIVE—To determine whether levosimendan, a calcium sensitiser that facilitates the activation of the contractile apparatus by calcium, improves myocardial contractile function during severe ischaemia and reperfusion without exacerbating the incidence of arrhythmias.
DESIGN—Pigs were pretreated orally twice daily for 10 days with 0.08 mg/kg levosimendan or placebo. On day 11 the left main coronary artery was ligated for 30 minutes, followed by 30 minutes of reperfusion. A bolus dose of levosimendan, 11.2 µg/kg intravenously, or placebo was given 30 minutes before coronary ligation, followed by a continuous infusion of 0.2 µg/kg/min levosimendan or placebo for the remainder of the experiment.
RESULTS—During the ischaemic period, cardiac output was higher in the levosimendan group than in the placebo group (mean (SD): 2.6 (0.5) v 2.0 (0.2) l/min, p < 0.05) and systemic vascular resistance was lower (2024 (188) v 2669 (424) dyne.s−1.cm−5, p < 0.005). During reperfusion, cardiac output and contractility (LVmaxdP/dt (pos), 956 (118) v 784 (130) mm Hg/s, p < 0.05) were increased by levosimendan. The incidence of ischaemic ventricular fibrillation and tachycardia was similar in the two groups but there were more arrhythmic events (ventricular tachycardia and ventricular fibrillation) in the levosimendan treated group (8/12 levosimendan v 1/9 control p = 0.05).
CONCLUSIONS—Levosimendan improved cardiac output and myocardial contractility during coronary artery ligation and reperfusion. However, it increased the number of arrhythmic events during ischaemia in this model of in vivo regional ischaemia.


Keywords: calcium sensitisers; myocardial ischaemia; arrhythmias

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Figure 1  .

Figure 1  

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Site of action of various inotropic agents. Most of the conventional inotropes increase cyclic adenosine monophosphate (cAMP), with a subsequent increase in intracellular calcium ion concentration which enhances contraction. However, increased calcium ion concentrations may promote arrhythmias, particularly during ischaemia and reperfusion. Calcium sensitisers such as levosimendan, pimobendan, and EMD 53998 may enhance myocardial contraction without increasing intracellular calcium ion concentration and the associated risk of increased arrhythmias. AMP, adenosine monophosphate; ATP, adenosine triphosphate; PDE, phosphodiesterase.

Figure 2  .

Figure 2  

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Diagrammatic representation of the experimental protocol. Animals were treated with levosimendan (levo) orally for 10 days. Thirty minutes before coronary artery ligation (CAL), animals were given a bolus dose of levosimendan intravenously, followed by a continuous infusion throughout coronary artery ligation and reperfusion.

Figure 3  .

Figure 3  

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Levosimendan increased blood flow in the peripheral ischaemic zone of the left ventricle before coronary artery ligation (before ischaemia) and during ischaemia and after reperfusion when compared with placebo treated hearts. The peripheral ischaemic zone was defined as the unstained (with patent blue) outer border of the ischaemic zone in the left ventricle. The ischaemic zone was delineated at the end of each experiment by injection of patent blue dye into the left atrium. *p < 0.05; **p < 0.001 (n = 5).

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