J Pharmacol Exp Ther. 1999 Aug;290(2):505-14.

Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.

The Journal of pharmacology and experimental therapeutics

E F Du Toit, C A Muller, J McCarthy, L H Opie

PMID: 10411556

Abstract

The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. Left ventricular developed pressure (LVDP) was used as an index of mechanical function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence of ischemia/reperfusion arrhythmias was also investigated. Control hearts (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of control hearts, 25% developed reperfusion ventricular tachycardia but not ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts.

Substances

• Anti-Arrhythmia Agents
• Calcium Channel Agonists
• Calcium Channel Blockers
• Hydrazones
• Nucleotides, Cyclic
• Pyridazines
• Phosphocreatine
• Lactic Acid
• Simendan
• Dobutamine
• Adenosine Triphosphate
• Cyclic AMP
• L-Lactate Dehydrogenase
• Cyclic GMP
• Glyburide

MeSH terms

• Adenosine Triphosphate / metabolism
• Animals
• Anti-Arrhythmia Agents / chemistry
• Anti-Arrhythmia Agents / pharmacology
• Arrhythmias, Cardiac / physiopathology
• Arrhythmias, Cardiac / prevention & control
• Calcium Channel Agonists / chemistry
• Calcium Channel Agonists / pharmacology
• Calcium Channel Blockers / pharmacology
• Cyclic AMP / metabolism
• Cyclic GMP / metabolism
• Dobutamine / pharmacology
• Glyburide / pharmacology
• Guinea Pigs
• Heart / drug effects
• Hydrazones / chemistry
• Hydrazones / pharmacology
• In Vitro Techniques
• L-Lactate Dehydrogenase / metabolism
• Lactic Acid / metabolism
• Myocardial Contraction / drug effects
• Myocardial Ischemia / metabolism
• Myocardial Ischemia / physiopathology
• Myocardial Reperfusion Injury / metabolism
• Myocardial Reperfusion Injury / physiopathology
• Myocardial Reperfusion Injury / prevention & control
• Myocardium / enzymology
• Myocardium / metabolism
• Nucleotides, Cyclic / metabolism
• Phosphocreatine / metabolism
• Pyridazines / chemistry
• Pyridazines / pharmacology
• Simendan
• Stereoisomerism

Publication Types

• Journal Article