Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation

• Published in: British journal of pharmacology Vol. 177; no. 19; pp. 4448 - 4463
• Main Authors: Moreira Souza, Ana Carolina, Grabe‐Guimarães, Andrea, Cruz, Jader dos Santos, Santos‐Miranda, Artur, Farah, Charlotte, Teixeira Oliveira, Liliam, Lucas, Alexandre, Aimond, Franck, Sicard, Pierre, Mosqueira, Vanessa Carla Furtado, Richard, Sylvain
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-10-2020; Wiley; John Wiley and Sons Inc
• Subjects: Action potential prolongation; Action Potentials; Animals; Antimalarial activity; Antimalarial agents; Arrhythmias, Cardiac; Artemether; Artemisinin; Calcium (intracellular); Calcium - metabolism; Calcium currents; CamKII phosphorylation; Cardiac muscle; Cardiology and cardiovascular system; Cardiomyocytes; Cardiotoxicity; Contraction; EKG; enhanced Na+/Ca2+ exchange; Heart; Human health and pathology; Life Sciences; Malaria; Mice; Myocytes; Myocytes, Cardiac - metabolism; Na+/Ca2+ exchanger; Neurotoxicity; Patch-Clamp Techniques; Pharmaceutical sciences; Pharmacology; Potassium currents; pro‐arrhythmogenic risks; Research Paper; Research Papers; Sodium-Calcium Exchanger; spontaneous Ca2+ waves; Ventricle; enhanced Na+/Ca2+ exchange; CamKII phosphorylation; pro-arrhythmogenic risks; spontaneous Ca2+ waves; Action potential prolongation; enhanced Na+ /Ca2+ exchange; proarrhythmogenic risks
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.15186

Background and Purpose
The artemisinin derivative, artemether, has antimalarial activity with potential neurotoxic and cardiotoxic effects. Artemether in nanocapsules (NC‐ATM) is more efficient than free artemether for reducing parasitaemia and increasing survival of Plasmodium berghei‐infected mice. NCs also prevent prolongation of the QT interval of the ECG. Here, we assessed cellular cardiotoxicity of artemether and how this toxicity was prevented by nanoencapsulation.
Experimental Approach
Mice were treated with NC‐ATM orally (120 mg·kg−1 twice daily) for 4 days. Other mice received free artemether, blank NCs, and vehicle for comparison. We measured single‐cell contraction, intracellular Ca2+ transient using fluorescent Indo‐1AM Ca2+ dye, and electrical activity using the patch‐clamp technique in freshly isolated left ventricular myocytes. The acute effect of free artemether was also tested on cardiomyocytes of untreated animals.
Key Results
Artemether prolonged action potentials (AP) upon acute exposure (at 0.1, 1, and 10 μM) of cardiomyocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to blockade of K+ currents, increased Ca2+ currents or promotion of a sustained Na+ current. AP lengthening was abolished by the NCX inhibitor SEA‐0400. Artemether promoted irregular Ca2+ transients during pacing and spontaneous Ca2+ events during resting periods. NC‐ATM prevented all effects. Blank NCs had no effects compared with vehicle.
Conclusion and Implications
Artemether induced NCX‐dependent AP lengthening (explaining QTc prolongation) and disrupted Ca2+ handling, both effects increasing pro‐arrhythmogenic risks. NCs prevented these adverse effects, providing a safe alternative to the use of artemether alone, especially to treat malaria.