The emergence of anti-malarial drug resistance poses a major threat to world health and necessitates a need to develop new anti-malarial agents. These new anti-malarial agents could arise through the process of drug repositioning. Work by Matthews et al., (2017) and Panwar et al., (2020) demonstrates the anti-amoebic drugs Emetine dihydrochloride (EDC) and Dehydroemetine (DHE) are effective anti-malarial compounds. However, both are associated with cardiotoxicity including arrhythmogenesis (DHE less so), which may compromise their clinical use. To elucidate the cellular basis of this cardiotoxicity, our previous work showed that only DHE produced sustained negatively inotropic alterations to Ca dynamics, but spontaneous Ca waves were fewer than in cells exposed to EDC. However, both transiently (1-2 beats) increased systolic Ca on application; indicative of ryanodine receptor (RyR) potentiation. To investigate this further, we next investigated the effects of EDC and DHE on induced intracellular Ca waves. All animals were killed in accordance with the Home Office Animal (Scientific Procedures) Act 1986. Sheep ventricular myocytes were loaded with the ratiometric Ca indicator Fura-2 then intracellular Ca waves induced using 0.3 mM ouabain octahydrate and 5 mM extracellular Ca. The effects of EDC (50 nM) or DHE (80 nM) were then measured using epi-fluorescent photometry. To estimate SR Ca threshold for waves, we measured the amplitude of caffeine (10 mM) evoked Ca transients on wave onset. DHE decreased Ca wave amplitude by 25 ± 6 % (n=20, p = 0.004) and increased wave frequency by 10 ± 4 % (n = 20, p = 0.02). DHE also decreased SR threshold Ca content for waves (Control (n = 9): 0.93 ± 0.15, DHE (n = 9): 0.49 ± 0.12, p = 0.03). EDC decreased Ca wave amplitude by 19.83 ± 3 % (n = 21, p = <0.001) but had no effect on wave frequency or SR Ca threshold. These data suggest DHE potentiates the RyR; a phenomenon associated with increased risk of arrhythmia. This contradicts our previous observation that DHE produces fewer spontaneous Ca waves. It may be that the negatively inotropic effects of DHE offset those on the RyR reducing net arrhythmogenicity. Certain evidence suggests that to an extent, EDC also potentiates the RyR. However, that we observe no negatively inotropic effects may explain why this drug produces more spontaneous Ca waves, providing a substrate for reported arrhythmia risk.
Future Physiology 2021 (Virutal) (2021) Proc Physiol Soc 47, PC05
Poster Communications: The effects of emetine based anti-malarial leads on calcium wave dynamics in sheep ventricular myocytes.
Matthew Jones1, Priyanka Panwar1, Natasha Hadgraft1, Niroshini Nirmalan1, David Greensmith1
1 The University of Salford, Salford, United Kingdom
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Where applicable, experiments conform with Society ethical requirements.