DEFAR - Departamento de Farmácia

URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530

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2013 - 20202

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Autor: search.filters.author.Cruz, Jader dos SantosTem arquivos: Sim

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    Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation.
    (2020) Souza, Ana Carolina Moreira; Guimarães, Andrea Grabe; Cruz, Jader dos Santos; Miranda, Artur Santos; Farah, Charlotte; Oliveira, Liliam Teixeira; Lucas, Alexandre; Aimond, Franck; Sicard, Pierre; Mosqueira, Vanessa Carla Furtado; Richard, Sylvain
    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 tech nique 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.
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    The positive inotropic effect of the ethyl acetate fraction from Erythrina velutina leaves on the mammalian myocardium : the role of adrenergic receptors.
    (2013) Passos, Amilton Gustavo da Silva; Gondim, Antônio Nei Santana; Campos, Danilo Roman; Cruz, Jader dos Santos; Garcia, Eduardo Antônio Conde; Araújo Neto, Vitor; Estevam, Charles dos Santos; Cerqueira, Sandra Valéria Santos; Brandão, Geraldo Célio; Oliveira, Alaíde Braga de; Vasconcelos, Carla Maria Lins de
    Objectives We studied the effects of ethyl acetate fraction (EAcF) obtained from Erythrina velutina leaves on mammalian myocardium. Methods The effect of EAcF on the contractility was studied using guinea-pig left atria mounted in a tissue bath (Tyrode’s solution, 29°C, 95% CO2, 5% O2) and electrically stimulated (1 Hz). Concentration-response curves of EAcF were obtained in the presence of propranolol (1 mm), nifedipine (1 mm) and in reserpinized animals (5 mg/kg). The involvement of l-type calcium current (ICa,L) on the EAcF effect was observed in cardiomyocytes of mice assessed using patch-clamp technique. Key findings EAcF (550 mg/ml) had a positive inotropic effect, increasing the atrial force by 164% (EC50 = 157 44 mg/ml, n = 6), but it was less potent than isoproterenol (EC50 = 0.0036 0.0019 mg/ml, n = 8). The response evoked by EAcF was abolished by propranolol or nifedipine. Reserpine did not alter the inotropic response of EAcF. Furthermore, an enhancement of the ICa,L peak (31.2%) with EAcF was observed. Chemical analysis of EAcF revealed the presence of at least 10 different flavonoid glycoside derivatives. Two were identified as vicenin II and isorhoifolin. Conclusions We conclude that EAcF increases the cardiac contractile force by increasing the l-type calcium current and activating the adrenergic receptor pathway.