β‐Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s‐limonene in the rat heart

Author:

Santos Joyce Francielle Ferreira1,de Souza Diego Santos1,Mota Karina Oliveira1,de Cerqueira Sandra Valéria Santos1,Durço Aimée Obolari2,Elasoru Seyi Elijah3,Nascimento Daniella Santos1,Roman‐Campos Danilo2ORCID,Dantas Cácia Oliveira1,de Vasconcelos Carla Maria Lins1

Affiliation:

1. Department of Physiology Federal University of Sergipe Sao Cristovao Brazil

2. Department of Biophysics Federal University of São Paulo Sao Paulo Brazil

3. Department of Biochemistry and Immunology Federal University of Minas Gerais Belo Horizonte Brazil

Abstract

AbstractS‐Limonene (s‐Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s‐Lim exerts its antiarrhythmic effect, focusing on the blockade of β‐adrenoceptor (β‐AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the β‐adrenergic pathway, sarcomeric shortening and L‐type calcium current (ICa,L). In isolated hearts, 10 μM of s‐Lim did not alter the ECG profile or LVPD. s‐Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 μM and reduced heart rate at the concentrations of 30 (12.4%) and 50 μM (16.6%). s‐Lim (10 μM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 μM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s‐Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker β1‐AR). In vivo, s‐Lim antagonized the effect of ISO (agonists β1‐AR), presenting a similar effect to propranolol (a non‐selective blocker β‐AR). In ventricular cardiomyocyte, s‐Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s‐Lim did not affect changes in the ECG effect mediated by 5 μM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO‐induced arrhythmia model, s‐Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s‐Lim is related to blockade of β‐AR in the heart.

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Fundação de Amparo à Pesquisa do Estado de São Paulo

Publisher

Wiley

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