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. 2024 Oct;51(10):e13915.
doi: 10.1111/1440-1681.13915.

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

Joyce Francielle Ferreira Santos  1 , Diego Santos de Souza  1 , Karina Oliveira Mota  1 , Sandra Valéria Santos de Cerqueira  1 , Aimée Obolari Durço  2 , Seyi Elijah Elasoru  3 , Daniella Santos Nascimento  1 , Danilo Roman-Campos  2 , Cácia Oliveira Dantas  1 , Carla Maria Lins de Vasconcelos  1
Affiliations

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

Joyce Francielle Ferreira Santos et al. Clin Exp Pharmacol Physiol. 2024 Oct.

Abstract

S-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.

Keywords: arrhythmia; cardiomyocyte; heart; limonene; β‐adrenergic receptors.

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References

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