(-)-Carvone Modulates Intracellular Calcium Signaling with Antiarrhythmic Action in Rat Hearts

Abstract

Background:

(-)-Carvone is a monoterpene found in essential oils with antioxidant and anti-inflammatory activity.

Objective:

The aim of this paper was to analyze the antiarrhythmic property of (-)-carvone in the rat heart and its effects on the intracellular Ca²⁺ signaling.

Methods:

The effects of (-)-carvone were evaluated on the ventricular (0.5 mM) and atrial contractility (0.01 – 4 mM) and on electrocardiogram (0.5 mM). Fractional shortening, L-type calcium current (I_Ca,L) and Ca²⁺ signaling were measured in the isolated cardiomyocyte (0.5 mM). Antiarrhythmic effect was evaluated in arrhythmia model induced by calcium overload (0.5 mM) (n = 5). P < 0.05 was used as the significance level.

Results:

In the atrium, (-)-carvone evoked negative inotropism that was concentration-dependent (EC50 0.44 ± 0.11 mM) and decreased the positive inotropism evoked by CaCl₂ (0.1 to 8.0 mM) or BAY K8644 (5 to 500 nM), an agonist of L-type Ca²⁺ channel. In isolated heart, (-)-carvone (0.5 mM) promoted reduction of ventricular contractility (73%) and heart rate (46%), increased PRi (30.7%, time from the onset of the P wave until the R wave) and QTc (9.2%, a measure of the depolarization and repolarization of the ventricles) without changing the QRS complex duration. (-)-Carvone decreased the fractional shortening (61%), I_Ca,L (79%) and Ca²⁺ intracellular transient (38%). Furthermore, (-)-carvone showed antiarrhythmic action, verified by decrease of the arrhythmia score (85%) and occurrence of ventricular fibrillation.

Conclusion:

(-)-Carvone decreases Ca²⁺ entry through L-type Ca²⁺ channels, reducing the cardiac contractility and intracellular Ca²⁺, and, therefore, presenting promising antiarrhythmic activity in the rat hearts.

Keywords:
Arrhythmias; Cardiac; Monoterpenes; Rats