Pharmacological evaluation of R(+)-pulegone on cardiac excitability: Role of potassium current blockage and control of action potential waveform

Abstract

IntroductionR(+)-pulegone is a ketone monoterpene and it is the main constituent of essential oils in several plants. Previous studies provided some evidence that R(+)-pulegone may act on isolated cardiac myocytes. In this study, we evaluated in extended detail, the pharmacological effects of R(+)-pulegone on cardiac tissue. MethodsUsing in vivo measurements of rat cardiac electrocardiogram (ECG) and patch-clamp technique in isolated myocytes we determinate the influence of R(+)-pulegone on cardiac excitability. ResultsR(+)-pulegone delayed action potential repolarization (APR) in a concentration-dependent manner (EC50=775.7±1.48, 325.0±1.30, 469.3±1.91μM at 10, 50 and 90% of APR respectively). In line with prolongation of APR R(+)-pulegone, in a concentration-dependent manner, blocked distinct potassium current components (transient outward potassium current (Ito), rapid delayed rectifier potassium current (IKr), inactivating steady state potassium current (Iss) and inward rectifier potassium current (IK1)) (EC50=1441±1.04; 605.0±1.22, 818.7±1.22; 1753±1.09μM for Ito, IKr, Iss and IK1, respectively). The inhibition occurred in a fast and reversible way, without changing the steady-state activation curve, but instead shifting to the left the steady-state inactivation curve (V1/2 from −56.92±0.35 to −67.52±0.19mV). In vivo infusion of 100mg/kg R(+)-pulegone prolonged the QTc (∼40%) and PR (∼62%) interval along with reducing the heart rate by ∼26%. ConclusionTaken together, R(+)-pulegone prolongs the APR by inhibiting several cardiomyocyte K+ current components in a concentration-dependent manner. This occurs through a direct block by R(+)-pulegone of the channel pore, followed by a left shift on the steady state inactivation curve. Finally, R(+)-pulegone induced changes in some aspects of the ECG profile, which are in agreement with its effects on potassium channels of isolated cardiomyocytes.