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

Abstract

Introduction: R(+)-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.Methods: Using 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.Results: R(+)-pulegone delayed action potential repolarization (APR) in a concentration-dependent manner (EC50 = 775.7 +/- 1.48, 325.0 +/- 1.30, 469.3 +/- 1.91 mu M 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 (I-to), rapid delayed rectifier potassium current (I-kr), inactivating steady state potassium current (I-ss) and inward rectifier potassium current (I-K1)) (EC50 = 1441 +/- 1.04; 605.0 +/- 1.22, 818.7 +/- 1.22; 1753 +/- 1.09 mu M for I-to, I-Kr, I-ss and I-K1, 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 (V-1/2 from -56.92 +/- 0.35 to 67.52 +/- 0.19 mV). in vivo infusion of 100 mg/kg R(+)-pulegone prolonged the QTc (similar to 40%) and PR (similar to 62%) interval along with reducing the heart rate by similar to 26%.Conclusion: Taken together, R(+)-pulegone prolongs the APR by inhibiting several cardiomyocyte 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. (C) 2014 Elsevier GmbH. All rights reserved.