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

Artur Santos-Miranda; Antonio Nei Gondim; Jose Evaldo Rodrigues Menezes-Filho; Carla Marina Lins Vasconcelos; Jader Santos Cruz; Danilo Roman-Campos

doi:10.1016/j.phymed.2014.05.007

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

Phytomedicine. 2014 Sep 15;21(10):1146-53. doi: 10.1016/j.phymed.2014.05.007. Epub 2014 Jun 7.

Authors

Artur Santos-Miranda¹, Antonio Nei Gondim², Jose Evaldo Rodrigues Menezes-Filho³, Carla Marina Lins Vasconcelos³, Jader Santos Cruz¹, Danilo Roman-Campos⁴

Affiliations

¹ Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
² Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil; Laboratório Laboratório de Biofísica e Farmacologia do Coração, Departamento de Educação - Campus XII, Universidade do Estado da Bahia, Guanambi, Bahia, Brazil.
³ Laboratório de Biofísica do Coração, Departamento de Fisiologia, Universidade Federal de Sergipe, Aracaju, Sergipe, Brazil.
⁴ Departamento de Biofísica, Universidade Federal de São Paulo/Escola Paulista de Medicina, São Paulo, Brazil. Electronic address: drcbio@gmail.com.

PMID: 24912864
DOI: 10.1016/j.phymed.2014.05.007

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 μM 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 μM 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 (V1/2 from -56.92±0.35 to -67.52±0.19 mV). In vivo infusion of 100 mg/kg R(+)-pulegone prolonged the QTc (∼40%) and PR (∼62%) interval along with reducing the heart rate by ∼26%.

Conclusion: Taken 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.

Keywords: Action potential; Electrocardiogram; Heart; Myocyte; Potassium current; Pulegone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects*
Animals
Cyclohexane Monoterpenes
Electrocardiography
Female
Heart / drug effects
Male
Monoterpenes / pharmacology*
Myocytes, Cardiac / drug effects*
Oils, Volatile / chemistry*
Patch-Clamp Techniques
Plant Oils / chemistry*
Potassium Channels / drug effects*
Rats
Rats, Wistar

Substances

Cyclohexane Monoterpenes
Monoterpenes
Oils, Volatile
Plant Oils
Potassium Channels
pulegone