title: Pharmacological evaluation of R(+)-pulegone on cardiac excitability: role of potassium current blockage and control of action potential waveform.
abstract: BACKGROUND
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Artur
authors.initials: A
authors.lastname: Santos-Miranda
authors.affiliation: 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.
authors.forename: Antonio Nei
authors.initials: AN
authors.lastname: Gondim
authors.affiliation: Laboratório de Biofísica do Coração, Departamento de Fisiologia, Universidade Federal de Sergipe, Aracaju, Sergipe, Brazil.
authors.forename: Jose Evaldo Rodrigues
authors.initials: JE
authors.lastname: Menezes-Filho
authors.affiliation: Laboratório de Biofísica do Coração, Departamento de Fisiologia, Universidade Federal de Sergipe, Aracaju, Sergipe, Brazil.
authors.forename: Carla Marina Lins
authors.initials: CM
authors.lastname: Vasconcelos
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Jader Santos
authors.initials: JS
authors.lastname: Cruz
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo/Escola Paulista de Medicina, São Paulo, Brazil. Electronic address: drcbio@gmail.com.
authors.forename: Danilo
authors.initials: D
authors.lastname: Roman-Campos
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000081005:Cyclohexane Monoterpenes; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects; D008297:Male; D039821:Monoterpenes / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009822:Oils, Volatile / Q000737:chemistry*; D018408:Patch-Clamp Techniques; D010938:Plant Oils / Q000737:chemistry*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000081005:Cyclohexane Monoterpenes; D039821:Monoterpenes; D009822:Oils, Volatile; D010938:Plant Oils; D015221:Potassium Channels; C039648:pulegone
keywords: Action potential; Electrocardiogram; Heart; Myocyte; Potassium current; Pulegone