Santos-Miranda Artur, Gondim Antonio Nei, Menezes-Filho Jose Evaldo Rodrigues, Vasconcelos Carla Marina Lins, Cruz Jader Santos, Roman-Campos Danilo
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
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.
Phytomedicine. 2014 Sep 15;21(10):1146-53. doi: 10.1016/j.phymed.2014.05.007. Epub 2014 Jun 7.
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.
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.
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%.
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.
R(+)-香芹酮是一种酮类单萜，是几种植物精油的主要成分。先前的研究提供了一些证据表明R(+)-香芹酮可能作用于分离的心肌细胞。在本研究中，我们更详细地评估了R(+)-香芹酮对心脏组织的药理作用。
利用大鼠心脏心电图（ECG）的体内测量和分离心肌细胞的膜片钳技术，我们确定了R(+)-香芹酮对心脏兴奋性的影响。
R(+)-香芹酮以浓度依赖性方式延迟动作电位复极化（APR）（在APR的10%、50%和90%时，EC50分别为775.7±1.48、325.0±1.30、469.3±1.91μM）。与APR延长一致，R(+)-香芹酮以浓度依赖性方式阻断了不同的钾电流成分（瞬时外向钾电流（I(to)）、快速延迟整流钾电流（I(Kr)）、失活稳态钾电流（I(ss)）和内向整流钾电流（I(K1)））（I(to)、I(Kr)、I(ss)和I(K1)的EC50分别为1441±1.04；605.0±1.22、818.7±1.22；1753±1.09μM）。这种抑制以快速且可逆的方式发生，不改变稳态激活曲线，而是使稳态失活曲线向左移动（V1/2从-56.92±0.35 mV变为-67.52±0.19 mV）。体内输注100 mg/kg R(+)-香芹酮可延长QTc（约40%）和PR（约62%）间期，同时使心率降低约26%。
综上所述，R(+)-香芹酮通过以浓度依赖性方式抑制几种心肌细胞钾电流成分来延长APR。这是通过R(+)-香芹酮直接阻断通道孔，随后使稳态失活曲线向左移动而发生的。最后，R(+)-香芹酮引起心电图波形某些方面的变化，这与其对分离心肌细胞钾通道的作用一致。
