Carnevali Luca, Vacondio Federica, Rossi Stefano, Macchi Emilio, Spadoni Gilberto, Bedini Annalida, Neumann Inga D, Rivara Silvia, Mor Marco, Sgoifo Andrea
Department of Neuroscience, University of Parma, Italy.
Department of Pharmacy, University of Parma, Italy.
Sci Rep. 2015 Dec 14;5:18218. doi: 10.1038/srep18218.
In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ventricular tachyarrhythmias, and (iv) corrected alterations of ventricular refractoriness. The anti-arrhythmic effect of URB694 was prevented by pharmacological blockade of the cannabinoid type 1 (CB1), but not of the CB2, receptor. These findings suggest that URB694 exerts anxiolytic-like and cardioprotective effects in HAB rats, the latter via anandamide-mediated activation of CB1 receptors. Thus, pharmacological inhibition of FAAH might be a viable pharmacological strategy for the treatment of anxiety-related cardiac dysfunction.
在人类中，慢性焦虑是心律失常和猝死的独立危险因素。在此，我们评估了具有高（HAB）和低（LAB）焦虑相关行为的雄性Wistar大鼠以及未选择（NAB）的动物，研究特质焦虑与心脏电不稳定性之间的关系，并探究内源性大麻素花生四烯乙醇胺介导的信号通路的药理学增强是否具有抗焦虑样和心脏保护作用。HAB大鼠表现出：（i）异丙肾上腺素诱导的室性快速心律失常发生率更高，以及（ii）通过心外膜标测方案评估的心室不应期空间离散度更大。在HAB大鼠中，用URB694（0.3mg/kg）对花生四烯乙醇胺降解酶脂肪酸酰胺水解酶（FAAH）进行急性药理学抑制，（i）减少了高架十字迷宫中的焦虑样行为，（ii）提高了心脏中花生四烯乙醇胺的水平，（iii）降低了异丙肾上腺素诱导的室性快速心律失常的发生率，以及（iv）纠正了心室不应期的改变。URB694的抗心律失常作用可通过对1型大麻素（CB1）受体而非CB2受体的药理学阻断来预防。这些发现表明，URB694在HAB大鼠中具有抗焦虑样和心脏保护作用，后者是通过花生四烯乙醇胺介导的CB1受体激活实现的。因此，对FAAH的药理学抑制可能是治疗焦虑相关心脏功能障碍的一种可行的药理学策略。
