Abstract
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.
Highlights
Chronic anxiety can be viewed as a dispositional tendency to experience an anxious state more frequently, at higher intensities and/or in inappropriate situations[1]
Given the above reported considerations, in the present study we used the HAB/LAB rat model in order to: (i) evaluate whether high levels of trait anxiety are associated with pro-arrhythmic electrical remodeling of the ventricular myocardium and increased vulnerability to pharmacologically-induced arrhythmias, (ii) assess whether the fatty acid amide hydrolase (FAAH) inhibitor URB694 exerts anxiolytic-like effects and improves cardiac electrical stability, and (iii) investigate whether the cardioprotective effects of URB694 are mediated by facilitation of AEA signaling at CB1 and/or CB2 receptors
The present study demonstrates that the heterogeneity in ventricular refractoriness is likely to represent the electrical substrate underlying the larger vulnerability to ventricular arrhythmias observed in rats with high levels of trait anxiety
Summary
URB694, in a rodent model of trait received: 13 August 2015 accepted: 02 November 2015 Published: 14 December 2015 anxiety. Chronic administration of URB69427, a second generation FAAH inhibitor with improved metabolic stability and selectivity[28,29], has recently been shown to prevent the adverse behavioral and cardiac effects of repeated social stress exposure in rats[30] Taken together, these findings prompt further investigation aimed at determining whether inhibition of FAAH activity may represent a viable pharmacological strategy for the treatment of the comorbidity of cardiovascular disease with anxiety and mood disorders. Given the above reported considerations, in the present study we used the HAB/LAB rat model in order to: (i) evaluate whether high levels of trait anxiety are associated with pro-arrhythmic electrical remodeling of the ventricular myocardium and increased vulnerability to pharmacologically-induced arrhythmias, (ii) assess whether the FAAH inhibitor URB694 exerts anxiolytic-like effects and improves cardiac electrical stability, and (iii) investigate whether the cardioprotective effects of URB694 are mediated by facilitation of AEA signaling at CB1 and/or CB2 receptors
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