Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

Abstract

Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR.Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis.Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13.Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study.

Cannabinoid receptor agonist attenuates angiotensin II–induced enlargement and mitochondrial dysfunction in rat atrial cardiomyocytes

“…Our findings demonstrate that the CBR ligand, CB13, attenuates atrial myocyte enlargement and mitochondrial dysfunction in NRAM through AMPK signaling, building upon previous evidence for beneficial effects of CBR ligands in stressed cardiomyocytes (Lu et al, 2014;Lu et al, 2020;Lee et al, 2021). In addition, our data may suggest that AMPK-dependent changes in Cx43 expression also contribute to the possible beneficial effect of CBR ligands.…”

“…For example, blocking the inner membrane ion channel, IMAC, was protective against arrhythmias by preventing ΔΨ m reduction, improving left ventricular developed pressure, and preventing action potential shortening (Billman et al, 1998;Aon et al, 2003;Brown et al, 2008). As noted above, we recently reported that CB13 treatment prevents atrial refractoriness shortening in an ex vivo rat model exposed to atrial tachypacing, suggesting prevention of action potential shortening by CB13 (Lee et al, 2021). It is plausible that CB13 counteracted the tachypacing-related remodeling by modulating ΔΨ m via IMAC.…”

“…Compounds that activate AMPK may mitigate the metabolic demands resulting from AF ( Harada et al, 2015 ; Kim and Young, 2015 ). In this regard, our group has found that cannabinoid receptor (CBR) ligands exert cardioprotective effects in ventricular hypertrophy models in vitro and in vivo presumably due to activation of AMPK ( Lu et al, 2014 ; Lu et al, 2020 ) Recently, we also demonstrated that CB13, a dual CBR agonist with limited brain penetration, is an AMPK activator that prevents tachycardia-induced electrical remodeling and improves energy metabolism in the rat atria ex vivo ( Lee et al, 2021 ). In addition to activating AMPK, CB13 appears to alter gap the junction, Cx43, a signal conduction protein that connects cardiomyocytes and is important for synchronous atrial contraction ( Qiu et al, 2016 ; Lee et al, 2021 ).…”

Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?

“…CB 1 -Rs and CB 2 -Rs were also identified in hearts of the guinea pig [ 72 ], rat [ 73 , 74 , 75 ], and mouse [ 76 , 77 ]. In detail, these receptors occur in the left ventricle [ 78 , 79 ] and left atrium of the rat [ 80 ], and in the left ventricle of the dog [ 81 ] and the mouse [ 67 , 82 , 83 ].…”

“…Moreover, prolongation of the AP in response to THC was found in sheep Purkinje fibers (receptor not determined; [ 197 ]). The synthetic agonist CB13 inhibited the tachypacing-induced shortening of the rat atrial effective refractory period protecting against atrial fibrillation (receptor not identified; [ 80 ]).…”