Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists

Abstract

Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, D9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K þ channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na þ /Ca 2þ exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting.

Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment‐Induced Cardioprotection against Ischemia‐Reperfusion Injury in Rats

“…Both CB1R and CB2R were expressed in adult rat cardiomyocytes [50]. In the myocardial I/R model, we found that propofol conditioning-induced antioxidation and cardioprotection could be fully reversed by CB2R antagonist AM630 (Figures 6 and 7).…”

Na/K-ATPase Signaling and Cardiac Pre/Postconditioning with Cardiotonic Steroids

“…Ouabain, and potentially other CTS, could therefore be added to the list of paracrine/autocrine factors that are released during preconditioning ischemia and trigger protection by binding to their respective receptors. Some of the most promising cardioprotective candidate drugs to date, opioid and cannabinoid receptor agonists [68,69] or adenosine receptor agonists [70], belong to this category.…”

Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

“…Initial studies on the role of cannabinoids in cardiac ischemia were predominantly performed ex vivo in papillary muscles or isolated heart. In these models, endocannabinoids ameliorated ischemia/reperfusion injury and reduced the early phase of heart remodeling (reviewed in [13,60,61]). It also has been pointed at the role of CB2 receptor activation in remote ischemic preconditioning [62][63][64][65].…”

“…The CB2 receptors, on the contrary, may play a compensatory anti-inflammatory, anti-oxidative, and anti-atherogenic role [9,10] contributing to cardiovascular protection.Nevertheless, the role of cannabinoid receptors in the heart under several pathological conditions remains controversial. Recent studies on hemodynamic, antiarrhythmic, and cardiometabolic effects of cannabinoids have been highlighted in several excellent reviews [2,3,[11][12][13][14]. Hence, these topics are not in the scope of this chapter.The aim of this review was to up-date on recent findings and controversies on the role of ECS in the myocardial injury with emphasis on pathophysiological processes such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction.…”

“…Nevertheless, the role of cannabinoid receptors in the heart under several pathological conditions remains controversial. Recent studies on hemodynamic, antiarrhythmic, and cardiometabolic effects of cannabinoids have been highlighted in several excellent reviews [2,3,[11][12][13][14]. Hence, these topics are not in the scope of this chapter.…”