Modulation of cardiac contractility and redox balance via cannabinoid type II receptor activation in healthy rats

The activation of cannabinoid receptor type II (CB2r) has been demonstrated to provide cardioprotective benefits against heart diseases. Nevertheless, the physiological effects of CB2r activation in healthy myocardial tissue remain poorly understood. Given the current gap in knowledge, particularly relevant in light of the growing therapeutic use of cannabinoids, this study aimed to investigate the effects of a single intraperitoneal injection of the selective synthetic CB2r agonist HU-308 on ventricular contractility, the expression of Ca²⁺-handling proteins, cyclic adenosine monophosphate (cAMP) levels, and redox biomarkers in male Wistar rats. Isolated left ventricular strips from HU-308-treated animals exhibited significant improvements in force of contraction (Fc), cardiac pumping capacity (CPC), and the rates of contraction (+ dF/dt) and relaxation (-dF/dt). Treatment with the CB2r agonist increased myocardial cAMP levels and upregulated the expression of sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a), phospholamban (PLB), and Na⁺/Ca²⁺ exchanger (NCX1). Additionally, HU-308 administration increased the glutathione (GSH)/oxidized glutathione (GSSG) ratio and the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Enhancement of the antioxidant defense system contributed to the maintenance of redox balance, as evidenced by decreased levels of lipid peroxidation (LPO), protein carbonyl (PC), and DNA strand breaks (DNA-sb). This study provides the first evidence that CB2r activation exerts antioxidative effects while enhancing both inotropy and lusitropy in the healthy rat myocardium, highlighting CB2r as a potential therapeutic target for preserving cardiac function.