Endocannabinoid GPR18 Receptor Activation Confers Cardiovascular Protection in Diabetic Rats

Abstract

The endocannabinoid receptor GPR18 lowers BP by reducing oxidative stress in brainstem nuclei that control sympathetic activity. We hypothesized that GPR18 activation confers cardiovascular protection in diabetes by reversing myocardial oxidative stress and dysfunction. Four weeks after diabetes induction (Streptozotocin; STZ, 55 mg/kg; i.p), diabetic rats received daily (100 ug/kg;i.p) of the GPR18 agonist, abnormal cannabidiol (Abn‐cbd) or antagonist, O‐1918, while control rats received vehicle, for 2 weeks before hemodynamic measurements in conscious rats. Abn‐cbd reversed the reduction in myocardial function by increasing left ventricular contractility index +dp/dtmax while maintaining the hypotensive response in diabetic rats, which inferred Abn‐cbd mediated reduction in vascular resistance. Ex vivo molecular findings demonstrated Abn‐cbd reversal of the diabetes‐induced: (i) reductions in plasma and myocardial nitrate /nitrite (NOX) levels; (ii) reductions in plasma adiponectin and increase in myocardial adiponectin receptor‐1 (Adipo R1) levels; (iii) reductions in myocardial protein kinase B (AKT), extracellular signaling kinase (ERK) and endothelial nitric oxide synthase (eNOS) phosphorylation; (iv) elevations in myocardial malondialdehyde (MDA) and antioxidant catalase levels; the latter might serve a counterbalancing role against diabetes‐evoked oxidative stress. The findings that Abn‐cbd enhanced, while the GPR18 antagonist O‐1918 reduced, myocardial GPR18 expression implicate GPR18 signaling in the Abn‐cbd evoked molecular and hemodynamic effects. These findings are the first to demonstrate a favorable cardiovascular role of GPR18 in diabetes and to elucidate the molecular mechanisms implicated in these clinically relevant effects.